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

Abstract

To provide potent and selective O-GlcNAcase inhibitors for treatment of Alzheimer's disease, tauopathies and other neurological diseases.SOLUTION: The invention provides substituted pyrrolidinylmethylthiazolamide derivatives, substituted piperidinylmethylthiazolamide derivatives, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same.SELECTED DRAWING: None

Description

Related Applications

[0001] 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 which are each incorporated herein by reference in their entirety. [Background technology]

[0002] A wide range of cellular proteins, both nuclear and cytoplasmic, are post-translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine), attached via an O-glycosidic bond. This monosaccharide is generally referred to as O-linked N-acetylglucosamine, or O-GlcNAc. The enzyme responsible for the post-translational attachment of β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of many nucleocytoplasmic proteins is O-GlcNAc transferase (OGTase). A second enzyme, known as O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase, or O-GlcNAcase, or OGA, removes this post-translational modification, liberating the protein, making O-GlcNAc modification a dynamic cycle that occurs several times during the protein's lifetime.

[0003] O-GlcNAc-modified proteins regulate a wide range of vital cellular functions, including transcription, proteasomal degradation, and intracellular signaling. O-GlcNAc is also found in many structural proteins, including tau, a cytoskeletal protein responsible for stabilizing the critical cellular network of microtubules, which are essential for the distribution of proteins and nutrients within neurons. Importantly, tau has been clearly implicated in the pathogenesis of several diseases, including tauopathies, Alzheimer's disease, Parkinson's disease, dementia, and cancer.

[0004] 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) composed of abnormal forms of tau. In AD patients, hyperphosphorylation of tau disrupts its normal function, leading to the formation of PHFs, which ultimately aggregate to form NFTs.

[0005] Six tau isoforms 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 has only two or three phosphate groups, tau in the brains of AD patients has an average of eight phosphate groups.

[0006] It has recently become clear that increased phosphorylation levels result in decreased O-GlcNAc levels, and conversely, increased O-GlcNAc levels correlate with decreased phosphorylation levels. It has been shown that decreased glucose availability in the brain leads to hyperphosphorylation of tau. A gradual decline in glucose transport and metabolism leads to decreased O-GlcNAc levels and hyperphosphorylation of tau (and other proteins). Therefore, inhibition of O-GlcNAcase (which prevents the removal of O-GlcNAc from tau, thereby preventing tau hyperphosphorylation) should counteract the age-related decline in glucose metabolism in the brains of healthy individuals and patients with Alzheimer's disease or related neurodegenerative disorders. do.

[0007] However, a major challenge in developing inhibitors to block the function of mammalian glycosidases, including O-GlcNAcase, is the presence of numerous functionally related enzymes in the tissues of higher eukaryotes. Therefore, the use of nonselective inhibitors complicates the study of the physiological role of a single enzyme in cells and organisms, as simultaneous inhibition of such functionally related enzymes can result in complex phenotypes. In the case of β-N-acetylglucosaminidase, existing compounds that act to block O-GlcNAcase function are nonspecific and potent, inhibiting lysosomal β-hexosaminidase.

[0008] In view of the above technical challenges, and considering the potential of modulating O-GlcNAcase to treat AD, tauopathies, and other neurological diseases, there remains a need for the development of potent and selective O-GlcNAcase inhibitors. Summary of the Invention

[0009] Described herein are compounds useful for the treatment of various diseases, disorders and conditions, including, but not limited to, those associated with proteins modified by O-GlcNAcase.

[0010] A first embodiment of the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ar is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; Y 1 and Y 2 are respectively CR c or N and Y 1 or Y 2 at least one of is N; Z is CR 2 R2 , 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 non-zero, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R 2 is independently at each occurrence -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, or C3-C 10 halocycloalkyl, or Or alternatively, two R 2 together with the carbon atoms to which they are attached, form C3-C 10 forming a cycloalkyl, R 3 is —H or C1-C4 alkyl; 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 form an optionally substituted 5- to 7-membered heterocyclyl.

[0011] Another embodiment of the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ar is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; Y 1 and Y 2 are respectively CR c or N and Y 1 or Y2 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 non-zero, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R 2 is independently at each occurrence -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, or C3-C 10 halocycloalkyl, or Or alternatively, two R 2 together with the carbon atoms to which they are attached, form C3-C 10 forming a cycloalkyl, R 3 is —H or C1-C4 alkyl; 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 form an optionally substituted 5- to 7-membered heterocyclyl.

[0012] Pharmaceutical compositions are provided that include at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0013] Also provided is a method for treating a subject suffering from 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 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.

[0014] Also provided is a method for inhibiting O-GlcNAcase in a subject in need thereof, the method comprising administering to the 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.

[0015] Also provided is a method for treating a disease or condition characterized by hyperphosphorylation of tau in the brain, comprising administering to the 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 OF THE INVENTION

[0016] Described herein are compounds useful for the treatment of various diseases, disorders and conditions, including, but not limited to, those associated with proteins modified by O-GlcNAcase.

[0017] In a first embodiment, the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the Summary of the Invention above for compounds represented by Formula (IA).

[0018] In a second embodiment, the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is halo, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R c is halo, C1-C4 alkyl, or C1-C4 haloalkyl, n is an integer from 1 to 7, and the other variables are as defined in the first embodiment.

[0019] In a third embodiment, the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is halo or C1-C4 alkyl, and the other variables are as defined in the first embodiment.

[0020] In a fourth embodiment, the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is independently at each occurrence -H or C1-C4 alkyl, and the other variables are as defined in the first, second, or third embodiment.

[0021] In a fifth embodiment, the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is, independently at each occurrence, —H or C1-C4 alkyl; R c is halo or C1-C4 alkyl, n is an integer from 1 to 7, and the other variables are as defined in the first, second, third, or fourth embodiment.

[0022] In a sixth embodiment, the compound of the present invention is represented by one of the following structural formulas: [ka] Other variables are as defined in the first, second, third, fourth, or fifth embodiment.

[0023] In a seventh embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, where n is an integer from 1 to 7, and the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0024] In an eighth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, where n is 0 or an integer from 1 to 7, and the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0025] In a ninth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, where n is 0 or an integer from 1 to 6, and the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0026] In a tenth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, where n is 0 or an integer from 1 to 3, and the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0027] In an eleventh embodiment, the compound of the present invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, where n is 0 or an integer from 1 to 3, and the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0028] In a twelfth embodiment, the compound of the invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2; are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0029] In a thirteenth embodiment, the compound of the invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, where n is 0, 1, or 2, and the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0030] In a fourteenth embodiment, the compound of the invention is represented by the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the Summary of the Invention above for compounds represented by Formula (IB) or a pharmaceutically acceptable salt thereof.

[0031] In a fifteenth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is halo or C1-C4 alkyl, and the other variables are as defined in the fourteenth embodiment.

[0032] In a sixteenth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is halo or C1-C4 alkyl, and the other variables are as defined in the fourteenth or fifteenth embodiment.

[0033] In a seventeenth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2is independently at each occurrence -H or C1-C4 alkyl, n is 0 or an integer from 1 to 3, and the other variables are as defined in the fourteenth, fifteenth, or sixteenth embodiment.

[0034] In an eighteenth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is independently at each occurrence -H or C1-C4 alkyl, n is 0 or an integer from 1 to 3, and the other variables are as defined in the fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0035] In a nineteenth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, where n is 0, 1, or 2, and the other variables are as defined in the fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0036] In a twentieth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, where n is 0, 1, or 2, and the other variables are as defined in the fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0037] In a twenty-first embodiment, in a compound 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.

[0038] In a twenty-second embodiment, in a compound 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 containing one or more nitrogen atoms.

[0039] In a twenty-third embodiment, in a compound 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.

[0040] In a twenty-fourth embodiment, in a compound 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.

[0041] In a twenty-fifth embodiment, in a compound 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 a pharmaceutically acceptable salt thereof, Ar is [ka] is.

[0042] In a twenty-sixth embodiment, in a compound 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 a pharmaceutically acceptable salt thereof, Ar is [ka] is.

[0043] In a twenty-seventh embodiment, in a compound 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 a pharmaceutically acceptable salt thereof, Ar is [ka] is.

[0044] In a twenty-eighth embodiment, in a compound 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 a pharmaceutically acceptable salt thereof, Ar is [ka] is.

[0045] 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-seventh, twenty-eighth, twenty-seventh ... 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 substituted with one or more groups selected from phenyl and monocyclic heteroaryl; where: The substituents of the C1-C4 alkyl group of Ar are optionally -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 , substituted with 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); Substituents for the C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl, and monocyclic heteroaryl groups of Ar are optionally and independently selected from 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 is replaced by Each R x and each R y are independently —H, C1-C4 alkyl, or C3-C8 cycloalkyl, where R x or R yis optionally substituted with one or more substituents selected from halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy); R z is —H, C1-C4 alkyl, C3-C8 cycloalkyl, or C3-C8 heterocyclyl, where R z is optionally substituted with one or more groups selected from -CN, halo, hydroxyl, C-C alkyl, C-C alkoxy, C-C cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH, halomethyl, halo, methoxy, and halomethoxy); i is 0, 1 or 2.

[0046] 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, twenty-seventh, twenty-eighth, twenty-third, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-seventh, twenty-eighth, twenty-seventh ... 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 Ry , -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 substituted with one or more groups selected from phenyl and monocyclic heteroaryl; where: The substituents of the C1-C4 alkyl group of Ar are optionally -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 Ry , -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 , substituted with 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); Substituents for the C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl, and monocyclic heteroaryl groups of Ar are optionally and independently selected from 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 Ry , -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 is replaced by Each R x and each R y are independently —H, C1-C4 alkyl, or C3-C8 cycloalkyl, where R x or R y is optionally substituted with one or more substituents selected from halo, hydroxyl, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy); R z is —H, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, or C3-C8 heterocyclyl, where R z is optionally substituted with one or more substituents selected from -CN, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy); i is 0, 1 or 2.

[0047] In a thirty-first embodiment, in a compound 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, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtyth embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally 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 , -NR x C(=O)R y , phenyl, and optionally substituted monocyclic heteroaryl.

[0048] In the thirty-second embodiment, the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, In the compounds of the invention according to the 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, or 31st embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally C1-C4 alkyl, C1-C4 haloalkyl, optionally substituted 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.

[0049] In a thirty-third embodiment, in a compound 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, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, or thirty-first embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally 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 C-C cycloalkyl and C-C heterocyclyl substituents of Ar are each optionally substituted with one or more groups selected from halo, C alkyl and C 1-4 substituted with one or more groups independently selected from alkoxy; x and R y are each independently —H, C1-C4 alkyl, or C3-C6 cycloalkyl, where R x and R y The C1-C4 alkyl group represented by 1-4 substituted with one or more substituents independently selected from alkoxy; z is H, C1-C4 alkyl, C3-C8 cycloalkyl, or C3-C6 heterocyclyl, where R z The C1-C4 alkyl, C3-C8 cycloalkyl, and C3-C6 heterocyclyl represented by the formula (I) are each optionally and independently substituted with one or more substituents independently selected from halo, —CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0050] In a thirty-fourth embodiment, in 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, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, or thirty-third embodiment, Ar is optionally selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, and -OR. z wherein R z is C1-C4 alkyl optionally substituted with one or more halo groups.

[0051] In a thirty-fifth embodiment, in a compound 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, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, or thirty-third embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally selected from the group consisting of —CH 3 , —CF 3 , —CHF 2 , —F, —Cl, —CN, —OCH 3 , —OCHF 2 , —OC 2 H 5 , —OCH 2 CF 3 , —O(CH 2 ) 2 (O)CH 3 , —OCH(CH 3 ) 2 , —O-(3-methoxycyclobutyl), —O-cyclobutyl, —O-cyclopentyl, [ka] -COCH3, -N(H)CH3, -N(CH3)C2H5, -N(H)cyclobutyl, -NHCH2CH3, -NHCH(CH3) 2、 -N(CH3)2, -N(CH3)(CH2CH2(O)CH3), -OH, azetidinyl, [ka] It is substituted with one or more groups selected from oxetanyl, pyrrolidinyl, morpholinyl, 4-methylpiperazinyl, and piperazinyl.

[0052] In a thirty-sixth embodiment, in a compound 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, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, 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.

[0053] In a thirty-seventh embodiment, in a compound 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, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, 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.

[0054] In a thirty-eighth embodiment, in a compound 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, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, or thirty-seventh embodiment, n is 0.

[0055] In a thirty-ninth embodiment, the compound of the invention is represented by one of the following structural formulas: [ka] or a pharmaceutically acceptable salt thereof, wherein Ar is [ka] each of which is optionally selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, and -OR z one substituent R selected from Ar is replaced by R z is H, C1-C4 alkyl, C3-C8 cycloalkyl, or C3-C6 heterocyclyl, where R z The C1-C4 alkyl, C3-C8 cycloalkyl, and C3-C6 heterocyclyl represented by the formula (I) are each optionally and independently substituted with one or more substituents independently selected from halo, —CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0056] In a fortieth embodiment, in the compound of the invention according to the thirty-ninth embodiment, Ar is represented by the following formula: [ka] Other variables are as defined in the thirty-ninth embodiment.

[0057] In a forty-first embodiment, in a compound of the invention according to the thirty-ninth or fortieth embodiment, R Ar is C1-C4 alkyl or -OR z and R z is H or C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halo, —CN, C1-C4 alkyl, and C1-C4 alkoxy, and the other variables are as defined in the thirty-ninth or fortieth embodiment.

[0058] In one embodiment, the compound of the invention is selected from: [ka] or a pharmaceutically acceptable salt thereof.

[0059] In another embodiment, the compound of the invention is selected from: [ka] or a pharmaceutically acceptable salt thereof.

[0060] In another embodiment, the compound of the invention is selected from: [ka] [ka] [ka] .

[0061] In another embodiment, the compound of the present invention is selected from the compounds described in the Examples herein.

[0062] In yet another embodiment, the compound of the invention is selected from: [ka]

[0063] In one embodiment, the compound of the invention, for example a compound according to the first or fourteenth embodiment, is selected from: N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,5R)-5-((5-fluoropyridin-2-yl)oxy)- 2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,5S)-5-((5-fluoropyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, (R)—N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, (S)—N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2R,4S)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4S)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2R,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-(pyridin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-fluoro-6-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-cyanopyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-chloro-4-methylpyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-ylacetamide, N-(5-(((2S,4R)-4-((6-(difluoromethyl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-fluoro-6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2-(difluoromethoxy)pyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, 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, (S)—N-(4-fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, (R)—N-(4-fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, (S)—N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, (R)—N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, (R)—N-(4-fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)propionamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, (S)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, (R)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,4S)-4-((2,6-dimethylpyridin-4-yl)oxy )-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2R,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,5S)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, (S)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, (R)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2R,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide N-(5-(((2S,5S)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, N-(5-(((2S,4R)-4-((6-methoxy-5-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2-methoxy-6-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, N-(5-(((2S,4R)-2-methyl-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyridine-2-yl) (2-methyl-1-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-((2-methylpyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)- 2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2R,4S)-2-methyl-4-((6-methylpyridin-3-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-((1r,3R)-3-methoxycyclobutoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-cyclobutoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, N-(5-(((2S,4R)-4-((6-ethoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-isopropoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,6-dimethylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-((6-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(dimethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(ethyl(methyl)amino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(cyclobutylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)a cetoamide, N-(5-(((2S,4R)-4-((6-(ethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(isopropylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-2-methyl-4-((6-(methylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(cyclopentyloxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl-4,5,6-13C3)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide-2,2,2-d3, 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, N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl-4-d)acetamide, N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide, and N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0064] In another embodiment, the compound of the invention, for example a compound according to the first or fourteenth embodiment, is selected from: N-(4-fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)a cetoamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)aceto amides, N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide, and N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0065] As used herein, the term "alkyl" refers to a fully saturated branched or straight-chain hydrocarbon moiety. Unless otherwise specified, alkyl 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 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.

[0066] As used herein, the term "alkoxy" refers to the group -OR, where R is alkyl or cycloalkyl, as those terms are 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.

[0067] As used herein, the terms "aryl," "aryl group," "aryl ring," "aromatic group," and "aromatic ring" are used interchangeably and refer to a 5- to 12-membered aromatic 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.

[0068] The number of carbon atoms in a group is referred to herein as "C x-xx " where x and xx are integers. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0069] As used herein, the term "halogen" or "halo" can refer to fluoro, chloro, bromo, or iodo.

[0070] As used herein, the term "haloalkyl" means one or more of the groups defined herein. It refers to an alkyl, as defined herein, substituted with a halo group as above.

[0071] As used herein, the terms “heterocyclyl,” “heterocyclyl group,” “heterocyclic,” and “heterocyclic ring” are used interchangeably and refer to saturated, unsaturated, non-aromatic, monocyclic, or bicyclic (e.g., fused) ring systems having 3 to 12 ring members, or particularly 3 to 6 ring members or 5 to 7 ring members, at least one of which is a heteroatom, and up to four (e.g., 1, 2, 3, or 4) heteroatoms, where the heteroatoms are independently selected from O, S, and N, and where C can be oxidized (e.g., C(═O)), and N can be oxidized (e.g., N(O)) or quaternized (e.g., N + ) and S may optionally be oxidized to sulfoxide and sulfone. Examples of non-aromatic heterocyclyls include aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, hydantoinyl, pyrrolidinonyl, tetrahydrothiopyranyl, tetrahydropyridinyl, and thiopyranyl. Examples of bicyclic non-aromatic heterocyclic ring systems include benzo[1,3]dioxolyl, tetrahydroindolyl, and 2-azaspiro[3.3]heptanyl.

[0072] As used herein, the terms "heteroaryl," "heteroaryl group," "heteroaryl ring," "heteroaromatic," and "heteroaromatic ring" are used interchangeably and refer to a 5- to 12-membered monocyclic or bicyclic aromatic ring system having 1 to 4 heteroatoms independently selected from O, S, and N, where N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. "Heteroaryl" includes heteroaromatic groups fused to a phenyl group or a non-aromatic heterocycle, such as tetrahydrofuran, pyran, pyrrolidine, piperidine, and the like. As used herein, the heteroaryl group Ar can be attached to the remainder of a compound of the invention at any ring with an open valence. Examples of monocyclic heteroaryl ring systems include pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, thiazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, thiazepinyl, 1-oxo-pyridyl, thienyl, valerolactamyl, and the like.

[0073] As used herein, the term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic (e.g., fused) hydrocarbon group of 3 to 12 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms.

[0074] As used herein, the term "halocycloalkyl" refers to a cycloalkyl, as defined herein, that is substituted with one or more halo groups, as defined herein.

[0075] 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., 2, 3, 4, 5, 6, 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 1 to 6, 1 to 3, or 1 to 2 substituents. Suitable substituents include those of formulae (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), The O-GlcNAcase inhibitory activity of compounds (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), and (IVB-2), or a pharmaceutically acceptable salt thereof, is not significantly reduced. Examples of suitable substituents for the alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl, or heterocyclyl group include C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, halo, -CN, -NO2, and -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 C1-C4 alkyl groups optionally include, but are not limited to, -CN, -NO2, -OR, -C1-C4 alkyl groups ... 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). Substituents on the C3-C6 cycloalkyl, phenyl, and monocyclic heteroaryl groups are optionally and independently selected from 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 xIn these substituents, each R x and each R y are independently —H, C1-C4 alkyl, or C3-C8 cycloalkyl, where 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 halo, hydroxyl, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, or halomethoxy). In these substituents, R z is —H, C1-C4 alkyl, or C3-C8 cycloalkyl, where R z is optionally substituted with one or more substituents selected from halo, hydroxyl, C-C cycloalkyl, and phenyl (optionally substituted with one or more groups selected from —CH, halomethyl, halo, methoxy, and halomethoxy), where i is 0, 1, or 2.

[0076] Pharmaceutically acceptable salts of the compounds disclosed herein are also included in the present invention.When the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid salts or base salts, it may be appropriate to prepare and administer the compounds as pharmaceutically acceptable salts.Examples of pharmaceutically acceptable salts include those containing physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate or α-ketoglutarate. - Organic acid addition salts formed with acids that form glycerophosphate. Inorganic salts can also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates and carbonates.

[0077] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with an appropriate acid that provides 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 made.

[0078] 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.

[0079] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers within the molecule. According to the present disclosure, any structure in which stereochemistry is not specified is to be understood as including all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization, synthesis by chiral synthesis from optically active starting materials, or chromatographic separation using chiral stationary phases) are well known in the art. The compounds of the present disclosure may also exist in tautomeric forms, and both mixtures and isolated individual tautomers are contemplated. Furthermore, some compounds may exhibit polymorphism.

[0080] When a particular stereoisomer (e.g., enantiomer, diastereomer, etc.) of a compound used in the methods of the disclosure 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" refers to the percent by weight of the desired stereoisomer relative to the total weight of all stereoisomers.

[0081] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses multiple stereoisomers (e.g., in the case of diastereomeric pairs), it is understood to include one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers. 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. Stereoisomeric purity, in this case, is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0082] In one embodiment, the present invention also provides isotopically labeled compounds that are identical to those listed herein, except that one or more atoms are replaced with atoms having atomic masses or mass numbers different from those usually found in nature.All isotopes of any particular atom or element designated are contemplated within the scope of the compounds of the present invention and their applications.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 Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14C) isotopes are useful for their ease of preparation and detectability. 2 Substitution with heavy isotopes such as H provides greater metabolic stability. Positron-emitting isotopes, such as 15 O. 13 N, 11 C and 18 F is 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 following schemes and / or examples herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0083] In one embodiment, the present invention provides deuterated compounds disclosed herein, where any hydrogen-occupied position is intended to include enrichment with deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, i.e., 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions at its natural abundance. The compounds described herein, or pharmaceutically acceptable salts thereof, may also exist in tautomeric forms, and mixtures and isolated individual tautomers are contemplated.

[0084] 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), or (IVB-2), or a pharmaceutically acceptable salt thereof. The glycosidase is preferably a glycoside hydrolase, more preferably glycoside hydrolase family 84, even more preferably O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase (O-GlcNAcase or OGA), and most preferably a mammalian O-GlcNAcase. In one embodiment, the cell is contacted in vitro or in vivo. In one embodiment, the contacting of the cell comprises administering the compound to a subject.

[0085] One aspect of the present invention includes a method for inhibiting glycosidases and / or glycosidase signaling pathways 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 glycosidases in the subject. The glycosidase is preferably a glycoside hydrolase, more preferably glycoside hydrolase family 84, even more preferably O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase (O-GlcNAcase or OGA), and most preferably a mammalian O-GlcNAcase.

[0086] One aspect of the present invention includes a method of promoting survival or extending the lifespan of a eukaryotic cell (e.g., a mammalian cell), 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), (VA-3), (VA-4), (VA-5), (VA-6), (VA-7), (VA-8), (VA-9), (VA-10), (VA-11), (VA-12), (VA-13), (VA-14), (VA-15), (VA-16), (VA-17), (VA-18), (VA-19), (VA-20), (VA-21), (VA-22), (VA-23), (VA-24), (VA-25), (VA-26), (VA-27), (VA-28), (VA-29), (VA-29), (VA-29), ( A compound of formula (I), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof, thereby promoting survival or extending the lifespan of the eukaryotic cell.

[0087] One aspect of the present invention includes a method for treating a disease or condition caused, mediated, and / or propagated by O-GlcNAcase activity 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), or (IVB-2), or a pharmaceutically acceptable salt thereof. Preferably, the disease or condition is neuropathy, diabetes, cancer, or stress. More preferably, the disease or condition is neuropathy. In one embodiment, the neurological disorder is acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBP), dementia pugilistica, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupe syndrome, or the like. and one or more tauopathies selected from Parkinsonism-type I, Hallervorden-Spatz disease (neurodegenerative disease type 1 with cerebral iron deposition), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontonigral degeneration, Guam Parkinsonism-Dementia Complex, Pick's disease (PiD), post-encephalitic Parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive supercortical gliosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary senile dementia, Huntington's disease, and Parkinson's disease.In another embodiment, the neurological disorder is one or more tauopathies 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, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. In yet another embodiment, the neurological disorder is Alzheimer's disease.

[0088] One aspect of the invention includes a method of treating a disease or condition characterized by tau hyperphosphorylation in a subject (e.g., tau hyperphosphorylation in the brain), 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. In one embodiment, the disease or condition is acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBP), dementia pugilistica, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia linked to chromosome 17, Parkinsonism with dementia type 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupe-type parkinsonism, Hallervorden-Spatz disease (neurodegenerative disease with cerebral iron deposition type 1), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontonigral degeneration, Guam parkinsonism-dementia complex, Pick's disease (PiD), post-encephalitic Parkinsonism In another 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, epilepsy, ischemic stroke, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. In yet another embodiment, the disease or condition is Alzheimer's disease.

[0089] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (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.

[0090] As used herein, the terms "treating" or "treatment" refer to obtaining a desired pharmacological and / or physiological effect, which may be a therapeutic effect, including partially or substantially achieving one or more of the following results: partially or completely reducing the severity of the disease, disorder, or syndrome, improving or reversing clinical symptoms or indicators associated with the disorder, and slowing, inhibiting, or reducing the likelihood of progression of the disease, disorder, or syndrome.

[0091] The term "effective amount" refers to 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, that, when administered to a subject, produces beneficial or desired results, including clinical results, i.e., reverses, alleviates, inhibits, reduces or slows the progression of a disease or condition treatable with a compound of formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (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, as compared to a control, as determined by, for example, clinical symptoms. (IVB-1), (IVB-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, which reduces the likelihood of recurrence of a disease or condition treatable with the 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 / kg body weight. The expression "effective amount" also encompasses the amounts which are effective for increasing normal physiological function.

[0092] Another embodiment of the present invention is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0093] 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), ( Also included herein is the use 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, optionally together with a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating one or more of the 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 a pharmaceutically acceptable salt thereof, for use in treating a subject having one or more of the diseases or conditions described herein. Further 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 of the diseases or conditions described herein.

[0094] 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 such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, and other salts or electrolytes, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropylmethylcellulose, lactose monohydrate, sodium lauryl sulfate, and croscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0095] Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th Ed., a Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19).

[0096] 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, or a composition of the present disclosure may be administered, for example, orally, parenterally, sublingually, topically, rectally, or intramuscularly. It may be administered by nasal administration, oral administration, vaginal administration, transdermal administration, patch administration, pump administration or implanted reservoir, and the pharmaceutical composition is formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal and topical administration methods.Parenteral administration can be by continuous infusion over a selected period of time.

[0097] Other dosage forms encompassed by the present disclosure are described in WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142 and WO2015 / 023915, the contents of which are incorporated herein by reference.

[0098] Useful dosages of the compounds described herein or pharmaceutically acceptable salts thereof can be identified by comparing their in vitro activity, and in vivo activity in animal models. Methods for translating effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated by reference in its entirety. [Example]

[0099] General method Chromatography on silica gel was performed using either a Teledyne ISCO Combiflash RF or a Grace Reveleris X2 equipped with an ELSD purification system using 20-40uM (particle size), 250-400 mesh, or 400-632 mesh silica gel.

[0100] AnalyticalHPLC Acidic HPLC: Performed on a Shimadza 20A instrument equipped with an Ultimate C18 3.0 x 50 mm, 3 um column, eluted with 2.75 mL / 4 L of TFA in water (solvent A) and 2.5 mL / 4 L of TFA in acetonitrile (solvent B) in the following manner. Method A: Use a gradient of 0% to 60% (solvent B) in 6 minutes with a 2 minute hold at 60%, eluting at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm, and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 6 minutes with a 2 minute hold at 60%, eluting at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm, and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 6 minutes with a 2 minute hold at 60%, eluting at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm, and 254 nm. Basic HPLC: Performed on a Shimadza 20A instrument equipped with an Xbridge Shield RP-18, 5 um, 2.1 x 50 mm column, eluted with 2 mL / 4 L of aqueous NH3H2O ​​(solvent A) and acetonitrile (solvent B) in the following manner. Method D: Use a gradient of 0% to 60% (solvent B) in 4.0 minutes and a 2 minute hold at 60%, with an elution flow rate of 1.2 ml / min. Method E: Use a gradient of 10% to 80% (solvent B) in 4.0 minutes with a 2 minute hold at 60%, eluting at a flow rate of 1.2 ml / min. Method F: Use a gradient of 30% to 90% (solvent B) in 4.0 minutes and a 2 minute hold at 60%, with an elution flow rate of 1.2 ml / min.

[0101] Analytical LCMS 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, The analysis was performed on a Shimadza 2010 series, Shimadza 2020 series, or Waters Acquity UPLC BEH (MS ionization: ESI) instrument 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 of TFA in water (solvent A) and 0.75 mL / 4 L of TFA in acetonitrile (solvent B), or on a Zorbax SB-C18 1.8 μm 4.6 × 15 mm Rapid Resolution cartridge with solvent A - acetonitrile, 0.1% formic acid, and solvent B - water (0.1% formic acid) using the following method. 1.5 division method: General method: Use a gradient of 5% to 95% (solvent B) in 0.7 minutes and hold at 95% for 0.4 minutes, elution at a flow rate of 1.5 ml / min. Wavelength: UV 220 nm and 254 nm. Dichotomous method: Method A: Use a gradient of 0% to 60% (solvent B) in 0.9 minutes and hold at 60% for 0.6 minutes, elution at a flow rate of 1.2 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 0.9 minutes and hold at 60% for 0.6 minutes, elution at a flow rate of 1.2 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 0.9 minutes and hold at 60% for 0.6 minutes, elution at a flow rate of 1.2 ml / min. Wavelength: UV 220 nm and 254 nm. 3.5 division method: Initial conditions: 95% solvent A: 5% solvent B, held from 0.0 to 0.1 min, linearly ramped from 0.1 to 3.25 min to 5% solvent A: 95% solvent B, and held from 3.25 to 3.5 min to 5% solvent A: 95% solvent B. Diode array / MS detection. Quadrant: Method A: Use a gradient of 0% to 60% (solvent B) in 3 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 3 minutes, hold at 60% for 0.5 minutes, and elution at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 3 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Seventh rule: Method A: Use a gradient of 0% to 60% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 6 minutes, hold at 60% for 0.5 minutes, and elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 900% (solvent B) in 6 minutes with a 0.5 minute hold at 60%, eluting at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Basic LCMS was performed on a Shimadza 2020 series or Waters Acquity UPLC BEH (MS ionization: ESI) instrument equipped with an XBridge Shield RP18, 5 µm column (2.1 mm × 30 mm, 3.0 mm id) or a 2.1 mm × 50 mm, C18, 1.7 µm column, using the following method: elution with 2 mL / 4 L of aqueous NH₃·H₂O (solvent A) and acetonitrile (solvent B). Trisection rule: Method A: Use a gradient of 0% to 60% (solvent B) in 2 minutes and hold at 60% for 0.48 minutes, elution at a flow rate of 1 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 2 minutes and hold at 60% for 0.48 minutes, elution at a flow rate of 1 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 2 minutes and hold at 60% for 0.48 minutes, elution at a flow rate of 1 ml / min. Wavelength: UV 220 nm and 254 nm. 3.5 division method: Initial conditions: 95% solvent A: 5% solvent B, held from 0.0 to 0.1 min, linearly ramped from 0.1 to 3.25 min to 5% solvent A: 95% solvent B, and held from 3.25 to 3.5 min to 5% solvent A: 95% solvent B. Diode array / MS detection. Seventh rule: Method A: Use a gradient of 0% to 60% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 6 minutes, hold at 60% for 0.5 minutes, and elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0102] SFC analysis separation Instrument: Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150 x 4.6 mm ID, 3 μm. Mobile phase: A is CO2, B is ethanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35 °C, wavelength: 220 nm.

[0103] Preparative HPLC purification General Methods: Preparative HPLC was performed on a Gilson UV / VIS-156 with UV detection at 220 / 254 nm on a Gilson 281 autocollection. Acidic conditions: Use a two-acid scoring system of hydrochloric acid and formic acid. Method A: Hydrochloric acid: YMC-Actus Triart C18 150 x 30 mm x 5 um, gradient 0-100% acetonitrile and water with the corresponding acid (0.05% HCl). Method B: Formic acid: Phenomenex Synergi C18 150 x 30 mm x 4 μm. Gradient was 0-100% acetonitrile and water with the corresponding acid (0.225% formic acid). Gradient shape was optimized for each individual separation. Neutral conditions: Xtimate C18 150 x 25 mm x 5 μm, gradient: 0-100% (water (10 mM NH4HCO3)-ACN), gradient shape was optimized for each individual separation. Basic conditions: Waters Xbridge Prep OBD C18 150 x 30 The gradient was 10 μm, and 0-100% water (0.04% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-acetonitrile was used, with the gradient shape optimized for each individual separation.

[0104] Preparative HPLC-MS purification Columns used: Acid: Waters SunFire Prep, C18 5um, OBD 19 x 100mm Base: Waters XSelect CSH Prep C18 5um OBD 19×100mm Gradient profile: 12-minute run: Initial conditions: A-95%:B-5%, initial hold from 0.0 to 0.5 minutes, linear ramp from A-5% to variable B-% (typical range: B-40% to B-75%) from 0.5 to 7.5 minutes, linear ramp from B-% to B-95% from 7.5 to 8.0 minutes, hold at A-5%:B-95% from 8.0 to 10.0 minutes, final DAD / MS detection, linear ramp down to initial conditions from 10.0 to 10.5 minutes, hold at initial conditions for 1.5 minutes. 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).

[0105] Preparative SFC purification Instrument: MG III preparative SFC (SFC-1). Column: ChiralCel OJ, 250 x 30 mm ID, 5 μm. Mobile phase: A is CO2, B is ethanol (0.1% NH3H2O). Gradient: 50% B. Flow rate: 40 mL / min. Back pressure: 100 bar. Column temperature: 38 °C, wavelength: 220 nm. Cycle time: approximately 8 min.

[0106] 1 H-NMR NMR spectra were recorded on a Bruker Avance III 600 MHz, Bruker AVANCE DRX 500, Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance III 400 MHz, Varian UNITYplus 400, Varian-400 VNMRS, or Varian-400MR. Chemical shifts are expressed in parts per million (ppm). Coupling constants (J) are in hertz (Hz). Splitting patterns indicate apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), or br (broad).

[0107] The following general reaction schemes 1-6 provide details useful for preparing compounds of the invention. The requisite intermediates may be commercially available or may be prepared according to literature procedures. These exemplary reaction schemes are not limited by the compounds depicted or by any particular substituents used for illustrative purposes; the substituent labels (i.e., R groups) shown in these reaction schemes do not necessarily correlate to those used in the claims; in many cases, for clarity, a single substituent is shown attached to the compound when multiple substituents are permitted under the definition of formula (IA) or (IB) above.

[0108] Scheme 1 [ka]

[0109] Scheme 2 [ka]

[0110] General Procedure

[0111] Intermediate 1 [ka] tert-Butyl (2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate: tert-Butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (5.00 g, 24. To a solution of 4-chloro-6-methoxypyrimidine (3.95 g, 27.3 mmol) and 4-chloro-6-methoxypyrimidine (3.95 g, 27.3 mmol) in THF (125 mL) at 0 °C, KHMDS solution (1.0 M in THF, 27.3 mL) was added over 10 min. The mixture was warmed to room temperature and stirred for 3 h. To the mixture was added 10 mL of saturated NH4Cl (aq), and then the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on SiO2 (0-70% EtOAc / heptane) to give the title compound (6.36 g, 82% yield). LCMS (ESI): [M+H] 310. 1 HNMR: (500 MHz, CDCl3) δ 8.42 (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 =14.04 Hz, 1H), 1.46 (s, 9H), 1.32 (br d, J=6.10 Hz, 3H). or tert-Butyl (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (150.00 g, 745.3 mmol) was added to a stirred mixture of 60% sodium hydride (44.7 g, 1.12 mol) in THF (800 mL) at room temperature. The mixture was refluxed for 2 hours. A solution of 4-chloro-6-methoxy-pyrimidine (107.7 g, 745.3 mmol) in THF (200 mL) was slowly added dropwise to the refluxing mixture. After 3 hours at reflux, the reaction was cooled and stirred at room temperature overnight. NH4Cl (saturated) solution (300 mL) was slowly added to the reaction cooled in an ice bath. The layers were separated and the aqueous layer was extracted (100 mL THF). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified in 35 g batches on 220 g of SiO (100% heptane for 5 min, up to 20% 3:1 EtOAc:EtOH over 30 min) to give the title compound (125 g, 54% yield). LCMS (ESI): [M+H] 310. 1 HNMR: (500 MHz, CDCl3) δ 8.43 (s, 1 H), 6.0 5 (s, 1 H), 5.52 (ddd, J=5.5, 3.5, 2.1 Hz, 1 H), 3.97 - 4.14 (m, 1 H), 3.90 - 3.97 (m, 3 H), 3.78 (br d, J=17.5 Hz, 1 H), 3.56 (br s, 1 H), 2.37 (br d, J=5.6 Hz, 1 H), 1.91 (br d, J= 14.2 Hz, 1 H), 1.43 - 1.51 (m, 9 H), 1.33 (br d, J=5.2 Hz, 3 H).

[0112] Intermediate 2 [ka] tert-Butyl (2S,4R)-4-((2-(difluoromethoxy)pyridin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate: 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) (0.086 g, 0.15 mmol), rac-BINAP (0.18 g, 0.298 mmol), and CsCO (0.97 A suspension of 1,3'-dichloromethane (2,3'-dichloromethane) (2.98 mmol) in toluene (3.75 mL) was heated to 120 °C and stirred for 16 h. 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 give the title compound (0.37 g, 72% yield). LCMS (ESI): [M+H] 345.

[0113] Intermediate 3 [ka] tert-Butyl (2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidine-1-carboxylate: To a solution of 6-fluoropyridin-3-ol (185 mg, 1.64 mmol) and tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (300 mg, 1.49 mmol) in THF (15.0 mL) was 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 silica gel (petroleum ether / EtOAc = 3 / 1) to give the title compound (92.0 mg, 21% yield). 1 HNMR: (400 MHz, CDCl3) δ7.78-7.79 ( m, 1H), 7.27-7.31 (m, 1H), 6.87 (dd, J=8.8, 3.2 Hz, 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=6.4 Hz, 3H).

[0114] Intermediate 4 Preparation 1 [ka] 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine hydrochloride: Acetyl chloride (14.1 mL, 197 mmol) was added dropwise over 10 minutes to MeOH (100 mL) at 0° C., and the mixture was stirred for an additional 20 minutes. To this anhydrous HCl solution at 0° C. was added dropwise a solution of tert-butyl (2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate (6.09 g, 19.69 mmol) in MeOH (30 mL). 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 (4.84 g, 99% yield). LCMS (ESI): [M+H] 210. 1 HNMR: (500 MHz, methanol-d4) δ 8.56 (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), 3.57-3.63 (m, 1H), 2.81 (ddd, J=6.71, 7.94, 14.65 Hz, 1H), 1.97 (dddd, J=1.22, 3.66, 7.94, 14.65 Hz, 1H), 1.52 (d, J=6.71 Hz, 3H). Preparation 2 [ka] 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine trifluoroacetate: To a solution of tert-butyl (2S,4R)-4-(6-methoxypyrimidin-4-yl)oxy-2-methyl-pyrrolidine-1-carboxylate (868 mg, 2.81 mmol) in CHCl (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. 1 H 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=6.7 8, 7.97, 14.62 Hz, 1H), 1.85-2.01 (m, 1H), 1.49 (d, J=6.78 Hz, 3H). or TFA (230 g, 2.02 mol, 154.4 mL) was added slowly to an ice-bath cooled solution of tert-butyl (2S,4R)-4-(6-methoxypyrimidin-4-yl)oxy-2-methyl-pyrrolidine-1-carboxylate (61.7 g, 199.5 mmol) in DCM (154 mL). The reaction was allowed to warm to room temperature. After 2 hours, the mixture was concentrated in vacuo. The residue was diluted with water (80 mL), and the mixture was cooled in an ice bath. To the mixture was added 50% aqueous NaOH (approximately 20 mL) dropwise, maintaining the internal temperature below 30° C. while bringing the mixture to a final pH of approximately 11. The mixture was extracted with DCM, dried over NaSO, filtered, and concentrated in vacuo to give the title compound (45 g, 100% yield). LCMS (ESI): [M+H] 210. 1 HNMR: (500 MHz, CDCl3) δ 8.41 (s, 1 H), 6.04 (d, J=0.6 Hz, 1 H), 5.47 (dtd, J=6.8, 3.4, 3.4, 1.6 Hz, 1 H), 3.94 (s, 3 H), 3.24 - 3.32 (m, 2 H), 3.14 (dd, J=13.0, 5.3 Hz, 1 H), 2.47 (dt, J=14.2 , 7.2 Hz, 1 H), 1.50 - 1.61 (m, 1 H), 1.32 (d, J=6.4 Hz, 4 H).

[0115] Example 1-1 [ka] 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 back-extracted with EtOAc and the combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on SiO (10-70% EtOAc:ethanol (3:1 v / v) / heptane) to give a foamy white residue. This material was dissolved in warm methanol, and a 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: (500 MHz, CDCl3) δ 11.76 (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=14.65 Hz, 1H), 3.14 (d, J= 11.60 Hz, 1H), 2.61 (dd, J=6.10, 11.60 Hz, 1H), 2.48-2.57 (m, 2H), 2.31 (s, 3H), 1.64-1 .72 (m, 1H), 1.26 (d, J=6.10 Hz, 3H).

[0116] Example 1-2 [ka] (S)—N-(5-((3-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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. 1 HNMR: (500 MHz, CDCl3) δ 12.55 (s, 1H), 7.93 (d, J=3.05 Hz, 1H), 7.30 (ddd, J=3.36, 7.78 , 9.00 Hz, 1H), 7.19 (s, 1H), 6.68 (dd, J=3. 66, 8.55 Hz, 1H), 5.07 (tt, J=3.97, 8.24 Hz, 1H), 3.68-3.82 (m, 2H), 2.94-3.01 (m, 1H), 2.62-2.72 (m, 1H), 2.36 (br t, J=9.16 Hz, 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).

[0117] Examples 1-3 [ka] (R)—N-(5-((3-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound is prepared by the synthesis of tert-butyl (R)-3-hydroxypiperidine-1-carboxylate, 2,5-difluoropyridin-2-yloxy, Prepared similarly to Scheme 1 from fluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 351. 1HNMR: (500 MHz, CDCl3) δ 12.50 (s, 1H), 7.93 (d, J=3.05 Hz, 1H), 7.28-7.33 (m, 1H), 7.19 (s, 1H), 6.68 (dd, J=3.36, 8.85 Hz, 1H), 5.07 (tt, J=3.97, 8.24 Hz, 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), 2.24-2.30 ( 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).

[0118] Examples 1-4 [ka] N-(5-(((2S,5R)-5-((5-fluoropyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 12.32 (br s, 1H), 7.90 (d, J=3.1 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.18 (s, 1H), 6.77 (dd, J=3.7, 9.2 Hz, 1H), 5.17 - 5.03 (m, 1H), 4.03 - 3.82 (m, 2H), 2.97 (dd, J=4.3, 12.2 Hz, 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=6.1 Hz, 3H).

[0119] Examples 1-5 [ka] N-(5-(((2S,5S)-5-((5-fluoropyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 12.15 (br s, 1H), 7.93 (d, J=3.66 Hz, 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), 4.0 0 (d, J=14.65 Hz, 1H), 3.89 (d, J=14.65 Hz, 1H), 3.17 (br dd, J=2.75, 10.68 Hz, 1H), 2.33-2.41 (m, 1H), 2.31 (s, 3H), 2.21 (t, J=10.07 Hz, 1H), 2.13-2.18 (m, 1H), 1.75-1.81 (m , 1H), 1.33-1.53 ​​(m, 2H), 1.22 (d, J=6.10 Hz, 3H).

[0120] Examples 1-6 [ka] (R)—N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 1 from tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate, 2,5-difluoropyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 337. 1 HNMR: (500 MHz, CDCl3) δ 12.66 (s, 1H), 7.93 (d, J=3.05 Hz, 1H), 7.30 (ddd, J=3.05, 7.63 , 8.85 Hz, 1H), 7.23 (s, 1H), 6.68 (dd, J=3. 66, 9.16 Hz, 1H), 5.32-5.43 (m, 1H), 3.71-3 .98 (m, 2H), 2.96 (dd, J=6.10, 10.99 Hz, 1H), 2.87 (m, 1H), 2.78 (dd, J=2.75, 10.68 Hz, 1H), 2.51-2.61 (m, 1H), 2.20-2.42 (m, 4H), 1.91-2.02 (m, 1H).

[0121] Examples 1-7 [ka] (S)—N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 1 from tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate, 2,5-difluoropyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 337. 1 HNMR: (500 MHz, CDCl3) δ 12.66 (s, 1H), 7.93 (d, J=3.05 Hz, 1H), 7.30 (ddd, J=3.05, 7.94 , 9.16 Hz, 1H), 7.23 (s, 1H), 6.68 (dd, J=3. 66, 9.16 Hz, 1H), 5.32-5.43 (m, 1H), 3.77-3 .92 (m, 2H), 2.96 (dd, J=6.10, 10.38 Hz, 1H), 2.83-2.90 (m, 1H), 2.78 (dd, J=2.75, 10.6 8 Hz, 1H), 2.51-2.62 (m, 1H), 2.26-2.39 (m, 4H), 1.90-2.02 (m, 1H).

[0122] Examples 1-8 [ka] N-(5-(((2R,4S)-4-((5-fluoropyridin-2-yl)oxy) (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: (500 MHz, CDCl3) δ 11.57 (br s, 1H), 7.92 (d, J=3.05 Hz, 1H), 7.27-7.33 (m, 1H), 7.22 (s, 1H), 6.71 (dd, J=3.66, 9.16 Hz, 1H), 5.22-5.29 (m, 1H), 4.1 3 (d, J=14.65 Hz, 1H), 3.60 (d, J=14.04 Hz, 1H), 3.14 (d, J=10.99 Hz, 1H), 2.61 (dd, J=6.41, 11.29 Hz, 1H), 2.47-2.57 (m, 2H), 2.30 (s, 3H), 1.63-1.72 (m, 1H), 1.26 (d, J=6.10 Hz, 3H).

[0123] Examples 1-9 [ka] N-(5-(((2S,4S)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 12.04 (br s, 1H), 7.93 (d, J=3.05 Hz, 1H), 7.27-7.34 (m, 1H), 7.20 (s, 1H), 6.63 (dd, J=3.66, 9.16 Hz, 1H), 5.22-5.33 (m, 1H), 4.1 1 (dd, J=1.22, 14.04 Hz, 1H), 3.55-3.67 (m, 2H), 2.79-2.88 (m, 1H), 2.40 (dd, J=4.58, 1 0.68 Hz, 1H), 2.31 (s, 3H), 2.07 (ddd, J=1.83, 6.26, 13.89 Hz, 1H), 1.90 (ddd, J=7.63, 9.92, 13.58 Hz, 1H), 1.20 (d, J=6.10 Hz, 3H).

[0124] Examples 1-10 [ka] N-(5-(((2R,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 12.14 (s, 1H), 7.93 (d, J=3.05 Hz, 1H), 7. 28-7.33 (m, 1H), 7.20 (s, 1H), 6.63 (dd, J=3.66, 9.16 Hz, 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, 10.38 Hz, 1H), 2.31 (s, 3H), 2.03-2.11 (m, 1H), 1.90 (m, 1H), 1.20 (d, J=6.10 Hz, 3H).

[0125] Examples 1-11 [ka] N-(5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1HNMR: (500 MHz, CDCl3) δ 12.07 (s, 1H), 7.92 (d, J=3.05 Hz, 1H), 7. 27-7.33 (m, 1H), 7.22 (s, 1H), 6.71 (dd, J=3.66, 9.16 Hz, 1H), 5.23-5.28 (m, 1H), 4.06- 4.18 (m, 1H), 3.59 (d, J=14.65 Hz, 1H), 3.14 (d, J=10.99 Hz, 1H), 2.61 (dd, J=6.41, 11.29 Hz, 1H), 2.48-2.56 (m, 2H), 2.31 (s, 3H), 1.65-1.73 (m, 1H), 1.26 (d, J=5.49 Hz, 3H).

[0126] Examples 1-12 [ka] N-(5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: (500 MHz, CDC l3) δ 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=14.04 Hz, 1H), 3.19 (d, J=10.99 Hz, 1H), 2.65 (dd, J=6.10, 10.99 Hz, 1H), 2.52-2.60 (m, 2 H), 2.31 (s, 3H), 1.68-1.77 (m, 1H), 1.27 (d, J=5.49 Hz, 3H).

[0127] Examples 1-13 [ka] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 11.87 (br s, 1H), 8.19-8.23 (m, 1H), 7.69 (dd, J=2.44, 8.55 Hz, 1H), 7.22 (s, 1H), 6.82 (d, J=9.16 Hz, 1H), 6.61 (t, J=56.20 Hz, 1H), 5.34-5.40 (m, 1H), 4.1 4 (d, J=13.43 Hz, 1H), 3.59 (d, J=14.65 Hz, 1H), 3.15 (d, J=10.99 Hz, 1H), 2.63 (dd, J=6.41, 11.29 Hz, 1H), 2.50-2.59 (m, 2H), 2.31 (s, 3H), 1.66-1.75 (m, 1H), 1.27 (d, J=6.10 Hz, 3H).

[0128] Examples 1-14 [ka] N-(5-(((2S,4R)-2-methyl-4-(pyridin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, CDCl3) δ 11.85 (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=14.65 Hz, 1H), 3.16 (d, J= 11.60 Hz, 1H), 2.64 (dd, J=6.71, 10.99 Hz, 1H), 2.50-2.58 (m, 2H), 2.30 (s, 3H), 1.66-1 .74 (m, 1H), 1.26 (d, J=5.49 Hz, 3H).

[0129] Examples 1-15 [ka] N-(5-(((2S,4R)-4-((5-fluoro-6-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound is prepared by the synthesis of tert-butyl(2S,4R)-4-hydroxy-2- Prepared analogously to Scheme 1 from methyl pyrrolidine-1-carboxylate, 6-chloro-3-fluoro-2-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 365. 1 HNMR: (500 MHz, CDCl3) δ 12.10 (br s, 1H), 7.24 (b rs, 1H), 7.20 (t, J=8.37 Hz, 1H), 6.51 (dd, J=2.75, 8.85 Hz, 1H), 5.25-5.32 (m, 1H), 4. 14 (br d, J=14.04 Hz, 1H), 3.55-3.67 (m, 1H), 3.13 (br d, J=10.99 Hz, 1H), 2.57-2.69 (m, 1H), 2.49-2.56 (m, 2H), 2.35 (d, J=3.05 Hz, 3H), 2.31 (s, 3H), 1.63-1.74 (m, 1H), 1.24-1.29 (m, 3H).

[0130] Examples 1-16 [ka] N-(5-(((2S,4R)-4-((5-cyanopyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1HNMR: (500 MHz, CDCl3) δ 11.82 (br s, 1H), 8.42 (d, J=2.44 Hz, 1H), 7.68-7.78 (m, 1H), 7.22 (s, 1H), 6.82 (d, J=8.55 Hz, 1H), 5.32-5.43 (m, 1H), 4.07-4.19 (m, 1H), 3.58 (d, J=14.04 Hz, 1H), 3.15 (d, J=10.99 Hz, 1H), 2.49-2.67 (m, 3H), 2.31 (s , 3H), 1.65-1.74 (m, 1H), 1.26 (d, J=5.49 Hz, 3H).

[0131] Examples 1-17 [ka] N-(5-(((2S,4R)-4-((6-chloro-4-methylpyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: ( 500 MHz, CDCl3) δ 11.50 (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=14.04 Hz, 1H), 3.57 (br d , J=14.04 Hz, 1H), 3.18 (d, J=10.99 Hz, 1H), 2.49-2.66 (m, 3H), 2.31 (s, 3H), 2.23 (s, 3 H), 1.74 (ddd, J=3.97, 8.70, 12.97 Hz, 1H), 1.26 (d, J=6.10 Hz, 3H).

[0132] Examples 1-18 [ka] N-(5-(((2S,4R)-4-((6-(difluoromethyl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 11.98 (br s, 1H), 8.76 (s, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 6.47 (t, J=55.55 Hz, 1H), 5.37-5.49 (m, 1H), 4.14 (d , J=14.65 Hz, 1H), 3.58 (d, J=14.04 Hz, 1H), 3.16 (d, J=11.60 Hz, 1H), 2.50-2.73 (m, 3H), 2.31 (s, 3H), 1.66-1.75 (m, 1H), 1.27 (d, J=5.49 Hz, 3H).

[0133] Examples 1-19 [ka] N-(5-(((2S,4R)-4-((5-fluoro-6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 12.07 (br s, 1H), 8.1 0 (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=14.65 Hz, 1H), 3.19 (d, J=10.99 Hz, 1H), 2.68 (dd, J=6.41, 11.29 Hz, 1H), 2.51-2.61 (m, 2H), 2.31 (s, 3H), 1.73-1.82 (m, 1H), 1.26 (d, J=6.10 Hz, 3H).

[0134] Examples 1-20 [ka] N-(5-(((2S,4R)-4-((2-(difluoromethoxy)pyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1HNMR: (500 MHz, CDCl3) δ 11.38 (br s, 1H), 7.95 (d, J=5.49 Hz, 1H), 7.44 (t, J=72.64 Hz, 1H), 7.23 (s, 1H), 6.58-6.61 (m, 1H), 6.22 (d, J =2.44 Hz, 1H), 4.66-4.75 (m, 1H), 4.11-4.16 (m, 1H), 3.61 (d, J=14.04 Hz, 1H), 3.18 (d, J=10.99 Hz, 1H), 2.49-2.68 (m, 3H), 2.31 (s , 3H), 1.70 (m, 1H), 1.26 (d, J=5.49 Hz, 3H) .

[0135] Examples 1-21 [ka] N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, CDCl3) δ 12.13 (br s, 1H), 8.51 (s, 1H), 7.22 (s, 1H), 6.77 (d, J=1.22 Hz, 1H), 5.30-5.48 (m, 1H), 4.13 (d, J=14.04 Hz, 1H), 3.56 (d, J=14.04 Hz, 1H), 3.14 (d, J=10.99 Hz, 1H), 2.47-2.73 (m, 3H), 1.66-1.72 (m, 1H), 1.26 (d, J=6.10 Hz, 3H).

[0136] Examples 1-22 [ka] 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 trifluoroacetic acid salt (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 literature procedures described in WO2018 / 140299A1) in 20 mL of EtOAc 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 was added sodium triacetoxyborohydride (1.45 g, 6.84 mmol). The mixture was heated to 50 °C for 1 h and then cooled to room temperature. To the mixture was added saturated NaHCO3 (aq) and EtOAc. The aqueous layer was removed and back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with heptane / EtOAc to give a pink solid (329 mg). The mother liquor was concentrated in vacuo, and the residue was purified on SiO2 (50% EtOAc / heptane) to give a yellow solid (98 mg). The solid (427 mg) was dissolved in MeOH (30 mL) and treated with charcoal. The suspension was filtered through Celite, and the eluent was concentrated in vacuo to give the title compound (402 mg, 46% yield). LCMS (ESI): [M+H] 382. 1H NMR (400 MHz, methanol-d4) δ 8.35 (s, 1H), 6.13 (s, 1H), 5.21-5.47 (m, 1H), 3.85-4.03 (m, 4H), 3.55 (d, J=14.56 Hz, 1H), 3.13 (d, J=11.29 Hz, 1H), 2.47-2.73 (m, 3H), 2.17 (s, 3H), 1.52-1.72 (m , 1H), 1.23 (d, J=5.52 Hz, 3H). or 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. A 1N HCl solution (315 mL) was slowly added to the reaction. The aqueous layer was separated and the organic layer was extracted with additional 1N HCl (150 mL). The combined HCl layers were treated with 50% NaOH while cooling in an ice bath to a final pH of approximately 11. The mixture was extracted with DCM, and the organics were dried over MgSO, filtered, and concentrated in vacuo. The residue was triturated with MeOH to give a pink solid. The solid was purified in two batches on SiO (220 g, 20% to 60% heptane / (3:1 EtOAc:EtOH 2% NHOH) to give the title compound (29 g, 48% yield). LCMS (ESI): [M+H] 382. 1 HNMR: (500 MHz, CDCl3) δ 11.16 (br s, 1 H), 8.36 - 8.41 (m, 1 H), 6.04 - 6.08 ( m, 1 H), 5.28 - 5.39 (m, 1 H), 3.98 (d, J=14. 6 Hz, 1 H), 3.89 - 3.94 (m, 3 H), 3.64 (d, J=14.6 Hz, 1 H), 3.16 (d, J=11.1 Hz, 1 H), 2.65 (dd, J=11.1, 6.1 Hz, 1 H), 2.48 - 2.57 (m, 2 H), 2.29 - 2.34 (m, 3 H), 1.60 - 1.72 (m, 2 H), 1.20 - 1.29 (m, 4 H). 19 FNMR: (471 MHz, CDCl3) δ -116 (s, 1F).

[0137] Intermediate 5 [ka] tert-Butyl (2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate: To a 1 L round-bottom flask containing tert-butyl (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (40 g, 198.75 mmol) in THF (100 mL) 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 reaction was 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 NHCl (sat.) 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 with a gradient of EtOAc / heptane (0→20→100%) to give the title compound (35.5 g, 113.3 mmol, 57% yield). LCMS (ESI): [M+H] 313.1. 1 HNMR: (500 MHz, CDCl3) δ 8.57 (s, 1H), 6.78 (s, 1H), 5.58 (t t, J=5.5, 2.1 Hz, 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 (br d, J=14.0 Hz, 1H), 1.59 (s, 1H), 1.43-1.49 (m, 9H), 1.33 ppm (br d, J=6.1 Hz, 3H).

[0138] Intermediate 6 [ka] tert-Butyl (2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate: To a 500 mL round-bottom flask containing 2-methoxyethanol (6.32 g, 83.08 mmol, 6.52 mL) in THF (200 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 the 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 give the title compound (16.5 g, 46.7 mmol, 62% yield). LCMS (ESI): [M+H] 354.2. 1 HNMR: (500 MHz, CDCl3) δ 8.40 (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=14.0 Hz, 1H), 1.47 (s, 9H), 1.24-1.36 (m, 5H), 0.86-0.90 ppm (m , 1H).

[0139] Intermediate 7 [ka] 4-(2-Methoxyethoxy)-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine: A 2 L round-bottom flask containing tert-butyl (2S,4R)-4-[6-(2-methoxyethoxy)pyrimidin-4-yl]oxy-2-methyl-pyrrolidine-1-carboxylate (28.58 g, 80.87 mmol) in DCM was cooled to 0 °C. Hydrogen chloride solution (4 M 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 about 11 with 50% NaOH. The mixture was extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated to give the title compound (19.21 g, 75.84 mmol, 93% yield). LCMS (ESI): [M+H] 254.1. 1 HNMR: (500 MHz, CD Cl3) δ 8.39 (s, 1H), 6.08 (s, 1H), 5.40 (ddd d, J=6.8, 5.1, 3.4, 1.2 Hz, 1H), 4.47-4.51 (m, 2H), 3.70-3.74 (m, 2H), 3.42-3.43 (m, 3H) ), 3.22 (d, J=12.8 Hz, 1H), 3.12-3.19 (m, 1H), 3.00-3.05 (m, 1H), 2.42 (dt, J=14.2, 7.2 Hz, 1H), 1.69 (br s, 2H), 1.45 (dddd, J=14.0, 7.9, 3.1, 1.2 Hz, 1H), 1.27 ppm (d, J=6.7 Hz, 3H).

[0140] Examples 1-23 [ka] 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, N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide (14.70 g, 78.12 mmol) was added to the mixture at 40°C. After 30 minutes, the reaction turned pink. After 2 hours at 40°C, the reaction was cooled to room temperature and stirred at room temperature for 1 hour. 1 M HCl was added (approximately 50 mL until bubbling ceased) to quench the reaction. The aqueous layer was separated from the organics, and the organics were extracted with approximately 75 mL of 1 M HCl. The aqueous layer was collected, and the pH was adjusted to approximately 11-12 with 50% NaOH (approximately 75 mL). The aqueous layer was extracted with EtOAc, and the organics were dried over sodium sulfate and concentrated. The residue was purified on silica gel with a gradient of heptane / [EtOAc / EtOH (3:1)] w / 1% TEA (0→50→100%) to give the title compound (25 g, 58.76 mmol, 77% yield). LCMS (ESI): [M+H] 426.1. 1 HNMR: (400 MHz, CD Cl3) δ 10.48 (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=14.7 Hz, 1H), 3.70-3.73 (m, 2H), 3.64 (d, J=14.7 Hz, 1H), 3.49 (d, J=5.5 H z, 1H), 3.42 (s, 3H), 3.15 (d, J=11.0 Hz, 1H ), 2.66 (dd, J=11.0, 6.1 Hz, 1H), 2.48-2.55 (m, 2H), 2.28-2.30 (m, 3H), 1.57-1.62 (m, 6 H), 1.24 (d, J=6.1 Hz, 3H), -0.12--0.01 (m, 1H).

[0141] Examples 1-24 [ka] N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4,6-dichloropyrimidine, azetidine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in a manner analogous to Example 1-23. LCMS (ESI): [M+H] 407. 1 HNMR: (400 MHz, methanol-d4) δ 8.12 (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=14.5 Hz, 1H), 3.17 (d, J=11.0 Hz, 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=5.5 Hz, 3H).

[0142] Examples 1-25 [ka] 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: This title compound was prepared 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 in a similar manner to Example 1-23. LCMS (ESI): [M+H] 425. 1 HNMR: (500 MHz, methanol-d4) δ 8.12 (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=14.5 Hz, 1H), 3.17 (d, J=11.0 H z, 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=5.5 Hz, 3H).

[0143] Examples 1-26 [ka] 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: This title compound was prepared 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 in a similar manner to Example 1-23. LCMS (ESI): [M+H] 443.1. 1 HNMR: (500 MHz, Methanol-d4) δ 8.20 (s, 1H), 5.78 (s, 1H), 5.2 6-5.29 (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=5.5 Hz, 3H).

[0144] Examples 1-27 [ka] (S)—N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ES I): [M+H] 368. 1HNMR: (400 MHz, methanol-d4) δ 8.36 (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).

[0145] Examples 1-28 [ka] (R)-N-(4-fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound is prepared by the synthesis of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate. This compound was prepared from acetone, 4-chloro-6-methoxypyrimidine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in the same manner as in Scheme 2. LCMS (ES I): [M+H] 368. 1 HNMR: (500 MHz, methanol-d4) δ 8.36 (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).

[0146] Examples 1-29 [ka] N-(4-Fluoro-5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, 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), 3.62-3.66 (m , 2H), 2.81-2.86 (m, 1H), 2.41-2.51 (m, 1H) , 2.29 (s, 3H), 2.01-2.07 (m, 1H), 1.83-1.9 1 (m, 1H), 1.15-1.22 (m, 3H).

[0147] Examples 1-30 [ka] N-(4-Fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from pyrazine tert-butyl (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 (400 MHz, methanol-d4) δ 8.35 (d, J=0.75 Hz, 1H), 6.07 (d, J=1.00 Hz, 1H), 5.28-5.37 (m, 1H), 5.28-5.37 (m, 1H), 3.90-4.00 (m, 4H), 3.67 (d, J=14.81 Hz, 1H), 3.57 (dd, J=6.27, 11.04 Hz, 1H), 2.88 (td, J=6.02, 10.29 Hz, 1H), 2.53 (dd, J=4.02, 11.04 Hz, 1H), 2.18 (s, 3H), 2.09 (ddd, J=1.76, 6.02, 13.80 Hz, 1H), 1.87 (ddd, J=7.28, 10.29, 13.80 Hz, 1H), 1.20 (d, J=6.27 Hz, 3H).

[0148] Examples 1-31 [ka] N-(4-Fluoro-5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol-d4) δ 8.35 (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 = 5.6 Hz, 3H).

[0149] Examples 1-32 [ka] (S)—N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (S)-3-hydroxypiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ES I): [M+H] 382. 1 HNMR: (400 MHz, methanol-d4) δ 8.33 (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).

[0150] Examples 1-33 [ka] (R)-N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (R)-3-hydroxypiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ES I): [M+H] 382. 1HNMR: (400 MHz, methanol-d4) δ 8.33 (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).

[0151] Examples 1-34 [ka] N-(4-Fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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, 1 H), 2.21 (s, 3H), 2.16 (m, 1H), 1.83-1.86 (m, 1H), 1.23 (d, J=6.0 Hz, 3H).

[0152] Examples 1-35 [ka] N-(4-Fluoro-5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, CDCl3) δ 10.95 (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=15.0 Hz, 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=6.5 Hz, 3H).

[0153] Examples 1-36 [ka] (S)-N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolyl) (S)-3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(5-formylthiazol-2-yl)acetamide. The title compound was prepared analogously to Scheme 2 from tert-butyl (S)-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) δ 8.36 (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, 1 H), 2.36-2.37 (m, 1H), 2.06-2.11 (m, 1H) 2. 20 (s, 3H), 1.83-1.94 (m, 1H).

[0154] Examples 1-37 [ka] (R)—N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 350. 1 HNMR: (500 MHz, methanol-d4) δ 8.39 (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, 1 H), 2.64-2.59 (m, 1H), 2.43-2.36 (m, 1H), 2 .22 (s, 3H), 2.02-1.96 (m, 1H).

[0155] Examples 1-38 [ka] N-(5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, methanol -d4) δ 8.34 (s, 1H), 7.24 (s, 1H), 6.08 (s, 1H), 5.31-5.33 (m, 1H), 4.12 (d, J = 14.5 Hz, 1H), 3.92 (s, 3H), 3.68 (d, J = 14.0 Hz, 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 = 6.0 Hz, 3H).

[0156] Examples 1-39 [ka] N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol -d4) δ 8.37 (s, 1H), 7.27 (s, 1H), 6.11 (s, 1H), 5.34-5.36 (m, 1H), 4.15 (d, J=14.4 Hz, 1H), 3.95 (s, 3H), 3.71 (d, J=14.0 Hz, 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=6.0 Hz, 3H).

[0157] Examples 1-40 [ka] N-(5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, methanol -d4) δ 8.34 (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=5.5 Hz, 3H).

[0158] Examples 1-41 [ka] (S)—N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (S)-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), 1.51-1.5 5 (m, 2H).

[0159] Examples 1-42 [ka] (R)—N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared analogously to Scheme 2 from tert-butyl (R)-3-hydroxypiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (400MHz, methanol-d4) δ 8.32 (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), 2.43-2.4 4 (m, 2H), 2.19 (s, 3H), 1.86-2.00 (m, 2H), 1.59-1.67 (m, 2H).

[0160] Examples 1-43 [ka] N-(5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, methanol -d4) δ 8.34 (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=6.0 Hz, 3H).

[0161] Examples 1-44 [ka] N-(5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(5-(chloromethyl)thiazol-2-yl)acetamide as described in Scheme 2. LCMS (ESI): [M+H] 378. 1 HNMR: (500 MHz, C DCl3) δ 11.4 (brs, 1H), 8.36 (s, 1H), 7.18 ( s, 1H), 6.12 (s, 1H), 5.19-5.21 (m, 1H), 3.96 (d, J=15.0 Hz, 1H), 3.93 (s, 3H), 3.87 (d, J=15.0 Hz, 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=6.0 Hz, 3H).

[0162] Examples 1-45 [ka] (R)-N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)propionamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine, and N-(4-fluoro-5-formylthiazol-2-yl)propionamide. LCMS (ESI): [M+H] 382. 1 HNMR (400 MHz, methanol-d4 ) δ 8.36 (s, 1H), 6.13 (d, J=0.75 Hz, 1H), 5.38-5.49 (m, 1H), 3.93 (s, 3H), 3.68-3.82 (m , 2H), 2.99 (dd, J=6.15, 11.17 Hz, 1H), 2.79-2.93 (m, 2H), 2.55-2.66 (m, 1H), 2.46 (q, J=7.53 Hz, 2H), 2.29-2.40 (m, 1H), 1.91-2.03 (m, 1H), 1.19 (t, J=7.65 Hz, 3H).

[0163] Examples 1-46 [ka] N-(4-chloro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol-d4) δ 8.34 (d, J=1.00 Hz, 1H), 6.13 (d, J=0.75 Hz, 1H), 5.28-5.40 (m, 1H), 4.04 (d, J=14.56 Hz, 1H), 3.92 (s, 3H), 3.56 ( d, J=14.56 Hz, 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=5.52 Hz, 3H).

[0164] Examples 1-47 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol-d4) δ 7.95 (d, J=2.4 Hz, 1H), 7.45-7.49 (m, 1H), 6.77 (dd, J=9.2, 3.2 Hz, 1H), 5.21-5.24 (m, 1H), 3.96 (d, J=14.8 Hz, 1H), 3.56 (d, J=14.8 Hz, 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=6.0 Hz, 3H).

[0165] Examples 1-48 [ka] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared from 4-chloro-2,6-dimethylpyridine, tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in the same manner as in Scheme 2. LCMS ( ESI): [M+H] 365.0. 1 HNMR: (500 MHz, CDCl3) δ 10.27 (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), 2.29-2.3 4 (m, 4H), 1.95-2.01.

[0166] Examples 1-49 [ka] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared from 4-chloro-2,6-dimethylpyridine, tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in the same manner as in Scheme 2. LCMS ( ESI): [M+H] 365.0. 1 HNMR: (400 MHz, CDCl3) δ 10.71 (br., s., 1H), 6.43 (s, 2H), 4.82-4.83 (m, 1H), 3.75 (s, 2H), 2.84-3.01 (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, 1 H).

[0167] Examples 1-50 [ka] 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 analogously to 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: (400 MHz, CDCl3) δ 10.67 (br. s., 1H), 6.4 5 (s, 2H), 4.71-4.73 (m, 1H), 3.96 (d, J = 15.2 Hz, 1H), 3.65 (d, J = 14.8 Hz, 1H), 3.17 ( d, J = 10.8 Hz, 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 = 6.0 Hz, 3H).

[0168] Examples 1-51 [ka] N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, CDCl3) δ 10.09 (br. s, 1H), 6. 39 (d, J = 2.8 Hz, 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 = 5.6 Hz, 3H).

[0169] Examples 1-52 [ka] 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 analogously 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 HNM R (400 MHz, methanol-d4) δ 7.19 (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, 13.68 Hz, 1H), 3.93 (td, J=5.99, 11.86 Hz, 1H), 3.63 (br d, J=13.80 Hz, 1H), 2.54-2.72 (m, 7H), 2.22 (s, 4H), 1.56 (d, J=6.27 Hz, 3H).

[0170] Examples 1-53 [ka] 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 analogously to Scheme 2 from 2,6-dimethylpyridin-4-ol, tert-butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379.0. 1 HNMR: (40 0 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).

[0171] Examples 1-54 [ka] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared from 4-chloro-2,6-dimethylpyridine, tert-butyl (S)-3-hydroxypiperidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in the same manner as in Scheme 2. LCMS ( ESI): [M+H] 379.1. 1HNMR: (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).

[0172] Examples 1-55 [ka] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared from 4-chloro-2,6-dimethylpyridine, tert-butyl (R)-3-hydroxypiperidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in the same manner as in Scheme 2. LCMS ( ESI): [M+H] 379.1. 1 HNMR: (500 MHz, CDCl3) δ 6.65 (s, 2H), 4.57-4.52 (m, 1H), 3.71-3.6 8 (m, 2H), 2.98-2.96 (m, 1H), 2.76-2.73 (m, 1H), 2.41 (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).

[0173] Examples 1-56 [ka] 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 analogously 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).

[0174] Examples 1-57 [ka] 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 analogously to 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. 1HNMR: (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).

[0175] Examples 1-58 [ka] (S)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, CDCl3) δ 11.25 (br., s., 1H), 7.16 (s, 1H), 6.35 (s, 2H), 4.75-4.79 (m, 1H), 3.73-3.81 (m, 2H), 2.94-2.98 (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).

[0176] Examples 1-59 [ka] (R)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 347 .0. 1 HNMR: (500 MHz, CDCl3) δ 11.43 (br s, 1 H), 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), 2.7 4-2.73 (m, 1H), 2.72 (s, 6H), 2.45-2.32 (m, 4H), 2.30-1.99 (m, 1H).

[0177] Examples 1-60 [ka] N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound can be prepared by the reaction of 4-bromo-2,6-dimethylpyridine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, and N-( Prepared from 5-(chloromethyl)thiazol-2-yl)acetamide as per Scheme 2. LCMS (ESI): [M+H] 361. 1 HNMR: (400 MHz, Methanol-d4) δ 7.29 (s, 1H), 6.58 (s, 2H), 4.7 0-4.85 (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).

[0178] Examples 1-61 [ka] N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, C DCl3) δ 11.94 (br s, 1H), 7.20 (s, 1H), 6.42 (s, 2H), 4.77-4.79 (m, 1H), 4.10-4.12 (m, 1 H), 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), 1.2 0 (d, J = 6.0 Hz, 3H).

[0179] Examples 1-62 [ka] 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 analogously 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: (500 MHz, Alcohol-d4) δ 7.10 (s, 1H), 6.69 (s, 2H), 4.86 (d, J=3.5 Hz, 1H), 4.01 (d, J=13.5 Hz, 1H), 3.60 (d, J=14.5 Hz, 1H), 3.44 (dd, J=11.5, 6.5 Hz, 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=6.0 Hz, 3H).

[0180] Examples 1-63 [ka] 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 analogously 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, Alcohol-d4) δ 7.30 (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, 3 H), 2.43 (s, 6H), 2.22 (s, 3H), 1.60-1.63 (m, 1H), 1.27 (d, J=5.5 Hz, 3H).

[0181] Examples 1-64 [ka] (S)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (S)-3-hydroxypiperidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361 .0. 1 HNMR: (500 MHz, CDCl3,) δ 11.02 (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 = 9.0 Hz, 1H), 2.78 (d, J = 11.5 Hz, 1H), 2.46-2.44 (m, 6H), 2.30-2.28 (m, 3H), 2.18-2.15 (m, 2 H), 2.05 (d, J = 9.5 Hz, 1H), 1.84-1.82 (m, 1H), 1.68 (m, 1H), 1.46 (m, 1H).

[0182] Examples 1-65 [ka] (R)—N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (R)-3-hydroxypiperidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361 .0. 1 HNMR: (400 MHz, CDCl3) δ 11.01 (br s, 1 H), 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, 3 H), 2.15-2.30 (m, 2H), 2.02-2.14 (m, 2H), 1 .51-1.68 (m, 2H).

[0183] Examples 1-66 [ka] 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 analogously 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: (400 MHz, Alcohol-d4) δ 7.23 (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=6.4 Hz, 3H).

[0184] Examples 1-67 [ka] 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 analogously 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: (400 MHz, Alcohol-d4) δ 7.22 (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, 1 H), 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 = 6.0 Hz, 3H).

[0185] Examples 1-68 [ka] N-(5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 3-chloro-6-methoxypyridazine, and N-(5-formylthiazol-2-yl)acetamide as described in Scheme 2. LCMS (ESI): [M+H] 364. 1 HNMR: (500 MHz, methanol -d4) δ 7.11 (s, 2H), 5.33-5.37 (m, 1H), 3.98-4.02 (m,1H), 3.99 (s, 3H), 3.57-3.60 (m, 1 H), 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).

[0186] Examples 1-69 [ka] N-(5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-methylpyrazine, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to Scheme 2. LCMS ( ESI): [M+H] 348.1. 1 HNMR: (500 MHz, methanol-d4) δ 8.05 (s, 1H), 7.99 (s, 1H), 7.26 (s, 1H), 5.27-5.30 (m, 1H), 4.13-4.15 (m, 1H), 3.5 4-3.57 (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=6.0 Hz, 3H).

[0187] Examples 1-70 [ka] 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: This title compound was prepared analogously to 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: (500 MHz, DMSO-d6) δ 11.95 (br s, 1H), 8.32 (s, 1H), 7.26 (s, 1H), 5.52 (s, 1H), 4.99 (br d, J=4.3 Hz, 1H), 4.02 (d, J=14.0 Hz, 1H), 2.89 (d, J=11.6 Hz, 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=6.1 Hz, 4H), 0.0 1-0.05 (m, 1H).

[0188] Examples 1-71 [ka] N-(5-(((2S,4R)-4-((6-methoxy-5-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.64 (s, 1H), 5.53 (br s, 1H), 4.77 (br d, J=12.8 Hz, 2H), 4.52 (br dd, J=13.7, 5.2 Hz, 1H), 3.92 (s, 4H), 3.60-3.79 (m, 2H), 2.82 (dt, J=14.2, 7.2 Hz, 1H), 2.16 (s, 4H), 1.96 (s, 3H ), 1.85-1.93 (m, 1H), 1.38-1.48 (m, 4H).

[0189] Examples 1-72 [ka] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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] 361. 1 HNMR: (400 MHz, methanol-d4) δ 8.00 (s, 1H), 7.28 (s, 1H), 6.71 (s, 1H), 4.90-4.91 (m, 1H), 4.15 (d, J=14.0 Hz, 1H), 3.61 (d, J=14.4 Hz, 1H), 3.14 (d, J=10.8 Hz, 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=5.6 Hz, 3H).

[0190] Example 1-73 [ka] N-(5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, DMSO-d6) δ 7.85-7.86 (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, 1 H), 2.39-2.44 (m, 3H), 2.10 (s, 3H), 1.47-1 .52 (m, 1H), 1.14 (d, J=6.0 Hz, 3H).

[0191] Examples 1-74 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, DMSO-d6) δ 11.95 (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=14.0 Hz, 1H), 3.85 (s , 3H), 3.47 (br d, J=14.0 Hz, 1H), 2.95 (d, J=11.6 Hz, 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, 4.3 Hz, 1H), 1.23 (s, 1H), 1.15 (d, J=6.1 Hz, 4H).

[0192] Examples 1-75 [ka] N-(5-(((2S,4R)-4-((2-methoxy-6-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1HNMR: (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.63 (s, 2H), 6.06 (s, 1H), 5.44-5.60 (m, 2H), 4 .75 (br d, J=13.4 Hz, 2H), 4.49 (br dd, J=13 .1, 4.6 Hz, 2H), 3.45-3.68 (m, 3H), 2.83 (dt, J=14.6, 7.3 Hz, 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=6.7 Hz, 3H).

[0193] Examples 1-76 [ka] N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, DMSO-d6) δ 12.27-12.45 (m, 1 H), 9.01 (s, 1H), 7.63 (s, 1H), 7.19-7.29 (m, 1H), 5.26 (s, 1H), 4.67 (br d, J=14.0 Hz, 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=6.1 Hz, 3H).

[0194] Examples 1-77 [ka] 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: This title compound was prepared analogously to 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: (500 MHz, DMSO-d6) δ 12.30 (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=12.8 Hz, 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=6.1 Hz, 4H).

[0195] Examples 1-78 [ka] N-(5-(((2S,4R)-4-((6-fluoropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound is prepared by the synthesis of tert-butyl(2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl Prepared from lysine-1-carboxylate, 4,6-difluoropyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide as in Scheme 2. LCMS (ESI): [M+H] 352.1. 1 HNMR: (500 MHz, DM SO-d6) δ 12.30 (br s, 1H), 8.66 (d, J=1.8 Hz , 1H), 7.63 (s, 1H), 6.80 (s, 1H), 5.52-5.68 (m, 1H), 4.76 (br d, J=14.0 Hz, 1H), 4.42-4 .62 (m, 1H), 3.50-3.82 (m, 2H), 2.87 (dt, J=14.6, 7.3 Hz, 1H), 2.16 (s, 3H), 1.77-1.97 (m, 1H), 1.37-1.48 (m, 4H).

[0196] Examples 1-79 [ka] N-(5-(((2S,4R)-2-methyl-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-(trifluoromethyl)pyrimidine, and N-[5-(trichloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 402.1 . 1 HNMR: (500 MHz, DMSO-d6) δ 12.26-12.37 ( m, 1H), 7.55-7.73 (m, 1H), 7.47 (s, 1H), 5.67 (br s, 2H), 4.77 (br d, J=12.8 Hz, 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=6.1 Hz, 5H).

[0197] Examples 1-80 [ka] N-(5-(((2S,4R)-4-((5-(difluoromethoxy)pyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, DMSO-d6) δ 11.95 (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=14.0 Hz, 1H), 2.95 (d, J=11.6 Hz, 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, 4.0 Hz, 1H), 1.17 (d, J=6.1H z, 4H).

[0198] Examples 1-81 [ka] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methano rule-d4) δ 7.81 (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, 3 H), 2.41 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H) , 1.72-1.73 (m, 1H), 1.31 (d, J=4.4 Hz, 3H).

[0199] Examples 1-82 [ka] N-(5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol -d4) δ 8.18 (d, J=5.77 Hz, 1H), 7.29 (s, 1H) , 6.67-6.82 (m, 2H), 4.78-4.92 (m, 1H), 4.1 6 (d, J=15.06 Hz, 1H), 3.52-3.66 (m, 1H), 3.13 (d, J=11.29 Hz, 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=6.02 Hz, 3H).

[0200] Example 1-83 [ka] N-(5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, methanol-d4) δ 7.40 (d, J=9.2 Hz, 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=6.0 Hz, 3H).

[0201] Examples 1-84 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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) δ 7.11 (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), 2.6 2-2.74 (m, 3H), 2.20 (s, 3H), 1.66-1.68 (m, 1H), 1.27 (d, J = 5.5 Hz, 3H).

[0202] Examples 1-85 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (5 00 MHz, methanol-d4) δ 7.75 (s, 1H), 7.46-7.50 (m, 1H), 6.98 (dd, J=8.8, 3.2 Hz, 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, 3 H), 2.18 (s, 3H), 1.56-1.63 (m, 1H), 1.25 (d, J=5.6 Hz, 3H).

[0203] Examples 1-86 [ka] N-(5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared analogously 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: (500 MHz, CDC l3) δ 12.14 (br s, 1 H), 8.26 (s, 2 H), 7.14 (s, 1 H), 5.05 - 5.19 (m, 1 H), 4.02 (d, J=14. 50 Hz, 1 H), 3.52 (d, J=14.50 Hz, 1 H), 3.10 (d, J=11.14 Hz, 1 H), 2.62 (dd, J=11.22, 6.48 Hz, 1 H), 2.40 - 2.55 (m, 2 H), 2.19 - 2.28 (m, 3 H), 1.70 (ddd, J=13.01, 8.66, 4.27 Hz, 1 H), 1.10 - 1.26 (m, 5 H), 0.81 (t, J=6.94 Hz, 1 H).

[0204] Examples 1-87 [ka] N-(5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (500 MHz, CDCl3) δ 11.46 (brs, 1H), 7.79 (s, 1H), 7.20 (s, 1H), 6.56 (d, J=5.0 Hz, 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, 1 H), 2.48-2.52 (m, 2H), 2.29 (s, 3H), 2.22 (s, 3H), 1.62-1.66 (m, 1H), 1.24 (d, J=5.5 Hz, 3H).

[0205] Examples 1-88 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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) δ 7.70 (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).

[0206] Examples 1-89 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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).

[0207] Examples 1-90 [ka] N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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: (40 0 MHz, CDCl3) δ 10.57 (br.s, 1H), 8.03 (d, J =2.4 Hz, 1H), 7.48 (dd, J=8.8, 2.4 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.25-5.27 (m, 1H), 3.97 (d, J=14.4 Hz, 1H), 3.64 (d, J=14.8 Hz, 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=5.2 Hz, 3H).

[0208] Examples 1-91 [ka] 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 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-4-methoxypyrimidine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide analogously to Scheme 2. LCMS (ESI): [M+H] 382. 1 HNMR: (400 MHz, CDCl3) δ 10.57 (br s, 1H), 8.13 (d , J=5.5 Hz, 1H), 6.33 (d, J=5.5 Hz, 1H), 5.2 2-5.28 (m, 1H), 3.95-3.96 (m, 1H), 3.94 (s, 3H), 3.62 (d, J=14.5 Hz, 1H), 3.22 (d, J=11.0 Hz, 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 = 5.5 Hz, 3H).

[0209] Examples 1-92 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((2-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1HNMR: (400 MHz, methanol-d4) δ 8.18 (d, J=6.0 Hz 1H ), 6.45 (d, J=6.0 Hz, 1H), 5.36-5.40 (m, 1H), 3.97-3.98 (m, 1H), 3.93 (s, 3H), 3.55-3.5 8 (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=5.6 Hz, 3H).

[0210] Examples 1-93 [ka] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, methanol Le-d4) δ 8.53 (d, J=5.0 Hz, 2H), 7.06 (t, J=5 .0 Hz, 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), 1.65-1.7 0 (m, 1H), 1.25 (d, J=6.0 Hz, 3H).

[0211] Examples 1-94 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (50 0 MHz, methanol-d4) δ 7.87 (d, J=5.0 Hz, 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), 3.56-3.59 ( 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=5.5 Hz, 3H).

[0212] Examples 1-95 [ka] N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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: (50 0 MHz, CDCl3) δ 10.82 (br s, 1H), 8.41 (s, 2H), 5.21-5.22 (m, 1H), 3.93 (d, J=14.5 Hz, 1H), 3.62 (d, J=14.5 Hz, 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=6.0 Hz, 3H).

[0213] Examples 1-96 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (50 0 MHz, methanol-d4) δ 8.07-8.10 (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,1H), 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 = 5.5 Hz, 3H).

[0214] Examples 1-97 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (50 0 MHz, methanol-d4) δ 7.96 (d, J=4.5 Hz, 1H), 6 .82 (d, J=6.0Hz, 1H), 6.55 (d, J=1.5 Hz, 1H), 4.89-4.92 (m, 1H), 3.96-4.00 (m, 1H), 3.5 7 -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 =5.5 Hz, 3H).

[0215] Examples 1-98 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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. 1HNMR: (500 MHz, methanol-d4) δ 7.74 (d, J=3.0 Hz, 1H), 7.31 (dd, J=3.0 Hz, 9.0Hz, 1H), 6.70-6.76 (m, 1H), 5.18-5.19 (m, 1H), 3.96 (d, J=15.0 Hz, 1H ), 3.79 (s, 3H), 3.56 (d, J=14.5 Hz, 1H), 3.11 (d, J=11.0 Hz, 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=5.5 Hz, 3H).

[0216] Examples 1-99 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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) δ 7.53 (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).

[0217] Examples 1-100 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, methanol-d4) δ 7.88 (d, J=6.0 Hz, 1H), 6.50 (d, J=4.5 Hz, 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=5.5 Hz, 3H).

[0218] Example 1-101 [ka] N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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. 1HNMR: ( 500 MHz, CDCl3) δ 11.18 (br s, 1H), 7.99 (d, J=5.5 Hz, 1H), 6.83 (dd, J=5.5, 2.0 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 5.30-5.31 (m, 1H), 3.97 (d, J=15.0 Hz, 1H), 3.63 (d, J=14.5 Hz, 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=5.5 Hz, 3H).

[0219] Intermediate 8 [ka] tert-Butyl (2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate: To a mixture of tert-butyl (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (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 reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / EtOAc = 5 / 1) to give the title compound (286 mg, 0.965 mmol, 74% yield).

[0220] Intermediate 9 [ka] 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-pyridyl)oxy]-2-methyl-pyrrolidine-1-carboxylate (720 mg, 2.43 mmol) in THF (20.0 mL) at −78° C. under N. After 0.5 h, hexachloroethane (1.73 g, 7.29 mmol, 826 uL) was added and the mixture was stirred for an additional 1 h. To this mixture was added NH4Cl (sat. aq., 15 mL), extracted with EtOAc (3×15 mL), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=10 / 1) to give the title compound (430 mg). LCMS (ESI): [M-tBu+H] 275.

[0221] Intermediate 10 [ka] tert-Butyl (2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate: tert-butyl (2S,4R)-4-[(4-chloro-5-fluoro-2-pyridyl)oxy]-2-methyl-pyrrolidine-1-carboxylate (200 mg, 0.604 mmol) and cesium fluoride A mixture of (459 mg, 3.02 mmol) in DMSO (3.00 mL) was stirred at 160 °C under N in a microwave for 2 h. Water (10 mL) was added, the mixture was extracted with EtOAc (3 x 10 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um, conditions: water (10 mM NHHCO)-ACN, start B: 48, end B: 78, gradient time (min): 10, 100% B retention time (min): to give the title compound (101 mg, 0.321 mmol, 53% yield). LCMS (ES I): [M-tBu+H] 259.

[0222] Examples 1-102 [ka] 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 analogously to 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: (500 MHz, CDCl3) δ 11.5 (br s, 1 H), 7.9 (d, 1 H), 6.5 (d, 1 H), 5.25 (m, 1 H), 3.9 (d , J=14 Hz, 1 H), 3.54 (d, J=14 Hz, 1 H), 3.10 (d, J=11.14 Hz, 1 H), 2.6 (dd, J=11, 6.5 Hz, 1 H), 2.40 (m, 2 H), 2.19 (s, 3 H), 1.10 - 1.26 (d, 3 H).

[0223] Intermediate 11 [ka] 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). 1HNMR: (500 MHz, CDCl3) δ: 8.38 (s, 1H), 6.48 (s, 1H), 3.76-3.80 (m, 4H), 3.62-3.63 (m, 4H).

[0224] Examples 1-103 [ka] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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. 1 HNMR: (400 MHz, CDCl3) δ 10.28 (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).

[0225] Examples 1-104 [ka] 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 analogously to 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: (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.45 (d, J=5.5 Hz, 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=7.3 Hz, 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=6.7 Hz, 4H).

[0226] Examples 1-105 [ka] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound can be prepared from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-methoxypyrazine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide according to the following scheme: Prepared similarly to 2. LCMS (ESI): [M+H] 382. 1 HNMR: (4 00 MHz, DMSO-d6) δ 7.85 (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=6.0 Hz, 3H).

[0227] Examples 1-106 [ka] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol-d4) δ 7.82 (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=5.0 Hz, 3H).

[0228] Examples 1-107 [ka] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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. 1 HNMR: (400 MHz, methanol-d4) δ 7.99 (s, 1H), 6.69 ( s, 1H), 4.86-4.89 (m, 1H), 3.97 (d, J=14.5 Hz, 1H), 3.60 (d, J=15.0 Hz, 1H), 3.16 (d, J= 11.0 Hz, 1H), 2.73 (dd, J=11.0, 5.5 Hz, 1H), 2.61-2.64 (m, 2H), 2.43 (s, 3H), 2.18 (s, 3 H), 2.12 (s, 3H), 1.60-1.63 (m, 1H), 1.24 (d, J=5.5 Hz, 3H).

[0229] Examples 1-108 [ka] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, methanol-d4) δ 8.05 (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 =6.0 Hz, 3H).

[0230] Examples 1-109 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 (a by-product isolated from Examples 1-22). LCMS (ESI): [M+H] 368. 1 HNMR: (4 00 MHz, methanol-d4) δ 8.04 (d, J=0.75 Hz, 1H), 5.61 (d, J=0.75 Hz, 1H), 5.08-5.23 (m, 1H), 3.95 (dd, J=0.88, 14.68 Hz, 1H), 3.55 (d, J =14.56 Hz, 1H), 3.13 (d, J=11.55 Hz, 1H), 2.47-2.70 (m, 3H), 2.17 (s, 3H), 1.53-1.71 (m , 1H), 1.16-1.31 (m, 3H)

[0231] Example 1-110 [ka] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol-d4) δ 8.17 (d, J=6.02 Hz, 1H), 6.66-6.85 (m, 2H), 4.87-4.93 (m, 1H), 3.97 (d d, J=1.00, 14.56 Hz, 1H), 3.58 (d, J=14.56 Hz, 1H), 3.15 (d, J=11.04 Hz, 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=6.02 Hz, 3H)

[0232] Examples 1-111 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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. 1 HNMR: (400 MHz, methanol-d4) δ 7.40 (d, J=9.2, 1.6 H z, 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=6.0 Hz, 3H).

[0233] Examples 1-112 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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) δ 8.46 (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).

[0234] Example 1-113 [ka] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound is prepared by the synthesis of 2-chloro-5-(difluoromethyl)pyrazin-2-yloxy. Prepared analogously to Scheme 2 from azidopropyl, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 4 02.0. 1 HNMR: (400 MHz, methanol-d4) δ 8.8 (s, 1H), 8.4 (s, 1H), 6.4 (t), 5.6 (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), 2.64-2.70 (m, 3H), 2.2 (s, 3H), 1.59-1.68 (m, 1H), 1.22 (d, J=6.0 Hz, 3H).

[0235] Examples 1-114 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (500 MHz, methanol-d4) δ 7.68 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 9.0, 3.0 Hz, 1H), 6.72 (d, J = 9.0 Hz, 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 = 6.0 Hz, 3H).

[0236] Examples 1-115 [ka] N-(5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: (500 MHz, methanol -d4) δ 7.75 (s, 1H), 7.46-7.49 (m, 1H), 7.28 (s, 1H), 6.97 (dd, J=9.0, 3.0 Hz, 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=5.5 Hz, 3H).

[0237] Examples 1-116 [ka] N-(5-(((2R,4S)-2-methyl-4-((6-methylpyridin-3-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared from 6-methylpyridin-3-ol, tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a similar manner to Scheme 2. LCMS ( ESI): [M+H] 347. 1 HNMR: (400 MHz, methanol-d4) δ 8.02 (d, J=2.76 Hz, 1 H), 7.29 (s, 1 H), 7.24 - 7.28 (m, 1 H), 7.18 - 7.22 (m, 1 H), 4.77 - 4.84 (m, 1 H), 4.16 (dd, J=14.18, 0.88 Hz, 1 H), 3.59 (d, J=14.31 Hz, 1 H), 3.14 (d, J= 11.04 Hz, 1 H), 2.54 - 2.68 (m, 3 H), 2.45 (s , 3 H), 2.21 (s, 3 H), 1.64 (s, 1 H), 1.27 (d, J=5.77 Hz, 3H).

[0238] Examples 1-117 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from 2-bromo-5-fluoro-4-methylpyridine, 5 tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 383. 1 HNMR: (400 MHz, methanol-d4) δ 11.08 (brs, 1H), 7.81 (s, 1H), 6.57 (d, J=4.8 Hz, 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=5.6 Hz, 3H).

[0239] Example 1-118 [ka] N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound can be prepared by the reaction of 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 as in Scheme 2. LCMS (ESI): [M+H] 399.0. 1HNMR: (400 MHz, methanol-d4) δ 7.75 (s, 1H), 6.45 (s, 1H), 5.25 (m, 1H), 3.9 (d, J=14 Hz, 1H), 3.5 (d, J=14 Hz, 1H), 3.1 (d, J=11 Hz, 1H), 2.49-2.6 (m, 3H), 2.2 (s, 3H), 1. 5-1.6 (m, 1H), 1.25 (d, J=6.0 Hz, 3H).

[0240] Examples 1-119 [ka] 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 analogously 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. 1 HNMR: (400 MHz, methanol Le-d4) δ 8.7 (s, 1H), 8.3 (s, 2H), 5.3 (m, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.53 (d, J=14.4 H z, 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).

[0241] Scheme 3 [ka] Representative Procedure A: To a solution of alcohol (3 equiv.) in DMSO (0.6 mL) was added tBuOK (2.5 equiv.). 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 HO / MeOH or HO / MeCN) to afford the desired product.

[0242] Examples 1-120 [ka] N-(5-(((2S,4R)-4-((6-((1r,3R)-3-methoxycyclobutoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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.

[0243] Examples 1-121 [ka] N-(5-(((2S,4R)-4-((6-cyclobutoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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.

[0244] Examples 1-122 [ka] N-(5-(((2S,4R)-4-((6-(2-Methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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.

[0245] Examples 1-123 [ka] N-(5-(((2S,4R)-4-((6-((1s,3S)-3-Methoxycyclobutoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: (400 MHz, DMSO+CCl4) δ 11.81 (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 = 14.0 Hz, 1H), 3.62 - 3.55 (m, 1H), 3.46 (d, J = 14.0 Hz, 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 = 5.4 Hz, 3H).

[0246] Examples 1-124 [ka] N-(5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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] 4 06.2.

[0247] Examples 1-125 [ka] 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: This title compound was prepared analogously to 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: (400 MHz, DMSO+CCl4) δ 12.12 - 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), 4.19 - 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).

[0248] Examples 1-126 [ka] N-(5-(((2S,4R)-4-((6-ethoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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.

[0249] Examples 1-127 [ka] N-(5-(((2S,4R)-4-((6-isopropoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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.

[0250] Scheme 4 [ka] Representative Procedure B: To a solution of N-(5-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide (1 equiv.) in DMSO (0.6 mL) was added tBuOK (1.2 equiv.). The mixture was stirred at ambient temperature for 30 min, followed by the addition of an aryl halide (1.2 equiv.). The mixture was stirred at 60 °C for 16-72 h. Upon completion, the mixture was subjected to C18 preparative HPLC-MS (gradient mixtures HO / MeOH or HO / MeCN) to afford the desired product.

[0251] Intermediate 12 [ka] (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 salt) and DCM (150 mL). Triethylamine (4.57 g, 45.13 mmol, 6.26 mL) was added and stirred for 10 minutes, after which imidazole (737.35 mg, 10.83 mmol) and tert-butyl-chloro-dimethyl-silane (8.16 g, 54.16 mmol) were added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with DCM, NaCHO (sat.) was added, the layers were separated, and extracted with DCM (2X). 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: (500 MHz, CDCl3) δ 4.34 (br dd, J=4.9, 2.4 Hz, 1H), 3.11-3.32 (m, 2H), 2.88-3.03 (m, 1H), 2.83 (ddd, J=11.9, 4. 9, 1.5 Hz, 1H), 2.15 (ddd, J=13.3, 7.5, 6.1 Hz, 1H), 1.25-1.33 (m, 4H), 0.88 (s, 9H), 0.05 ppm (s, 6H).

[0252] Intermediate 13 [ka] 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 with a gradient of Hept / [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: (500 MHz, CDCl3) δ 7.20 (s, 1H), 4.21-4.41 (m, 1H), 4.01-4.06 (m, 1H), 3.59 (d, J=14.7 Hz, 1H), 2.87 (dd, J=10.1, 2.1 Hz, 1H), 2.43-2.57 (m, 2H), 2.30 (s, 3H), 2.24 (dt, J=12.8, 7.0 Hz, 1H), 1.44-1.68 (m, 3H), 1.22 -1.31 (m, 3H), 1.18 (d, J=6.1 Hz, 3H), 0.84-0.89 (m, 11H), -0.02-0.02 ppm (m, 8H).

[0253] Intermediate 14 [ka] 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)silyl]oxy-2-methyl-pyrrolidin-1-yl]methyl]thiazol-2-yl]acetamide (11.1 g, 29.90 mmol). MeOH (119.6 mL) and KHF2 (5.84 g, 74.8 mmol, 2.46 mL) were added and stirred at 60 °C for 16 h. The reaction was cooled to room temperature, filtered through Celite, and concentrated. Silica gel purification [heptane / EtOH (3:1) with 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. 1 HNMR: (500 MHz, MeOD) δ 7.24 (s, 1H), 4.17-4.22 (m, 1H), 4. 05-4.10 (m, 1H), 3.48 (d, J=14.0 Hz, 1H), 2.89 (d, J=10.4 Hz, 1H), 2.34-2.49 (m, 3H), 2.19 (s, 3H), 1.39-1.46 (m, 1H), 1.21 ppm (d, J=6.1 Hz, 3H).

[0254] Intermediate 15 [ka] 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 Hunig's 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 (approximately 10 drops) of saturated NaHCO3 were added to the mixture and co-evaporated with MeCN. The residue was purified on SiO2 (EtOAc / EtOH3 / 1) to give the title compound (430 mg, 34% yield).

[0255] Examples 1-128 [ka] 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 μL). The mixture was stirred at room temperature for 40 min. The mixture was purified on SiO (100% EtOAc to 3 / 1 EtOAc / EtOH) to give the title compound (23 mg, 43% yield). LCMS (ESI): [M+H] 362. 1 H NMR (400 MHz, meta Nor-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)

[0256] Examples 1-129 [ka] N-(5-(((2S,4R)-2-methyl-4-((6-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound is a mixture of N-(5-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and 4 Prepared from -chloro-6-(pyrrolidin-1-yl)pyrimidine analogously to Scheme 4. LCMS (ESI): [M+H] 403.

[0257] Examples 1-130 [ka] N-(5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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 (E SI): [M+H] 419.0.

[0258] Scheme 5 [ka] 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 equiv.), amine (1.5 equiv.), and DIPEA (2 equiv.) 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 mixtures HO / MeOH or HO / MeCN) to afford the desired product.

[0259] Example 1-131 [ka] N-(5-(((2S,4R)-4-((6-(dimethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, DMSO+C Cl4) δ 11.81 (s, 1H), 8.04 (s, 1H), 7.11 (s, 1H), 5.73 (s, 1H), 5.29 - 5.25 (m, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.42 (d, J = 13.9 Hz, 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 = 5.3 Hz, 3H).

[0260] Example 1-132 [ka] N-(5-(((2S,4R)-4-((6-(ethyl(methyl)amino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: (400 MHz, DMSO+CCl4) δ 11.81 (s, 1H), 8.03 (s, 1H), 7.11 (s, 1H), 5.70 (s, 1H), 5.29 - 5.24 (m, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.53 (q, J = 7.3, 6.5, 6.5 Hz, 2H), 3.42 (d, J = 14.0 Hz, 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 = 5.3 Hz, 3H), 1.10 (t, J = 7.0, 7.0 Hz, 3H) ).

[0261] Example 1-133 [ka] N-(5-(((2S,4R)-4-((6-(Azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, DMS O+CCl4) δ 11.77 - 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 = 13.9 Hz, 1H), 2.93 (d, J = 11.1 Hz, 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 = 5.4 Hz, 3H).

[0262] Examples 1-134 [ka] N-(5-(((2S,4R)-4-((6-(cyclobutylamino)pyrimidine-4 N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and cyclobutanamine. LCMS (ESI): [M+H] 403.2. 1 HNMR: (400 MHz, DMSO+CCl4) δ 11.81 (s, 1H), 7.95 (s, 1H), 7.11 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 5.51 (s , 1H), 5.25 - 5.18 (m, 1H), 4.36 - 4.03 (m, 1 H), 4.00 (d, J = 14.0 Hz, 1H), 3.42 (d, J = 13.9 Hz, 1H), 2.93 (d, J = 11.2 Hz, 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 = 5.3 Hz, 3H).

[0263] Examples 1-135 [ka] N-(5-(((2S,4R)-4-((6-(ethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: (400 MHz, DMS O+CCl4) δ 11.81 (s, 1H), 7.96 (s, 1H), 7.11 (s, 1H), 6.74 (t, J = 5.6, 5.6 Hz, 1H), 5.57 (s, 1H), 5.25 - 5.19 (m, 1H), 4.01 (d, J = 14 .0 Hz, 1H), 3.42 (d, J = 14.0 Hz, 1H), 3.02 ( s, 2H), 2.93 (d, J = 11.1 Hz, 1H), 2.49 - 2.3 8 (m, 3H), 2.10 (s, 3H), 1.59 - 1.48 (m, 1H), 1.20 (d, J = 5.3 Hz, 3H), 1.14 (t, J = 7.2, 7 .2 Hz, 3H).

[0264] Examples 1-136 [ka] N-(5-(((2S,4R)-4-((6-(isopropylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, DMSO+CCl4) δ 11.81 (s, 1H), 7.96 (s, 1H), 7.11 (s, 1H), 6.59 (d, J = 7.8 Hz, 1H), 5.56 (s , 1H), 5.25 - 5.18 (m, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.43 (d, J = 13.9 Hz, 1H), 3.19 (d, J = 5.2 Hz, 1H), 2.93 (d, J = 11.1 Hz, 1H), 2.47 - 2.42 (m, 3H), 2.10 (s, 3H), 1.61 - 1.47 (m, 1H), 1.20 (d, J = 5.3 Hz, 3H), 1.14 (d, J = 6.4 Hz, 6H).

[0265] Examples 1-137 [ka] N-(5-(((2S,4R)-2-methyl-4-((6-(methylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, DMSO+CCl4) δ 11.82 (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 = 4.8 Hz, 3H) , 2.50 - 2.37 (m, 2H), 2.11 (s, 3H), 1.56 - 1 .52 (m, 1H), 1.21 (s, 3H).

[0266] Scheme 6 [ka] Representative Procedure D: To a solution of the alcohol (1.3 equiv) in THF (2 mL) was added KHMDS (1.2 equiv) and the solution was stirred at ambient temperature for 1 h. N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide (1 equiv) was added and stirring was continued at room temperature for 2 h, after which the temperature was raised to 60 °C. Upon completion, the mixture was neutralized with AcOH (1 equiv), concentrated under reduced pressure, and subjected to C18 preparative HPLC-MS (gradient mixtures HO / MeOH or HO / MeCN) to give the desired product.

[0267] Example 1-138 [ka] N-(5-(((2S,4R)-4-((6-(cyclopentyloxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound is N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl Prepared analogously to Scheme 6 from (2-hydroxybenzoyl-2-yl)acetamide and cyclopentanol. LCMS (ESI): [M+H] 418.2.

[0268] Examples 1-139 [ka] N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously 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.

[0269] Examples 1-140 [ka] 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: This title compound was prepared analogously to 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] 42 4. 1 HNMR: (500 MHz, CDCl3) δ 10.78 (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=15.0 Hz, 1H), 3.63 (d, J=14.5 Hz, 1H), 3.15 (d, J=11.5 Hz, 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=5.5 Hz, 3H).

[0270] Example 1-141 [ka] 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: This title compound was prepared analogously to 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 (E SI): [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), 3.2 3-3.25 (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).

[0271] Example 1-142 [ka] tert-Butyl (2S,4R)-4-(5-chloropyrazin-2-yl)oxy-2-methyl-pyrrolidine-1-carboxylate: To a solution of tert-butyl (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (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 h, the reaction was concentrated under reduced pressure, and the residue was purified on SiO (PE / EtOAc = 10 / 1) to give tert-butyl (2S,4R)-4-(5-chloropyrazin-2-yl)oxy-2-methyl-pyrrolidine-1-carboxylate (785 mg, 74% yield). tert-Butyl (2S,4R)-2-methyl-4-(5-morpholinopyrazin-2-yl)oxy-pyrrolidine-1-carboxylate: A mixture of tert-butyl (2S,4R)-4-(5-chloropyrazin-2-yl)oxy-2-methyl-pyrrolidine-1-carboxylate (200 mg, 0.64 mmol), morpholine (278 mg, 3.19 mmol, 277 μL), Pd(dba) (58 mg, 63.74 μmol), t-BuONa (122 mg, 1.27 mmol), and BINAP (40 mg, 63.7 μmol) in toluene (10.0 mL) was stirred at 110 °C under N for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified on SiO2 (PE / EtOAc = 3 / 1) to give tert-butyl (2S,4R)-2-methyl-4-(5-morpholinopyrazin-2-yl)oxy-pyrrolidine-1-carboxylate as a yellow solid (157 mg, 430.80 umol, 68% yield). N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared 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 in a similar manner to Example 1-22. LCMS (ESI): [M+H] 437. 1 HNMR: (400 MHz, methanol-d4) δ ppm 7.81 (d, J=1.17 Hz, 1 H), 7.70 (d, J=1.57 Hz, 1 H), 5.13 - 5.23 (m, 1 H), 3.97 (d, J=14.48 Hz, 1 H), 3.74 - 3 .84 (m, 4 H), 3.56 (d, J=14.48 Hz, 1 H), 3.32 - 3.38 (m, 4 H), 3.12 (br d, J=10.96 Hz, 1 H), 2.65 (dd, J=11.35, 6.26 Hz, 1 H), 2.49 - 2.61 (m, 2 H), 2.18 (s, 3 H), 1.54 - 1.69 (m, 1 H), 1.25 (d, J=5.48 Hz, 3 H).

[0272] Example 1-143 [ka] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously 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=6.26 Hz, 1 H), 6.51 (dd, J=6.26, 2.29 Hz, 1 H), 6.13 (d, J=2.14 Hz, 1 H), 5.09 - 5.24 (m, 1 H), 3.96 (d, J=14.65 Hz, 1 H), 3.71 - 3.84 (m, 4 H), 3.55 (d, J=14.65 Hz, 1 H), 3.21 - 3 .29 (m, 4 H), 3.10 (d, J=11.14 Hz, 1 H), 2.64 (dd, J=11.14, 6.26 Hz, 1 H), 2.50 - 2.59 (m, 2 H), 2.18 (s, 3 H), 1.54 - 1.67 (m, 1 H), 1. 24 (d, J=5.49 Hz, 3 H).

[0273] Examples 1-144 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: (400 MHz, CDCl3) δ 9.95 (br s , 1 H), 7.71 (d, J=1.47 Hz, 1 H), 7.68 (d, J= 1.47 Hz, 1 H), 5.07 - 5.17 (m, 1 H), 4.25 - 4.39 (m, 2 H), 3.91 (d, J=15.16 Hz, 1 H), 3.66 (dd, J=5.26, 3.79 Hz, 2H), 3.58 (d, J=14.67 Hz, 1 H), 3.36 (s, 3 H), 3.09 (d, J=11.00 Hz , 1 H), 2.57 (dd, J=11.13, 6.24 Hz, 1 H), 2.36 - 2.50 (m, 2 H), 2.21 (s, 3 H), 1.54 - 1.64 (m, 1 H), 1.18 (d, J=5.62 Hz, 3 H).

[0274] Examples 1-145 [ka] 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: This title compound was prepared analogously to 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: (400 MHz, CDCl3) δ ppm 9.72 (br s, 2 H), 7.75 (d, J =6.11 Hz, 2 H), 6.19 (dd, J=6.11, 2.45 Hz, 1 H), 5.89 (d, J=2.20 Hz, 2 H), 5.30 (br d, J=3.91 Hz, 2 H), 3.95 (br d, J=14.67 Hz, 2 H), 3 .63 (d, J=14.67 Hz, 1 H), 3.41 - 3.55 (m, 3 H ), 3.32 (s, 3 H), 3.13 (br d, J=11.00 Hz, 1 H ), 2.95 (s, 3 H), 2.56 - 2.66 (m, 1 H), 2.41 - 2.54 (m, 2 H), 2.25 (s, 3 H), 1.22 (d, J=5.6 2 Hz, 4 H)

[0275] Example 1-146 [ka] tert-Butyl (2S,4R)-4-[(5-bromo-2-pyridyl)oxy]-2-methyl-pyrrolidine-1-carboxylate: To a solution of 5-bromo-2-fluoro-pyridine (315 mg, 1.79 mmol, 184 μL) in THF (5.0 mL) was added NaH (119 mg, 2.98 mmol, 60% purity) and tert-butyl (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (300 mg, 1.49 mmol), and the mixture was stirred at 90 °C for 2 h. The reaction was quenched with saturated NH Cl (aq. 4 mL). The mixture was concentrated, then treated with HO (10 mL), and extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (10 mL), dried over Na SO , filtered, and concentrated. The residue was purified on SiO.sub.2 (petroleum ether / EtOAc=15 / 1 to 5 / 1) to give tert-butyl (2S,4R)-4-[(5-bromo-2-pyridyl)oxy]-2-methyl-pyrrolidine-1-carboxylate (458 mg, 86% yield). tert-Butyl (2S,4R)-2-methyl-4-[(5-morpholino-2-pyridyl)oxy]pyrrolidine-1-carboxylate: To a solution of morpholine (243.87 mg, 2.80 mmol, 243.87 μL) in toluene (8.00 mL) was added tert-butyl (2S,4R)-4-[(5-bromo-2-pyridyl)oxy]-2-methyl-pyrrolidine-1-carboxylate (200 mg, 560 μmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (51 mg, 56 μmol), and CsCO (365 mg, 1.12 mmol). The mixture was stirred at 110 °C under N for 15 h. The mixture was concentrated and purified on SiO (petroleum ether / EtOAc = 15 / 1 to 5 / 1) to give tert-butyl (2S,4R)-2-methyl-4-[(5-morpholino-2-pyridyl)oxy]pyrrolidine-1-carboxylate (197 mg, 97% yield). LCMS (ESI): [M+H] 359. N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared from tert-butyl (2S,4R)-2-methyl-4-[(5-morpholino-2-pyridyl)oxy]pyrrolidine-1-carboxylate and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide in a similar manner to Example 1-22. LCMS (ESI): [M+H] 436. 1 HNMR: (400 MHz, methanol-d4) δ ppm 7.72 (d, J=2.93 Hz, 1 H), 7.41 (dd, J=9.05, 3.18 Hz, 1 H), 6.70 (d, J=9.05 Hz, 1 H), 5.12 - 5.24 (m, 1 H), 3.95 (d, J=14.67 Hz, 1 H), 3.75 - 3.87 (m, 4 H) , 3.55 (d, J=14.43 Hz, 1 H), 3.10 (br d, J=11.25 Hz, 1 H), 2.99 - 3.07 (m, 4 H), 2.65 (dd, J=11.13, 6.24 Hz, 1 H), 2.48 - 2.60 (m, 2 H), 2.18 (s, 3 H), 1.61 (ddd, J=15.77, 11.86, 3 .91 Hz, 1 H), 1.24 (d, J=5.62 Hz, 3 H).

[0276] Examples 1-147 [ka] tert-Butyl (2S,4R)-4-[[5-(2-methoxyethoxy)-2-pyridyl]oxy]-2-methyl-pyrrolidine-1-carboxylate: A mixture of tert-butyl (2S,4R)-4-[(5-fluoro-2-pyridyl)oxy]-2-methyl-pyrrolidine-1-carboxylate (200 mg, 675 μmol), 2-methoxyethanol (257 mg, 3.37 mmol, 264 μL), and potassium t-butoxide (152 mg, 1.35 mmol) in DMSO (8.00 mL) was stirred for 12 hours at 120° C. The reaction was extracted (3×10 mL) with EtOAc, dried over NaSO, filtered, and concentrated. The residue was purified on SiO2 (petroleum ether / EtOAc = 3 / 1) to give tert-butyl (2S,4R)-4-[[5-(2-methoxyethoxy)-2-pyridyl]oxy]-2-methyl-pyrrolidine-1-carboxylate (79 mg, 33% yield). LCMS (ESI): [M+H] 353. N-(4-Fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared from tert-butyl (2S,4R)-4-[[5-(2-methoxyethoxy)-2-pyridyl]oxy]-2-methyl-pyrrolidine-1-carboxylate and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide in a similar manner to Example 1-22. LCMS (ESI): [M+H] 425. 1 HNMR: (400 MHz, methanol-d4) δ ppm 7.87 (d, J=5.87 Hz, 1 H), 6.54 (dd, J=5.87, 1.9 6 Hz, 1 H), 6.29 (d, J=1.71 Hz, 1 H), 5.12 - 5.29 (m, 1 H), 4.08 - 4.21 (m, 2 H), 3.96 (br d, J=14.43 Hz, 1 H), 3.69 - 3.79 (m, 2 H), 3.5 5 (br d, J=14.43 Hz, 1 H), 3.40 (s, 3 H), 3.1 1 (br d, J=11.25 Hz, 1 H), 2.65 (br dd, J=11.13, 6.24 Hz, 1 H), 2.47 - 2.61 (m, 2 H), 2.18 (s, 3 H), 1.52 - 1.69 (m, 1 H), 1.24 (br d, J=5.38 Hz, 3 H).

[0277] Example 1-148 [ka] tert-Butyl (2S,4R)-4-(4-fluorophenoxy)-2-methyl-pyrrolidine-1-carboxylate: To a solution of 4-fluorophenol (50 mg, 446 μmol) in DMF (5.00 mL) was added sodium hydride (36 mg, 892 μmol, 60% purity) at 25° C. and stirred for 30 minutes. tert-Butyl (2S,4S)-2-methyl-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (83 mg, 297 μmol) 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.sub.2 (PE:EtOAc=3 / 1) to give tert-butyl (2S,4R)-4-(4-fluorophenoxy)-2-methyl-pyrrolidine-1-carboxylate (35 mg, 40% yield). N-(4-fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared from tert-butyl (2S,4R)-4-(4-fluorophenoxy)-2-methyl-pyrrolidine-1-carboxylate and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide in the same manner as in Example 1-22. LCMS ( ESI): [M+H] 368. 1HNMR: (400 MHz, CDCl3) δ 10.73 (br s, 1 H), 6.88 - 6.99 (m, 2 H), 6.70 - 6.80 (m, 2 H), 4.53 - 4.67 (m, 1 H), 3.98 (d, J=14.48 Hz, 1 H), 3.66 (d, J=14.87 Hz, 1 H), 3.19 (d, J=10.56 Hz, 1 H), 2.61 (dd, J=10.5 6, 5.87 Hz, 1 H), 2.50 - 2.58 (m, 1 H), 2.41 - 2.49 (m, 1 H), 2.30 (s, 3 H), 1.66 - 1.73 (m, 1 H), 1.24 (d, J=5.87 Hz, 3 H).

[0278] Examples 1-149 [ka] 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: This title compound was prepared 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 in a similar manner to Example 1-146. LCMS (ESI): [M+H] 449. 1 HNMR: (400 MHz, methanol-d 4) δ ppm 7.73 (d, J=2.88 Hz, 1 H), 7.42 (dd, J=9.01, 3.00 Hz, 1 H), 6.70 (d, J=9.01 Hz, 1 H), 5.13 - 5.23 (m, 1 H), 3.95 (d, J=14.51 Hz, 1 H), 3.56 (d, J=14.51 Hz, 1 H), 3.06 - 3.1 5 (m, 5 H), 2.49 - 2.70 (m, 7 H), 2.34 (s, 3 H ), 2.15 - 2.21 (m, 4 H), 1.52 - 1.69 (m, 1 H), 1.23 (d, J=5.63 Hz, 3 H).

[0279] Examples 1-150 [ka] tert-Butyl (2S,4R)-4-[[4-(2-methoxyethoxy)-2-pyridyl]oxy]-2-methyl-pyrrolidine-1-carboxylate: tert-Butyl (2S,4R)-4-[(4-fluoro-2-pyridyl)oxy]-2-methyl-pyrrolidine-1-carboxylate (100 mg, 337 μmol) was added to a mixture of 2-methoxyethanol (51 mg, 675 μmol, 53 μL), 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 (3 x 10 mL EtOAc), washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated to give tert-butyl (2S,4R)-4-[[4-(2-methoxyethoxy)-2-pyridyl]oxy]-2-methyl-pyrrolidine-1-carboxylate (106 mg, 88% yield). N-(4-Fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to Scheme 2 from tert-butyl (2S,4R)-4-[[4-(2-methoxyethoxy)-2-pyridyl]oxy]-2-methyl-pyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 425. 1 HNMR: (500 MHz, methanol-d4) δ ppm 7.76 (d, J=3.05 Hz, 1 H), 7.33 (dd, J=9.00, 3.05 Hz, 1 H), 6.70 (d, J=9.00 Hz, 1 H), 5.10 - 5. 24 (m, 1 H), 4.09 (dd, J=5.26, 3.74 Hz, 2 H), 3.97 (d, J=14.65 Hz, 1 H), 3.71 (dd, J=5.34 , 3.66 Hz, 2 H), 3.58 (d, J=14.65 Hz, 1 H), 3 .41 (s, 3 H), 3.12 (d, J=11.29 Hz, 1 H), 2.68 (dd, J=11.22, 6.33 Hz, 1 H), 2.49 - 2.62 (m, 2 H), 2.18 (s, 3 H), 1.55 - 1.68 (m, 1 H), 1. 24 (d, J=5.65 Hz, 3 H).

[0280] Example 1-151 [ka] 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 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 in a manner analogous to Example 1-146. LCMS (ESI): [M+H] 438. 1 HNMR: ( 400 MHz, methanol-d4) δ ppm 7.56 (d, J=3.18 Hz, 1 H), 7.26 (dd, J=9.05, 3.18 Hz, 1 H), 6.66 (d, J=8.80 Hz, 1 H), 5.08 - 5.17 (m, 1 H), 3. 95 (d, J=14.67 Hz, 1 H), 3.48 - 3.60 (m, 3 H) , 3.35 - 3.45 (m, 2 H), 3.32 (s, 2 H), 3.10 (br d, J=11.25 Hz, 1 H), 2.89 (s, 3 H), 2.65 (d d, J=11.00, 6.36 Hz, 1 H), 2.48 - 2.59 (m, 2 H), 2.18 (s, 3 H), 1.54 - 1.67 (m, 1 H), 1.24 (d, J=5.62 Hz, 3 H).

[0281] Example 1-152 [ka] 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: This title compound was prepared 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 in a similar manner to Example 1-22. LCMS (ESI): [M+H] 449. 1 HNMR: (400 MHz, methanol Le-d4) δ ppm 7.74 (d, J=6.11 Hz, 1 H), 6.51 (dd, J=6.36, 2.20 Hz, 1 H), 6.13 (d, J=1.96 Hz , 1 H), 5.14 - 5.21 (m, 1 H), 3.97 (br d, J=14.67 Hz, 1 H), 3.56 (br d, J=14.67 Hz, 1 H), 3 .33 - 3.39 (m, 4 H), 3.11 (br d, J=11.00 Hz, 1 H), 2.65 (br dd, J=11.13, 6.24 Hz, 1 H), 2.51 - 2.60 (m, 5 H), 2.35 (s, 3 H), 2.18 (s, 3 H), 1.54 - 1.67 (m, 2 H), 1.24 (d, J=5.62 Hz, 3 H).

[0282] Intermediate 16 [ka] Pyrimidine-4,6-diol-4,5,6- 13 C3: A mixture of formamide (2.48 g, 2.19 mL, 55.2 mmol) and sodium ethoxide (26.0 g, 30 mL, 80.9 mmol) in ethanol (21 wt%) was added to the mixture of diethyl malonate- 13C3 (4.00 g, 3.72 mL, 24.5 mmol) was added over 1 h at 65-70° C. 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%).

[0283] Intermediate 17 [ka] 4,6-Dichloropyrimidine-4,5,6- 13 C3: In a solution of phosphorus oxychloride (40.4 g, 24.5 mL, 263 mmol), pyrimidine-4,6-diol-4,5,6- 13 C3 (2.82 g, 24.5 mmol) was added in one portion, followed by N,N-dimethylaniline (4.75 g, 4.97 mL, 39.2 mmol). The resulting mixture was heated to reflux for 2 h. 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 x 100 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give an additional 1.2 g. These crude products were combined and purified on SiO to give the title compound (1.85 g, 50%).

[0284] Intermediate 18 [ka] 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 to 4,6-dichloropyrimidine-4,5,6- 13C3 (624 mg, 4.11 mmol) in methanol (4.6 mL) was added dropwise, maintaining the temperature at room temperature. The resulting solution was stirred at room temperature for 1 hour, after which additional 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%).

[0285] Intermediate 19 [ka] tert-Butyl(2S,4R)-4-((6-methoxypyrimidin-4-yl-4,5,6- 13 C3) (oxy)-2-methylpyrrolidine-1-carboxylate: A three-necked round-bottom flask was charged with THF (10.3 mL) and NaH (60% solution in mineral oil, 0.43 g, 10.8 mmol) was slowly added. t-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. In a separate round-bottom flask, 4-chloro-6-methoxypyrimidine-4,5,6- 13 C3 (1.14 g, 7.71 mmol) in THF (3.43 mL) was added. This solution was heated to 60°C, and the above mixture was slowly added at this temperature. The resulting mixture was heated to 60 °C for 1.5 h, after which the mixture was cooled to room temperature and saturated aqueous NH4Cl was added (4 mL). 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%).

[0286] Intermediate 20 [ka] 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine-4,5,6- 13C3: In a three-necked round-bottom flask, tert-butyl(2S,4R)-4-((6-methoxypyrimidin-4-yl-4,5,6- 13 C3)oxy)-2-methylpyrrolidine-1-carboxylate (1.30 g, 4.20 mmol) was dissolved in DCM. The solution was cooled to 0° C., and TFA (2.90 g, 1.9 mL, 25.0 mmol) was added dropwise. The mixture was stirred at room temperature overnight. Additional TFA (1.5 equiv.) was added, and stirring was continued at room temperature overnight. The mixture was cooled to 0° C. 2 M NaOH (aq.) was added until pH=11. The layers were separated, and the alkaline aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 786 mg of the title compound.

[0287] Example 1-153 [ka] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl-4,5,6-13C3)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 at 40–50°C for 2 hours. 1 M aqueous HCl (5 mL) was added slowly. The layers were separated, and the organic layer was extracted again with 1 M aqueous HCl (10 mL). The combined acidic layers were cooled to 0°C and basified with 2 M aqueous NaOH (20 mL) until pH = 11. A solid precipitated. The mixture was stirred and cooled to room temperature. DCM (50 mL) was then added to the mixture, and the layers were separated. The aqueous layer was extracted again with DCM (50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product (1.36 g). The solid was suspended in MeOH (5 mL) and stirred at reflux for 10 minutes. The mixture was filtered, and the solid was washed with cold MeOH to give 485 mg of the title compound. The solution was concentrated, and more solid precipitated. The solid was filtered to give another 217 mg. A total of 702 mg of the title compound was obtained. LCMS (EI): [M+H] 385.4.

[0288] Intermediate 21 [ka] N-(5-Formylthiazol-2-yl)acetamide-2,2,2-d3: To a solution of 2-aminothiazole-5-carbaldehyde (491 mg, 3.83 mmol) and pyridine (930 μL, 11 mmol) in DCM (10 mL) was added acetyl-d3 chloride (550 μL, 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 ethyl acetate in dichloromethane as the eluent to give the title compound (452 ​​mg, 68% yield). LCMS (ESI): [M+H] 174.1. 1HNMR: (400 MHz, methanol-d4) δ 9.93 (s, 1H), 8.23 ​​(s, 1H).

[0289] Intermediate 22 [ka] N-(4-fluoro-5-formylthiazol-2-yl)acetamide-2,2,2-d3: Step 1: 2-Amino-4-fluorothiazole-5-carbaldehyde: 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, filtered, and then washed with ether to give the title compound as a pale yellow solid (376 mg, 158% yield, adjusted), which was used in the next step without further purification. LCMS (ES) I): [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). 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 μL, 2.1 mmol) in DCM (2.5 mL) was cooled to 0 °C. Acetic anhydride-2,2,2-d3 (130 μL, 1.4 mmol) was slowly added and 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. A sample was purified by silica gel chromatography to the title compound (23 mg, 18% yield or 28% yield over two steps). 1HNMR: (600 MHz, methanol-d4) δ 9.89 (s, 1H). 19 FNMR: (565 MHz, methanol-d4) δ -100.90 (br s, 1F).

[0290] Intermediate 23 [ka] N-(5-(chloromethyl-d)thiazol-2-yl)acetamide: Step 1: N-(5-(hydroxymethyl-d)thiazol-2-yl)acetamide: To a stirred solution of N-(5-formylthiazol-2-yl)acetamide (300 mg, 1.76 mmol) in MeOH (3.3 mL) and THF (5.0 mL) at 0 °C, sodium borodeuteride (147 mg, 3.51 mmol) was slowly added, and the mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was concentrated, treated with aqueous NH4Cl, extracted with EtOAc (3x), washed with saturated NaCl, 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).

[0291] Intermediate 24 [ka] N-(5-(chloromethyl-d)thiazol-2-yl)acetamide: Step 1: N-(5-(hydroxymethyl-d)thiazol-2-yl)acetamide: To a stirred solution of N-(5-formylthiazol-2-yl)acetamide (300 mg, 1.76 mmol) in MeOH (3.3 mL) and THF (5.0 mL) at 0 °C, sodium borodeuteride (147 mg, 3.51 mmol) was slowly added, and the mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was concentrated, treated with aqueous NH4Cl, extracted with EtOAc (3x), washed with saturated NaCl, 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).

[0292] Intermediate 25 [ka] 2-Acetamido-4-fluorothiazole-5-carboxylic acid: N-(4-fluoro-5-formylthiazol-2-yl)acetamide (500 mg, 2.66 mmol), monopotassium phosphate (1.09 g, 7.98 mmol) in water (5.0 mL) and 2-methyl-2-butene (3.7 mL, 35 mmol) in tert-butanol (28 mL) To a stirred mixture of 1 L of HCl (250 mL), sodium chlorite (1.80 g, 16.0 mmol, 80% purity) in water (3.0 mL) was added dropwise under ice bath cooling. 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 saturated sodium chloride. The organics were dried over sodium sulfate, filtered, and evaporated. The sample was purified by silica gel chromatography using 0-50% methanol in methylene chloride as the eluent. 450 mg of the isolated material contained 25% starting material. 320 mg was repurified by preparative HPLC (ACN / HO, 0.1% TFA modifier) ​​to give the title compound (174 mg, 45% adjusted yield). LCMS (ESI): [M+H] 205.0. 1 HNMR: (400 MHz, methanol-d4) δ 2.2 2 (s, 3H). 19 FNMR: (376 MHz, methanol-d4) δ -97.03 (s, 1F).

[0293] Intermediate 26 [ka] Methyl 2-acetamido-4-fluorothiazole-5-carboxylate: In a 20 mL vial, 2-acetamido-4-fluorothiazole-5-carboxylic acid (50 mg, 0.25 mmol) and oxalyl chloride (26 μL, 0.31 mmol) were dissolved in acetonitrile (1 mL). After 5 minutes, DMF (10 μL, 0.13 mmol) was added dropwise at room temperature, resulting in significant gas evolution. The reaction was stirred at room temperature for 2 hours. Methanol (1 mL) was added in one portion, and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc and washed with saturated NaHCO solution followed by brine. The organics were dried over NaSO, filtered, and evaporated in vacuo to give the crude title compound (33 mg, 63% yield). LCMS (ESI): [M+H] 219.1. 1HNMR: (400 MHz, methanol-d4) δ 3.83 (s, 3H), 2.22 (s, 3H). 19 FNMR: (376 MHz, methanol-d4) δ -96.25 (s, 1F).

[0294] Intermediate 27 [ka] 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 added deuterated lithium triethylborate (310 uL, 1 M THF solution) slowly at 0° C. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0° C., and additional deuterated lithium triethylborate (310 uL, 1 M THF solution) was added slowly, 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. Silica gel chromatography revealed that acetic acid Purification using ethyl in heptane as the eluent gave 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).

[0295] Intermediate 28 [ka] 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 added deuterated lithium triethylborate (310 uL, 1 M in THF) slowly at 0° C. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0° C., and additional deuterated lithium triethylborate (310 uL, 1 M in THF) was added slowly, 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 by silica gel chromatography using ethyl acetate in heptane as the eluent gave 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).

[0296] Intermediate 29 [ka] 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 added deuterated lithium triethylborate (310 uL, 1 M in THF) slowly at 0° C. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0° C., and additional deuterated lithium triethylborate (310 uL, 1 M in THF) was added slowly, 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 by silica gel chromatography using ethyl acetate in heptane as the eluent gave 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).

[0297] Example 1-154 [ka] N-(5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1 HNMR: (400 MHz, methanol-d4) δ 8.33 (d, J=1.00 Hz, 1H), 7.26 (s, 1H), 6.12 (d, J=0.75 Hz, 1H), 5.29-5.36 (m, 1H), 4.13 (dd, J=1.13, 14.18 Hz, 1H), 3.54 (d, J=14.31 Hz, 1H), 3.10 (d, J=11.55 Hz, 1H), 2.50-2.66 (m, 3H), 2.19 (s , 3H), 1.57-1.67 (m, 1H), 1.24 (d, J=5.77 Hz, 3H).

[0298] Example 1-155 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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: (400 MHz, methanol-d4) δ 8.35 (d, J=1.00 Hz, 1H), 6.13 (d, J=1.00 Hz, 1H), 5.28-5.37 (m, 1H), 3.96 (dd, J=1.00, 14.56 Hz, 1H), 3.56 (d, J=14.31 Hz, 1H), 3.13 (d, J=11.29 Hz, 1H), 2.67 (dd, J=5.77, 11.04 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). 19FNMR: (376 MHz, methanol-d4) δ -117.94 (s, 1F).

[0299] Example 1-156 [ka] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide-2,2,2-d3: This title compound is prepared by the synthesis of tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidin-4-yl. Prepared similarly to Scheme 1 from N-(5-formylthiazol-2-yl)acetamide-2,2,2-d3. LCMS (ESI): [M+H] 367.2. 1 HNMR: (400 MHz, methanol-d4) δ 8.34 (d, J=0.75 Hz, 1H), 7.26 (s, 1H), 6.13 (d, J=0.75 Hz, 1H) H), 5.27-5.37 (m, 1H), 4.13 (dd, J=1.00, 14 .31 Hz, 1H), 3.92 (s, 3H), 3.55 (d, J=14.31 Hz, 1H), 3.10 (d, J=11.29 Hz, 1H), 2.51-2.6 7 (m, 3H), 1.57-1.69 (m, 1H), 1.25 (d, J=6.02 Hz, 3H).

[0300] Example 1-157 [ka] 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: This title compound was prepared analogously to 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: (600 MHz, meta Nor-d4) δ 8.43 (br s, 1H), 6.21 (br s, 1H), 5.66 (br s, 1H), 4.70 (br d, J=14.67 Hz, 1H), 4.46 (br d, J=14.67 Hz, 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 M Hz, methanol-d4) δ -77.14 (br s, 3F), -110.91 (br s, 1F).

[0301] Example 1-158 [ka] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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. 1HNMR: (400 MHz, methanol-d4) δ 8.34 (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).

[0302] Example 1-159 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide: This title compound was prepared analogously 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: (400 MHz, methanol-d4) δ 8.35 (d, J=1.00 Hz, 1H), 6.14 (d, J=1.00 Hz, 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, 11.23 Hz, 1H), 2.53-2.64 (m, 2H), 2.18 (s, 3H), 1.56-1.67 (m, 1H), 1.24 (d, J=5.52 Hz, 3H). 19FNMR: (376 MHz, methanol-d4) δ -117.92 (br s, 1F).

[0303] Intermediate 30 [ka] tert-Butyl (5-(hydroxymethyl-d2)thiazol-2-yl)carbamate: Lithium aluminum deuteride (54 mg, 1.3 mmol) was added to a solution of ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate (300 mg, 1.10 mmol) in THF (5 mL) at 0° C. 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 μL). After 10 minutes, 15% aqueous NaOH (55 μL) was added, followed by 165 μL of water. After an additional 10 minutes, the mixture was filtered through a pad of CELITE®, washing with ether, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography using EtOAc in heptane as the 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).

[0304] Intermediate 31 [ka] 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 methyl ether (LCMS sample in MeOH): [M-C4H8+H] 191.1 .

[0305] Intermediate 32 [ka] 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 μL, 1.8 mmol) was added dropwise. tert-Butyl (5-(chloromethyl-d2)thiazol-2-yl)carbamate (111 mg, 0.44 mmol) was added dropwise as a solution in acetonitrile (2.0 mL). After 2 h, 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 (ES I): [M+H] 424.2. 1 HNMR: (600 MHz, methanol-d4) δ 8.34 (s, 1H), 7.17 (s, 1H), 6.14 (s, 1H), 5.29-5.38 (m, 1H), 3.92 (s, 3H), 3.10 (d, J=11.74 Hz, 1H), 2.53-2.68 (m, 3H), 1.63 (ddd , J=3.67, 8.99, 13.02 Hz, 1H), 1.54 (s, 9H), 1.25 (d, J=5.87 Hz, 3H).

[0306] Intermediate 33 [ka] 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 mL) and to this was added hydrogen chloride (0.30 mL, 4 M in dioxane). The reaction was stirred at room temperature for 4 hours, then evaporated to dryness and co-distilled with DCM to give the title compound as the HCl salt. LCMS (ESI): [M+H] 324.1.

[0307] Example 1-160 [ka] N-(5-(((2S,4R)-4-((6-Methoxypyrimidin-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 salt) was taken up in DCM (2.0 mL) and pyridine (50 uL, 0.62 mmol). To this was added acetic anhydride (27 uL, 0.29 mmol) followed by additional 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 the eluent to give the title compound (17 mg, 32% yield over two steps). LCMS (ESI): [M+H] 366.1 . 1 HNMR: (600 MHz, methanol-d4) δ 8.34 (s, 1H), 7.27 (s, 1H), 6.13 (s, 1H), 5.29-5.36 (m, 1 H), 3.92 (s, 3H), 3.09 (d, J=11.01 Hz, 1H), 2.52-2.68 (m, 3H), 2.19 (s, 3H), 1.58-1.68 (m, 1H), 1.25 (d, J=5.14 Hz, 3H).

[0308] Example 1-161 [ka] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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] 3 84.2. 1 HNMR: (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).

[0309] Intermediate 34 [ka] tert-Butyl (4-bromo-5-formylthiazol-2-yl)carbamate: To a solution of diisopropylamine (3.3 mL, 23 mmol) in THF (20 mL) at 0 °C, n-butyllithium (14.8 mL, 1.6 M in hexanes) was slowly added. The reaction was stirred for 20 min, after which tert-butyl (5-bromothiazol-2-yl)carbamate (2.00 g, 7.16 mmol) was slowly added as a solution in THF (20 mL). The mixture was stirred at 0 °C for 30 min, after which DMF (1.8 mL, 23 mmol) was added. The solution was stirred at room temperature for 2 h. 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 ethyl acetate in heptane as eluent to give the title compound (1.53 g, 70% yield). 81 LCMS (ESI) for Br: [M+H] 308.9. 1 HNMR: (400 MHz, methanol-d4) δ 9.83 (s, 1H), 1.56 (s, 9H).

[0310] Intermediate 35 [ka] tert-Butyl (5-formylthiazol-2-yl-4-d)carbamate: To a flask containing a mixture of tert-butyl (4-bromo-5-formylthiazol-2-yl)carbamate (202 mg, 0.66 mmol) and sodium acetate (113 mg, 1.38 mmol) under nitrogen, palladium on carbon (91 mg, 10%) and anhydrous methanol-d4 (5.0 mL) were added. Deuterium gas was slowly bubbled through the suspension with stirring for 15 minutes, and then the reaction flask was connected to a balloon filled with deuterium gas overnight with vigorous stirring. The palladium black was filtered off and rinsed with methanol. The filtrate was concentrated. The residue was taken up in water and EtOAc. The organics were 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).

[0311] Intermediate 36 [ka] tert-Butyl (5-(hydroxymethyl)thiazol-2-yl-4-d)carbamate: tert-butyl (5-formylthiazol-2-yl-4-d)carbamate (131 mg, 0.57 mmol) in MeOH (1.4 mL) and THF (2.2 mL) To a stirred solution of at 0° C., sodium borohydride (58 mg, 1.5 mmol) was slowly added and the mixture was stirred at room temperature for 2 h. The reaction was quenched by the dropwise addition of saturated aqueous NH4Cl (2 mL). The reaction was concentrated, treated with aqueous NH4Cl, extracted with EtOAc (3x), washed with saturated NaCl, 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 4.6 8 (s, 2H), 1.54 (s, 9H).

[0312] Intermediate 37 [ka] tert-Butyl (5-(chloromethyl)thiazol-2-yl-4-d)carbamate: Thionyl chloride (160 uL, 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 methyl ether (LCMS sample in methanol): [M-C4H8+H] 190 .1.

[0313] Intermediate 38 [ka] 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 to this was added TEA (340 uL, 2.45 mmol) dropwise. tert-Butyl (5-(chloromethyl)thiazol-2-yl-4-d)carbamate (0.55 mmol) was added dropwise as a solution in acetonitrile (1.5 mL) 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 the eluent to give the title compound (177 mg, 68% yield over two steps). LCMS (ESI): [M+H] 423.2. 1 HNMR: (4 00 MHz, methanol-d4) δ 8.34 (d, J=0.75 Hz, 1H), 6.14 (d, J=0.75 Hz, 1H), 5.29-5.35 (m, 1H), 4.11 (d, J=14.06 Hz, 1H), 3.92 (s, 3H), 3.5 4 (d, J=14.31 Hz, 1H), 3.11 (d, J=11.29 Hz, 1H), 2.50-2.68 (m, 3H), 1.57-1.66 (m, 1H), 1.54 (s, 9H), 1.24 (d, J=5.77 Hz, 3H). Intermediate 39 [ka] 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 after which the reaction was evaporated to dryness and coevaporated once with MeOH, then twice with DCM to give the title compound. LCMS (ESI): [M+H] 323.1.

[0314] Example 1-162 [ka] 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 taken up in DCM (1.5 mL) and pyridine (1.0 mL). To this was added acetic anhydride (52 uL, 0.55 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 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 two steps). LCMS (ESI): [M+H] 365.2. 1 HNMR: (400 MHz, Methanol-d4) δ 8.33 (d, J=1.00 Hz, 1H), 6.13 (d, J=0.75 Hz, 1H), 5.29-5.35 (m, 1H), 4.13 (d, J=14.06 Hz, 1H), 3.92 (s, 3H), 3.55 (d, J= 14.05 Hz, 1H), 3.10 (d, J=11.55 Hz, 1H), 2.50-2.67 (m, 3H), 2.19 (s, 3H), 1.58-1.67 (m, 1H), 1.24 (d, J=5.77 Hz, 3H).

[0315] Example 1-163 [ka] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide: This title compound was prepared from tert-butyl (2S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate-4-d, 4-chloro-6-methoxypyrimidine, and N-(5-(chloromethyl)thiazol-2-yl)acetamide as in Scheme 1. The product mixture was purified by HPLC [XSelect CSH Prep C1 Separation of the individual diastereomers was achieved by SFC [CHIRALPAK AD-H 30 x 250 mm, 5 μm, Method: 40% IPA with 0.1% DEA in CO2 (Flow Rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, Column Temperature 40 °C)] followed by SFC [8 OBD 5 μm 30 x 100 mm, Method: (A) 95% H2O / / (B) 5% acetonitrile w / 0.2% NH4OH (initial conditions held for 0.5 min), followed by a linear gradient to 50% (A) / 50% (B) over 12 min (Flow Rate: 50 mL / min)]. LCMS (ESI): [M+H] 365.2. 1 HNMR: (400 MHz, methanol-d4) δ 8.33 (d, J=0.75 Hz, 1H), 7.26 (s, 1H), 6.13 (d, J=0.75 Hz, 1H), 4.13 (dd, J=0.88, 14.18 Hz, 1H), 3.92 (s, 3H), 3.54 (d, J=14.06 Hz, 1H), 3.09 (d, J=11.29 Hz, 1H), 2.63 (d, J=11.55 Hz, 1H), 2.51-2.60 (m, 2H), 2.19 (s, 3H), 1.56-1.67 (m, 1H), 1.23-1.2 7 (m, 3H).

[0316] Example 1-164 [ka] N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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 individual diastereomers by HPLC [XSelect CSH Prep C18 OBD 5 um 30 x 100 mm, Method: (A) 95% {H2O} / / (B) 5% {acetonitrile} w / 0.2% NH4OH (initial conditions held for 0.5 min), followed by a linear gradient to 50% (A) / 50% (B) over 12 min (Flow rate: 50 mL / min)] followed by SFC [CHIRALPAK AD-H 30 x 250 mm, 5 um, 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: (400 MHz, methanol-d4) δ 8.34 (s, 1H), 7.24 (s, 1H), 6. 08 (d, J=0.75 Hz, 1H), 4.13 (d, J=14.05 Hz, 1H), 3.92 (s, 3H), 3.69 (d, J=14.31 Hz, 1H), 3.54 (d, J=11.04 Hz, 1H), 2.84-2.93 (m, 1H), 2.50 (d, J=11.29 Hz, 1H), 2.20 (s, 3H), 2. 10 (dd, J=6.15, 13.93 Hz, 1H), 1.89 (dd, J=10.29, 13.80 Hz, 1H), 1.21 (d, J=6.02 Hz, 3H).

[0317] Example 1-165 [ka] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidine-4 N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide: This title compound was prepared analogously to 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 individual diastereomers by SFC [CHIRALPAK AD-H 30 x 250 mm, 5 um, Method: 45% MeOH w / 0.1% DEA in CO2 (Flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, Column temperature 40 °C)]. LCMS (ES I): [M+H] 383.2. 1 HNMR: (400 MHz, methanol-d4) δ 8.35 (d, J=1.00 Hz, 1H), 6.13 (d, J=1.00 Hz, 1H), 3.96 (dd, J=1.00, 14.56 Hz, 1H), 3.92 (s, 3H), 3.55 (d, J=14.56 Hz, 1H), 3.12 (d , J=11.29 Hz, 1H), 2.66 (d, J=11.29 Hz, 1H), 2.50-2.62 (m, 2H), 2.18 (s, 3H), 1.55-1.66 (m, 1H), 1.24 (d, J=5.77 Hz, 3H). 19 FNMR: (376 MHz, methanol-d4) δ -117.94 (s, 1F).

[0318] Example 1-166 [ka] N-(4-Fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide: This title compound was prepared analogously to 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 individual diastereomers by SFC [CHIRALPAK AD-H 30 x 250 mm, 5 um, Method: 45% MeOH w / 0.1% DEA in CO2 (Flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, Column temperature 40 °C)]. LCMS (ES I): [M+H] 383.2. 1 HNMR: (400 MHz, methanol-d4) δ 8.34 (d, J=0.75 Hz, 1H), 6.07 (d, J=1.00 Hz, 1H), 3.95 (dd, J=0.75, 14.81 Hz, 1H), 3.92 (s, 3H), 3.66 (d, J=14.56 Hz, 1H), 3.56 (d , J=10.79 Hz, 1H), 2.80-2.92 (m, 1H), 2.52 (d, J=10.79 Hz, 1H), 2.18 (s, 3H), 2.08 (dd, J=6.15, 13.93 Hz, 1H), 1.86 (dd, J=10.16, 1 3.93 Hz, 1H), 1.20 (d, J=6.02 Hz, 3H). 19 FNMR: (376 MHz, methanol-d4) δ -118.18 (s, 1F).

[0319] Biological Data

[0320] Biochemical assay for inhibition of OGA enzyme

[0321] 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 a McIlvaine buffer system (0.2 M NaHPO mixed with 0.1 M citric acid) at pH 6.4 and 0.01% BSA. Reactants contains 1 nM OGA, 100 μM 4-MUGlcNAc (K m ), and compound in a final volume of 10 μl. Reactions were incubated for 90 minutes at room temperature, quenched with 40 μl of 3 M glycine, pH 10, and read on a Perkin Elmer Envision plate reader (Ex: 355 nm / Em: 460 nm). Compounds were tested in a 10-point dose response starting at 20 μM with 4-fold dilutions. Data were fitted using GraphPad Prism using a 4-parameter fit with variable slope.

[0322] Description of the cellular OGA-tau MSD assay

[0323] HEK-293T cells were transfected with OGT and tau-V5 plasmids using lipofectamine and grown overnight. The next day, cells were harvested and plated in 96-well plates at 1 x 10 cells per well. 5The cells were replated with 1 μM of 10-point compound at 3:1 dilutions. After incubation at 37°C for 4 hours, compounds were added at 1 μM in 10-point dose sets. The cell plates were incubated with compounds overnight at 37°C. The following day, the media was gently aspirated from the wells, and 120 μl of 1x cell lysis buffer mixed with a protease and phosphatase cocktail was added to each well. After freeze-thawing at -80°C, the mixture was mixed, and then 50 μl of the mixture 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 following day, the plate was 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. The data was analyzed using GraphPad or Genedata, and the data was normalized and plotted as % activity versus the logarithm of compound concentration. IC 50 Values ​​were obtained from a four-parameter fit.

[0324] Description of the Rat Liver Microsome Stability Assay

[0325] Compounds (final concentration 1 μM) were incubated with rat liver microsomes (0.5 mg / mL) in 0.1 M sodium phosphate buffer (pH 7.4) supplemented with 3.3 mM magnesium chloride in the presence or absence of 1 mM nicotinamide adenine dinucleotide phosphate (NADPH) at 37° C. Aliquots (40 μL) at 0, 5, 10, 15, 25, and 40 min after addition of NADPH (or compound for reactions in the absence of NADPH) 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 plates containing these samples were centrifuged (10 min, 3220 × g ) and 50 uL of supernatant from each well was transferred to a well of a 96-well plate of clean analytical samples containing 300 uL of 20:80:0.1 acetonitrile / water / formic acid, mixed, and then placed directly into the LC / MS / MS system for sample analysis.

[0326] HPLC and mass spectrometry conditions for stability assays

[0327] The LC / MS / MS system consisted of an ultra-high-throughput RapidFire® 300 system (Agilent Technologies, Santa Clara, CA) connected to a Triple Quad 5500 mass spectrometer (ABSciex, Foster City, CA). Sample loading and washing were performed on a RapidFire® C4 cartridge using water containing 0.1% formic acid as mobile phase A, and sample elution was performed using acetonitrile:methanol (1:1 v / v) containing 0.1% formic acid as mobile phase B.

[0328] [Table 1]

[0329] [Table 2]

[0330] Data Analysis:

[0331] CLint,app (apparent intrinsic clearance) was calculated for microsomal stability using the following formula:

number

number

[0332] Description of the MDR1-MDCK Efflux Ratio Assay

[0333] MDR1-MDCK cell monolayers were grown to confluence on microporous polyester membranes in 96-well Corning insert plates. The permeability assay buffer was Hank's 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- and low-permeability comparators, respectively.

[0334] Test compounds or positive control P-gp substrates / permeability comparators were added to the apical and basolateral chambers, respectively, for bidirectional assessment of permeability. Receiver buffer (transport buffer supplemented with 1% bovine serum albumin) was added to each receiving chamber. MDR1-MDCK cells were incubated with test compounds at 37°C with 5% CO2 for 2 hours. Samples were collected from the donor chamber at both 0 and 120 minutes and from the receiving chamber at 120 minutes. The concentrations of test and control compounds were determined using LC-MS / MS analysis. Each measurement was performed in triplicate. Apparent permeability (P app ), emission ratio, and mass balance (recovery rate) were calculated as follows: P app =(dC r / dt)xV r / (AxC E ) Mass balance = 100 x ((V r xC r final )+(V d xC d final )) / (V d xC E ) Emission ratio=P app(B-A) / P app(A-B) where: dC r / dt is μMs -1 is the cumulative concentration in the receiving compartment versus time in units of V r is cm3 is the volume of the receiving compartment in units V d is cm 3 is the volume of the supply compartment in units, A is the area of ​​the insert (0.143 cm for 96-well inserts) 2 ) C E is the estimated experimental concentration of the dosing solution (time = 0), C r final is the concentration of the receiver at the end of the incubation period C d final is the donor concentration at the end of the incubation period.

[0335] Table 1 below shows activity data for some of the compounds of the present invention. In some cases, the OGA inhibition, MDR1-MDCK efflux ratio, and rat liver microsome stability assays were repeated, and whenever the final data from subsequent assays differed, the data is provided below and indicated with an asterisk (*). The symbol "-" indicates that data was not available. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0336] While many embodiments of the present disclosure have been described, it will be apparent that the basic examples may be modified to produce other embodiments that utilize the compounds and methods of the present disclosure. Accordingly, the scope of the present disclosure is determined by the appended claims rather than by the specific embodiments that have been presented by way of example. It will be clear that the scope will be defined.

[0337] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are to be given the meaning commonly known to those of ordinary skill in the art.

Claims

1. A compound represented by the following structural formula: 【Chemistry 1】 or a pharma- ceutical acceptable salt thereof, wherein Ar is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; Y １ and Y ２ are respectively CR ｃ or N, and 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 C.H. ２ C(=O), R ｃ is -H, halo, C １ -C ４ Alkyl, or C １ -C ４ is haloalkyl, n is 0 or an integer from 1 to 8; When n is other than 0, R １ is independently assigned to each occurrence of halo, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, or C １ -C ４ is an alkoxy; R ２ is independently for each occurrence -H, halo, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C １０ Cycloalkyl or C ３ -C １０ halocycloalkyl, or alternatively, two R ２ together with the carbon atom to which they are attached, C ３ -C １０ Forming a cycloalkyl, R ３ is -H or C １ -C ４ is alkyl, R ４ is -H, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl or C ３ -C ６ cycloalkyl, or Or alternatively, R ３ and R ４ taken together with their intervening atoms to form an optionally substituted 5- to 7-membered heterocyclyl, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, represented by the following structural formula: 【Chemistry 2】 or a pharma- ceutical acceptable salt thereof, wherein R １ Ha, Haro, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, or C １ -C ４ Alkoxy, R ｃ Ha, Haro, C １ -C ４ Alkyl, or C １ -C ４ haloalkyl and n is an integer from 1 to 7, or a pharma- ceutically acceptable salt thereof.

3. 2. The compound of claim 1, represented by the following structural formula: 【Chemistry 3】 or a pharma- ceutical acceptable salt thereof, wherein R １ is halo or C １ -C ４ or a pharma- ceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, represented by the following structural formula: 【Chemistry 4】 or a pharma- ceutical acceptable salt thereof, wherein R ２ is independently at each occurrence -H or C １ -C ４ or a pharma- ceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, represented by the following structural formula: 【Chemistry 5】 or a pharma- ceutical acceptable salt thereof, wherein R ２ is independently at each occurrence -H or C １ -C ４ alkyl, R ｃ is halo or C １ -C ４ alkyl and n is an integer from 1 to 7, or a pharma- ceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, represented by one of the following structural formulas: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, represented by the following structural formula: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, wherein n is an integer from 1 to 7, or a pharma- ceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 7, represented by one of the following structural formulas: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof, wherein n is 0 or an integer from 1 to 7, or a pharma- ceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 8, represented by the following structural formula: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof, wherein n is 0 or an integer from 1 to 6, or a pharma- ceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 9, represented by the following structural formula: 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof, wherein n is 0 or an integer from 1 to 3, or a pharma- ceutically acceptable salt thereof.

11. The compound according to any one of claims 1 to 10, represented by the following structural formula: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof, wherein n is 0 or an integer from 1 to 3, or a pharma- ceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 11, represented by one of the following structural formulas: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, wherein n is 0, 1, or 2;

13. The compound according to any one of claims 1 to 12, represented by the following structural formula: 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof, wherein n is 0, 1, or 2;

14. A compound represented by the following structural formula: 【Chemistry 14】 or a pharma- ceutical acceptable salt thereof, wherein Ar is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; Y １ and Y ２ are respectively CR ｃ or N, and 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 C.H. ２ C(=O), R ｃ is -H, halo, C １ -C ４ Alkyl, or C １ -C ４ is haloalkyl, n is 0 or an integer from 1 to 7; When n is other than 0, R １ is independently assigned to each occurrence of halo, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, or C １ -C ４ is an alkoxy; R ２ is independently for each occurrence -H, halo, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C １０ Cycloalkyl or C ３ -C １０ halocycloalkyl, or Or alternatively, two R ２ together with the carbon atom to which they are attached, C ３ -C １０ Forming a cycloalkyl, R ３ is -H or C １ -C ４ is alkyl, R ４ is -H, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl or C ３ -C ６ cycloalkyl, or Or alternatively, R ３ and R ４ taken together with their intervening atoms to form an optionally substituted 5- to 7-membered heterocyclyl, or a pharma- ceutically acceptable salt thereof.

15. 15. The compound of claim 14, represented by one of the following structural formulas: 【Chemistry 15】 or a pharma- ceutical acceptable salt thereof, wherein R １ is halo or C １ -C ４ or a pharma- ceutically acceptable salt thereof.

16. 16. The compound of claim 14 or claim 15, represented by the following structural formula: 【Chemistry 16】 or a pharma- ceutical acceptable salt thereof, wherein R １ is halo or C １ -C ４ or a pharma- ceutically acceptable salt thereof.

17. The compound according to any one of claims 14 to 16, represented by the following structural formula: 【Chemistry 17】 or a pharma- ceutical acceptable salt thereof, wherein R ２ is independently at each occurrence -H or C １ -C ４ alkyl, and n is 0 or an integer of 1 to 3, or a pharma- ceutically acceptable salt thereof.

18. The compound according to any one of claims 14 to 17, represented by the following structural formula: 【Chemistry 18】 or a pharma- ceutical acceptable salt thereof, wherein R ２ is independently at each occurrence -H or C １ -C ４ alkyl, and n is 0 or an integer of 1 to 3, or a pharma- ceutically acceptable salt thereof.

19. The compound according to any one of claims 14 to 18, represented by one of the following structural formulas: 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof, wherein n is 0, 1, or 2;

20. The compound according to any one of claims 14 to 19, represented by the following structural formula: 【Chemistry 20】 or a pharma- ceutically acceptable salt thereof, wherein n is 0, 1, or 2;

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

22. The compound of any one of claims 1 to 20, wherein Ar is an optionally substituted monocyclic heteroaryl containing one or more nitrogen atoms.

23. 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein Ar is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl.

24. 24. The compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein Ar is pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.

25. Ar is 【Chemistry 21】 25. The compound according to any one of claims 1 to 24, wherein:

26. Ar is 【Chemical 22】 26. The compound according to any one of claims 1 to 25, wherein:

27. Ar is 【Chemistry 23】 27. The compound according to any one of claims 1 to 26, wherein:

28. Ar is 【Chemistry 24】 28. The compound according to any one of claims 1 to 27, wherein:

29. Ar is optionally C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocyclyl, halo, -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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; Where: C of Ar １ -C ４ The alkyl group substituents are optionally -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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 , C ３ -C ６ Cycloalkyl (optionally, -CH ３ , halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH ３ , halomethyl, halo, methoxy and halomethoxy) or phenyl (optionally substituted with one or more groups selected from -CH ３ , halomethyl, halo, methoxy, and halomethoxy; C of Ar ３ -C ６ Cycloalkyl, C ３ -C ６ Substituents for the heterocyclyl, phenyl and monocyclic heteroaryl groups are optionally and independently selected from the group consisting of C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, halo, -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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 is replaced by Each R ｘ And each R ｙ are independently -H, C １ -C ４ Alkyl, or C ３ -C ８ cycloalkyl, wherein R ｘ Or R ｙ C represented by １ -C ４ Alkyl or C ３ -C ８ Cycloalkyl is optionally selected from halo, hydroxyl, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ６ Cycloalkyl and phenyl (optionally -CH ３ , halomethyl, halo, methoxy and halomethoxy; R ｚ is -H, C １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl, or C ３ -C ８ heterocyclyl, wherein R ｚ C represented by １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl, or C ３ -C ８ The heterocyclyl group is optionally selected from -CN, halo, hydroxyl, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ６ Cycloalkyl and phenyl (optionally -CH ３ , halomethyl, halo, methoxy and halomethoxy; 29. The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein i is 0, 1 or 2.

30. Ar is optionally C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocyclyl, halo, -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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; Where: C of Ar １ -C ４ The alkyl group substituents are optionally -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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 , C ３ -C ６ Cycloalkyl (optionally, -CH ３ , halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH ３ , halomethyl, halo, methoxy and halomethoxy) or phenyl (optionally substituted with one or more groups selected from -CH ３ , halomethyl, halo, methoxy, and halomethoxy; C of Ar ３ -C ６ Cycloalkyl, C ３ -C ６ Substituents for the heterocyclyl, phenyl and monocyclic heteroaryl groups are optionally and independently selected from the group consisting of C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, halo, -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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 is replaced by Each R ｘ And each R ｙ are independently -H, C １ -C ４ Alkyl, or C ３ -C ８ cycloalkyl, wherein R ｘ Or R ｙ C represented by １ -C ４ Alkyl or C ３ -C ８ Cycloalkyl is optionally selected from halo, hydroxyl, C ３ -C ６ Cycloalkyl and phenyl (optionally -CH ３ , halomethyl, halo, methoxy and halomethoxy; R ｚ is -H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ８ Cycloalkyl, or C ３ -C ８ heterocyclyl, wherein R ｚ C represented by １ -C ４ Alkyl or C ３ -C ８ The cycloalkyl group is optionally selected from the group consisting of -CN, halo, hydroxyl, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ６ Cycloalkyl and phenyl (optionally -CH ３ , halomethyl, halo, methoxy and halomethoxy; 30. The compound according to any one of claims 1 to 29, wherein i is 0, 1 or 2, or a pharma- ceutically acceptable salt thereof.

31. Ar is optionally substituted C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ 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 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, wherein the compound is substituted with one or more groups selected from the group consisting of aryl, phenyl, and optionally substituted monocyclic heteroaryl.

32. Ar is optionally C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ 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 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, wherein the compound is substituted with one or more groups selected from phenyl and optionally substituted monocyclic heteroaryl.

33. Ar is optionally C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocyclyl, halo, -CN, -OR ｚ , -NR ｘ R ｙ and -C(=O)R ｘ wherein the C of Ar is substituted with one or more groups selected from ３ -C ６ Cycloalkyl and C ３ -C ６ The heterocyclyl substituents are each optionally selected from halo, C １ - ４ Alkyl and C １－４ alkoxy; R ｘ and R ｙ are each independently -H, C １ -C ４ Alkyl or C ３ -C ６ cycloalkyl, wherein R ｘ and R ｙ C represented by １ -C ４ The alkyl group is optionally selected from halo and C １－４ alkoxy; R ｚ is H, C １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl or C ３ -C ６ heterocyclyl, wherein R ｚ C represented by １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl and C ３ -C ６ Heterocyclyl is optionally and independently selected from halo, -CN, C １ -C ４ Alkyl and C １ -C ４ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, substituted with one or more substituents independently selected from alkoxy.

34. Ar is optionally C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, halo, -CN, and -OR ｚ wherein R ｚ is C optionally substituted with one or more halo groups; １ -C ４ 34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

35. Ar is optionally -CH ３ , -CF ３ , -CHF ２ , -F, -Cl, -CN, -OCH ３ , -OCHF ２ , -OC ２ H ５ , -OCH ２ CF ３ , -O(CH ２ ) ２ (O) CH ３ , -OCH(CH ３ ) ２ , —O-(3-methoxycyclobutyl), —O-cyclobutyl, —O-cyclopentyl, 【Chemistry 25】 -COCH ３ , -N(H)CH ３ , -N(CH ３ ) C ２ H ５ , -N(H)cyclobutyl, -NHCH ２ CH ３ , -NHCH(CH ３ ) ２ , -N(CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ２ (O) CH ３ ), —OH, azetidinyl, 【Chemistry 26】 34. The compound according to any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, which is substituted with one or more groups selected from the group consisting of oxetanyl, pyrrolidinyl, morpholinyl, 4-methylpiperazinyl, and piperazinyl.

36. Ar is optionally -CH ３ , -CF ３ , -CHF ２ , -F, -Cl, -CN, -OCH ３ , -O(CH ２ ) ２ (O) CH ３ , and -OCHF ２ 36. The compound of any one of claims 1 to 35, or a pharma- ceutically acceptable salt thereof, substituted with one or more groups selected from:

37. Ar is optionally -CH ３ , -CF ３ , -CHF ２ , -F, -Cl, -CN, -OCH ３ , and -OCHF ２ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, substituted with one or more groups selected from:

38. The compound according to any one of claims 8 to 37, wherein n is 0.

39. 2. The compound of claim 1, represented by one of the following structural formulas: 【Chemical 27】 or a pharma- ceutical acceptable salt thereof, wherein Ar is 【Chemistry 28】 each of which is optionally １ -C ４ Alkyl, C １ -C ４ Haloalkyl, halo, -CN, and -OR ｚ one substituent R selected from Ａｒ is substituted with R ｚ is H, C １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl or C ３ -C ６ heterocyclyl, wherein R ｚ C represented by １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl and C ３ -C ６ Heterocyclyl is optionally and independently selected from halo, -CN, C １ -C ４ Alkyl and C １ -C ４ The compound or a pharma- ceutically acceptable salt thereof, wherein the compound is substituted with one or more substituents independently selected from alkoxy.

40. 40. The compound of claim 39, wherein Ar is represented by the formula: 【Chemical Formula 29】 。

41. R Ａｒ But, C １ -C ４ Alkyl or -OR ｚ and R ｚ is H or halo, -CN, C １ -C ４ Alkyl and C １ -C ４ C optionally substituted with 1 to 3 substituents independently selected from alkoxy １ -C ４ 40. The compound of claim 38 or 39, which is alkyl.

42. N-(4-fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetate Toamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl) Acetamide, N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazole -2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, 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, 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, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide, and N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide 2. The compound of claim 1 selected from:

43. 43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

44. A method for treating a subject suffering from 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 according to any one of claims 1 to 42, or an effective amount of a pharmaceutical composition according to claim 43.

45. 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's disease, corticobasal degeneration (CBP), martial dementia, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Sträussler-Scheiker disease, Guadeloupe-type parkinsonism, Hallervorden-Spatz disease (neurodegenerative disease with brain iron deposition 1 type), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontinigral 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 epicortical gliosis (progressive 45. The method of claim 44, wherein the disease is selected from acute myocardial infarction, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary senile dementia, Huntington's disease, and Parkinson's disease.

46. 46. ​​The method of any one of claims 44 and 45, wherein 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, epilepsy, ischemic stroke, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease.

47. The method of any one of claims 44 to 46, wherein the disease or condition is Alzheimer's disease.

48. 1. A method for inhibiting O-GlcNAcase in a subject in need of inhibition of O-GlcNAcase, comprising: The method comprises administering to the subject an effective amount of a compound according to any one of claims 1 to 42, or an effective amount of a pharmaceutical composition according to claim 43.

49. 44. A method for treating a disease or condition characterized by hyperphosphorylation of tau in the brain, comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 42, or an effective amount of a pharmaceutical composition according to claim 43.

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