EGFR mutant inhibitors

Abstract

The present disclosure provides compounds represented by structural formula (I): or a pharmaceutically acceptable salt thereof, useful for treating cancer. TIFF2023508976000316.tif4267

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 953,030, filed December 23, 2019. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002] EGFR (epidermal growth factor receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. Upon binding to its ligand, e.g., epidermal growth factor (EGF), EGFR can form homodimers in the cell membrane or heterodimers with other receptors in the family, e.g., erbB2, erbB3, or erbB4. The formation of these dimers can lead to phosphorylation of key tyrosine residues in EGFR cells, thereby activating many downstream signaling pathways in the cell. These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis. Disruptions to the EGFR signal transduction pathway, including increased ligand and receptor expression, EGFR gene amplification, and alterations, e.g., mutations, deletions, etc., can promote malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. For example, mutations, such as mutations and deletions in the EGFR gene, are found in non-small cell lung cancer (NSCLC) tumors. The two most common EGFR alterations found in NSCLC tumors are a short in-frame deletion in exon 19 (del19) and L858R, and a single missense mutation in exon 21 (Cancer Discovery 2016, Vol. 6 (No. 6), p. 601). These two alterations cause ligand-independent EGFR activation and are referred to as primary or activating mutations in EGFR gene mutation-positive (EGFR mutant) NSCLC (EGFR M+).Clinical experience has demonstrated objective response rates (ORR) of approximately 60-85% in patients with EGFR M+ NSCLC treated in the first line (1L) with the EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib (Lancet Oncol. 2010 Vol. 11, p. 121; Lancet Oncol. 2016 Vol. 17, p. 577; N. Engl. J. Med. 2017 Nov. 18 Doi:10.1056 / NEJMoa1713137; Lancet Oncol. 2011, Vol. 12, p. 735), thus demonstrating that EGFR mutation-positive NSCLC tumors depend on oncogenic EGFR activity for survival and proliferation, establishing del19 and L858R mutant EGFR as oncogenic drivers of the disease and thus validating drug targets and biomarkers for the treatment of NSCLC.

[0003] However, after a mean of 10–12 months of treatment with first-generation (erlotinib and gefitinib) and second-generation (afatinib) EGFR TKIs, resistance to these small molecule inhibitors has been observed in nearly all NSCLC patients (Lancet Oncol. 2010, February 11(2):121-8; Lancet Oncol. 2016, May 17(5):577-89; Lancet Oncol. 2011, August 12(8):735-42). The most prominent resistance mechanism to first- and second-generation EGFR TKIs is due to a secondary mutation in the EGFR T790M, which occurs in 50%–70% of patients who progress on first- and second-generation EGFR inhibitors (Blakely, 2012; Kobayashi, 2005). This secondary mutation reduces the affinity of the drug with the target, thereby creating drug resistance and leading to tumor recurrence or progression.

[0004] Considering the prevalence of this mutation in drug resistance resulting from EGFR-targeted therapy for lung cancer, many companies have attempted to develop new small molecule EGFR inhibitors to treat these patients with drug-resistant lung cancer by inhibiting the resistant mutation EGFR-T790M. For example, the third-generation EGFR TKI, osimertinib (Tagrisso®), has been developed to treat NSCLC patients whose cancer cells are positive for the primary EGFR mutation del19 or L858R with or without the T790M mutation in the gene encoding EGFR.

[0005] The third-generation EGFR TKI, osimertinib, has shown efficacy in patients with NSCLC. Unfortunately, resistance mediated by the exon 20 C797 mutation in EGFR typically develops within approximately 10 months (European Journal of Medicinal Chemistry 2017, Vol. 142:32-47) and accounts for the majority of osimertinib-resistant cases (Cancer Letters 2016, Vol. 385:51-54). The EGFR del19 / L858R T790M C797S cis-mutation kinase variant commonly emerges in second-line (2L) patients after treatment with osimertinib, referred to as "triple mutant" EGFR, which can no longer be inhibited by first-, second-, or third-generation EGFR inhibitors.

[0006] Approved EGFR TKIs cannot inhibit triple mutant variants. Therefore, there is a need to develop new EGFR inhibitors that can inhibit highly selective EGFR gene mutations with the triple mutation del19 / L858R T790M C797S while at the same time having no or low activity against wild-type EGFR. In addition to treating EGFR mutant forms for which no current treatments exist, such selective EGFR inhibitors are likely to be more suitable as therapeutic agents, particularly for the treatment of cancer, due to their reduced toxicology (diarrhea, rash) associated with wild-type EGFR inhibition. Summary of the Invention [Problem to be solved by the invention]

[0007] The present applicant has developed novel compounds that are effective inhibitors of several mutant forms of EGFR (see Synthesis Examples 1-43). In particular, compounds of the present disclosure have been demonstrated to effectively inhibit several mutant forms of EGFR. The compounds of the present disclosure (also referred to herein as "disclosed compounds") or pharmaceutically acceptable salts thereof effectively inhibit EGFRs with one or more alterations, including an L858R and / or exon 19 deletion mutation, a T790M mutation, and / or a C797S mutation. The compounds of the present disclosure or pharmaceutically acceptable salts thereof effectively inhibit EGFRs with an L858R and / or exon 19 deletion mutation, a T790M mutation, and a C797S mutation (hereinafter "EGFRs with LRTMCS mutations" or "triple mutant EGFRs") (see Biological Example 1) and can be used to treat a variety of diseases, such as lung cancer (see Biological Example 2). Importantly, the disclosed compounds are selective EGFR inhibitors, i.e., they have no or low activity against wild-type EGFR and the kinome. Advantages associated with such selectivity may include facilitating effective dosing and reducing EGFR-mediated target toxicity. Some of the disclosed compounds exhibit excellent penetration of the brain and blood-brain barrier (e.g., PGP efflux ratios of less than 5). Therefore, the disclosed compounds or pharmaceutically acceptable salts thereof are expected to be effective in treating metastatic cancer, including leptomeningeal disease and other systemic metastases, including brain metastases. Some of the disclosed compounds also have the advantage of high microsomal stability. The disclosed compounds may also have a favorable toxicity profile relative to other non-kinase targets. [Means for solving the problem]

[0008] In one aspect, the present disclosure provides a compound of the following structural formula (I):

[0009] [ka]

[0010] or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below. In other aspects, the present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof ("pharmaceutical compositions of the present disclosure").

[0011] The present disclosure provides a method for treating a subject with cancer, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In one embodiment, the cancer is non-small cell lung cancer. In another embodiment, the subject's cancer has metastasized to the brain. In another embodiment, the subject has brain metastasis from non-small cell lung cancer.

[0012] In one embodiment, the cancer to be treated has an epidermal growth factor receptor (EGFR) L858R mutation and / or an exon 19 deletion mutation and a T790M mutation. In another embodiment, the cancer to be treated may further have an epidermal growth factor receptor (EGFR) L858R mutation and / or an exon 19 deletion mutation, a T790M mutation, and a C797S mutation. In another embodiment, the cancer to be treated in any of the foregoing embodiments is lung cancer, e.g., non-small cell lung cancer. In a specific embodiment, the cancer is non-small cell lung cancer with brain metastasis.

[0013] The methods of treatment disclosed herein further comprise administering an effective amount of afatinib, osimertinib, erlotinib, or gefitinib. The present disclosure also provides a method of inhibiting epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0014] The present disclosure also provides the use of an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the preparation of a medicament for the treatment of cancer.

[0015] In another aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, for use in treating cancer. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition The term "halo," as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.

[0017] The term "alkyl," used alone or as part of a larger moiety, such as "alkoxy" or "haloalkyl," means a saturated aliphatic straight-chain or branched monovalent hydrocarbon group. Unless otherwise specified, an alkyl group generally has 1 to 4 carbon atoms, i.e., (C1-C4) alkyl. As used herein, a "(C1-C4) alkyl" group means a group having 1 to 4 carbon atoms in a straight-chain or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0018] The term "alkenyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced by double bonds. The term "alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0019] The term "aminoalkyl" refers to an alkyl group substituted by -NH2. The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.

[0020] The term "cycloalkyl" means a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, a cycloalkyl has 3 to 6 carbon atoms. For example, C 3~ C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless otherwise specified, "cycloalkyl" has from 3 to 6 carbon atoms.

[0021] The term "heterocyclyl" or "heterocyclic" refers to a 4- to 12-membered non-aromatic ring system having a carbon atom ring and one to four heteroatom rings, each heteroatom independently selected from nitrogen, tetravalent nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone ("4- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 4- to 10-membered non-aromatic ring system having a carbon atom ring and one to four heteroatom rings, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("4- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, depending on valence. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") systems; polycyclic ring systems include fused, bridged, or spiro ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can contain heteroatoms in one or more rings in the polycyclic ring system. Substituents (e.g., R 1 ) may be present in one or more rings in polycyclic ring systems.

[0022] Bridged bicyclic systems have two non-aromatic rings containing 7 to 12 ring atoms (heterocyclyl or cycloalkyl) that share three or more atoms, including two bridgehead atoms, separated by a bridge containing at least one atom. "Bridged heterocyclyl" includes bicyclic or polycyclic hydrocarbon or aza-bridged hydrocarbon groups; examples include 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, and 8-oxa-3-azabicyclo[3.2.1]octanyl.

[0023] Fused bicyclic ring systems have two non-aromatic rings (heterocyclyl or cycloalkyl) containing 7 to 12 ring atoms and sharing two adjacent ring atoms. Examples of fused bicyclic ring systems include hexahydro-1H-furo[3,4-b]pyrrolyl and hexahydro-1H-furo[3,4-c]pyrrolyl.

[0024] Spiro-bicyclic systems contain 7 to 12 ring atoms (heterocyclyl or cycloalkyl) and have two non-aromatic rings that share one ring atom. Examples of spiro-bicyclic systems include 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, and 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl. Compounds of the Disclosure Disclosed herein are embodiments of compounds having the general structure of formula (I). These compounds are selective inhibitors of LRTM and LRTMCS EGFR. Unlike other EGFR inhibitors, such as osimertinib, which irreversibly bind EGFR, the compounds of the present disclosure are non-covalent inhibitors.

[0025] In a first embodiment, the present disclosure provides a compound of the following structural formula (I):

[0026] [ka]

[0027] [In the formula, Z is O or NH; Each A 1 , A 2 , and A 3 is independently N or CR; each R is independently H, halogen, or CH; Ring A is a 4- to 10-membered heterocyclyl; Each R 1 are independently halogen, CN, OH, NR a R b, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or —O—C3-C6 cycloalkyl, and R 1 The alkyl, alkoxy or cycloalkyl represented by or R 1 In the group represented by the formula a R b , C1-C2 alkyl, and C1-C2 alkoxy; m is 0, 1, 2, 3, 4, 5, or 6; R 2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, and R 2 The alkyl, alkoxy or cycloalkyl represented by is optionally substituted with 1 to 3 groups selected from halogen and OH; R 3 is H or methyl; R 4 is H or methyl; R 5 is H, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered monocyclic heterocyclyl, and R 5 The alkyl, cycloalkyl or heterocyclyl represented by the formula (I) is selected from halogen, CN, OH, NR a R b , C1-C2 alkyl, and C1-C2 alkoxy; R 6 is H or halogen, CN, OH, NR a R b and C1-C2 alkoxy; Each R a and R b are independently H or C1-C4 alkyl. or a pharmaceutically acceptable salt thereof.

[0028] In an alternative first embodiment, the present disclosure provides a compound having the following structural formula (I):

[0029] [ka]

[0030] [In the formula, Z is O or NH; Each A 1 , A 2 , and A 3 is independently N or CR; each R is independently H, halogen, or CH; Ring A is a 4- to 10-membered heterocyclyl; Each R 1 are independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or —O—C3-C6 cycloalkyl, and R 1 The alkyl, alkoxy or cycloalkyl represented by or R 1 In the group represented by the formula a R b , C1-C2 alkyl, and C1-C2 alkoxy; m is 0, 1, 2, 3, 4, 5, or 6; R 2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, and R 2 The alkyl, alkoxy or cycloalkyl represented by the formula: a , and N.R. a R b optionally substituted with 1 to 3 groups selected from: R 3 is H or methyl; R 4 is H or methyl; R 5is H, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered monocyclic heterocyclyl, and R 5 The alkyl, cycloalkyl or heterocyclyl represented by the formula (I) is selected from halogen, CN, OH, NR a R b , C1-C2 alkyl, and C1-C2 alkoxy; R 6 is H or halogen, CN, OH, NR a R b and C1-C2 alkoxy; Each R a and R b are independently H or C1-C4 alkyl. or a pharmaceutically acceptable salt thereof.

[0031] In a second embodiment, the present disclosure provides a compound represented by structural formula (II-A), (II-B), (II-C), (II-D), or (II-E):

[0032] [ka]

[0033] wherein the variables are as defined in the first embodiment. or a pharmaceutically acceptable salt thereof. In a third embodiment, the present disclosure provides a compound represented by structural formula (II-A):

[0034] [ka]

[0035] wherein the variables are as defined in the first embodiment. or a pharmaceutically acceptable salt thereof. In a fourth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein Z is O, and the remainder of the variables are as described in the first embodiment.

[0036] In a fifth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluorine, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, and R 2 is optionally substituted with 1 to 3 groups selected from halogen and OH, and the remainder of the variables are as defined in the first or fourth embodiment. In an alternative fifth embodiment, R 2 is H, fluorine, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, and R 2 is optionally substituted with 1 to 3 groups selected from halogen, OH, and NH, and the remainder of the variables are as defined in the first or fourth embodiment.

[0037] In a sixth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein R 6 is H, methyl, ethyl, C1-C2 haloalkyl, or C1-C2 aminoalkyl, and the remainder of the variables are as defined in the first, fourth, or fifth embodiment.

[0038] In a seventh embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein R 5 is H; halogens, CN, and NR aR b C1-C4 alkyl optionally substituted with 1 to 3 of 3 groups selected from: C3-C6 cycloalkyl; or 4-6 membered monocyclic heterocyclyl optionally substituted with C1-C4 alkyl; R a and R b are each independently selected from H, methyl, and ethyl; and the remainder of the variables are as defined in the first, fourth, fifth, or sixth embodiment.

[0039] In an eighth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein the A ring is selected from the group consisting of 1 to 6 R 1 and the remainder of the variables are as defined in the first, fourth, fifth, sixth, or seventh embodiment.

[0040] In a ninth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein the A ring is selected from the group consisting of 1 to 6 R 1 and the remainder of the variables are as defined in the first, fourth, fifth, sixth or seventh embodiment.

[0041] In a tenth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, 4, or 5; 1 are independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, -O-C3-C6 cycloalkyl, and R 1 The alkyl, alkoxy, or cycloalkyl represented by or R 1 In the group represented by the formula aR b , C1-C2 alkyl, and C1-C2 alkoxy; and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0042] In an eleventh embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, methyl, ethyl, isopropyl, CH(CH3)CH2F, CH(CH3)CH2OH, CF3, OCH3, OCH2CH3, or cyclopropyl, and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In an alternative eleventh embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, methyl, ethyl, isopropyl, CH(CH3)CH2F, CH(CH3)CH2OH, CF3, OCH3, OCH2CH3, C(CH3)2NH2, or cyclopropyl, and the remainder of the variables are as defined in the first, fourth, fifth (or alternative fifth), sixth, seventh, eighth, ninth, or tenth embodiment.

[0043] In a twelfth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein R 6 is H, CH3, or CH2NH2, and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0044] In a thirteenth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein the A ring is selected from the group consisting of 1 to 6 R1 and the A ring is optionally substituted with pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, hexahydro-1H-furo[3,4-b]pyrrolyl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl or 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl, and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, tenth, eleventh, or twelfth embodiment.

[0045] In a fourteenth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein at least one R 1 is OH, C1-C4 alkoxy, or —O—C3-C6 cycloalkyl, and R 1 The alkoxy or cycloalkyl represented by or R 1 In the group represented by a R b , C1-C2 alkyl, and C1-C2 alkoxy, and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0046] In a fifteenth embodiment, there is provided a compound according to the present disclosure, structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein each R 1is independently F, CN, OH, NH, CH, CHCH, CHF, CH(OH)CH, CHOH, CHNH, CHCHNH, OCH, OCD, OCHCHOH, OCHCH(OH)CH, OCHC(OH)(CH), OCHCHOCH, OCHCHNH, OCHCHNHCH, OCHCHN(CH), -O-cyclopropyl, NHCH, N(CH), and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment. In certain embodiments, each R 1 is independently F, OH, Me, Et, OMe, OCD, or OCHCHOH. 1 are independently F, OH, Me, or OCD3.

[0047] In a sixteenth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof:

[0048] [ka]

[0049] teeth,

[0050] [ka]

[0051] and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0052] [ka]

[0053] teeth,

[0054] [ka]

[0055] is. In a seventeenth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or isopropyl, and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0056] In an eighteenth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceutically acceptable salt thereof, wherein the A ring comprises one to six R 1 piperidinyl optionally substituted with R 2 is H or isopropyl, and the remainder of the variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0057] In one embodiment, the compound of the present disclosure is any one of the compounds disclosed in the Examples and Table 1, or a pharmaceutically acceptable salt thereof. The term " pharmaceutically acceptable salt " refers to pharmaceutical salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without excessive toxicity, irritation, and allergic reactions, and with a reasonable benefit / risk ratio.Pharmaceutically acceptable salts are well known in the art.For example, S.M. Berge et al. describe pharmacologically acceptable salts in J.Pharm.Sci., 1977, vol. 66, pp. 1-19.

[0058] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with a pharmaceutically acceptable base. Suitable pharmaceutically acceptable addition salts of the compounds described herein include salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfuric acid, etc.) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, succinic acid, etc.). Compounds of the present teachings with an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with a pharmaceutically acceptable base. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts), and alkaline earth metal salts (e.g., magnesium salts and calcium salts).

[0059] Compounds with one or more asymmetric centers can exist in various stereoisomeric forms; that is, each asymmetric center can have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more asymmetric centers that are not identical and are not mirror images of each other.

[0060] When the stereochemical configuration of a chiral center in a compound having one or more chiral centers is indicated by its chemical name (e.g., when the configuration is indicated in the chemical name by "R" or "S") or structure (e.g., when the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% (except when the designation "rac" or "racemic" accompanies the structure or name, as explained in the next two paragraphs). The "enrichment of the indicated configuration relative to the opposite configuration" is a mole percent and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0061] The stereochemical configuration at a chiral center in a compound is indicated by the chemical name (e.g., when the configuration is indicated in the name by "R" or "S") or structure (e.g., when the configuration is indicated by a "wedge" bond), and a racemic mixture is intended when the designation "rac" or "racemic" accompanies the structure or is specified in the chemical name.

[0062] Where two stereoisomers are designated by their chemical names or structures and the chemical names or structures are connected by "and," a mixture of the two stereoisomers is intended. When two stereoisomers are depicted by their chemical names or structures and the names or structures are connected by "or", either one or the other of the two stereoisomers is intended, but not both.

[0063] When a disclosed compound having an asymmetric center is represented by a structure that does not indicate a configuration at the asymmetric center, the structure is meant to encompass compounds having the S configuration at the asymmetric center, compounds having the R configuration at the asymmetric center, or compounds having a mixture of R and S configurations at the asymmetric center. When a disclosed compound having an asymmetric center is represented by its chemical name that does not indicate a configuration at the asymmetric center, bearing "S" or "R," the name is meant to encompass compounds having the S configuration at the asymmetric center, compounds having the R configuration at the asymmetric center, or compounds having a mixture of R and S configurations at the asymmetric center.

[0064] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, as well as mixtures of diastereomers of the compounds disclosed herein.

[0065] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0066] "Peak 1" in the experimental section refers to a desired reaction product compound obtained from chromatographic separation / purification that elutes earlier than a second desired reaction product compound obtained from the same aforementioned reaction, which second desired product compound is referred to as "Peak 2."

[0067] When a disclosed compound is designated by a name or structure that represents a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or designated enantiomers divided by the total weight of the mixture of both enantiomers.

[0068] When the stereochemistry of a disclosed compound is named or depicted by structure, and when the named or depicted structure encompasses more than one stereoisomer (e.g., in the case of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or a mixture of any of the encompassed stereoisomers is included unless otherwise indicated. 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.

[0069] In the compounds of the present disclosure, any position specifically designated as "D" or "deuterium" is understood to have a deuterium enrichment of 50, 80, 90, 95, 98, or 99%. "Deuterium enrichment" is a mole percent and is determined by dividing the number of compounds having deuterium at the indicated position by the total number of all compounds. If a position is designated as "H" or "hydrogen," then that position has hydrogen at its natural abundance. If a position is unchanged with respect to whether hydrogen or deuterium is present, then the position has hydrogen at its natural abundance. Certain alternative embodiments are directed to compounds of the present disclosure that have a deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98, or 99% at one or more positions not specifically designated as "D" or "deuterium."

[0070] As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl, or heterocyclyl) are referred to as "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise indicated, it indicates that any portion of that moiety known to those of skill in the art as being available for substitution can be substituted, including one or more substituents. When two or more substituents are present, then each substituent can be independently selected. Such means for substitution are well known in the art and / or taught by this disclosure. An optional substituent can be any substituent suitable for binding to that moiety.

[0071] The compounds of the present disclosure are selective EGFR inhibitors. As used herein, the term "selective EGFR inhibitor" refers to a compound that selectively inhibits a specific mutant EGFR kinase relative to wild-type EGFR and kinome. Alternatively, the selective EGFR inhibitor has no or low activity against wild-type EGFR and kinome. Compared with its inhibitory activity against wild-type EGFR and many other kinases, the inhibitory activity of a selective EGFR inhibitor against a specific mutant EGFR kinase is higher than IC 50 is more powerful in terms of value (i.e., IC 50 (Values ​​are subnanomolar.) Potency can be measured using known biochemical assays.

[0072] Some compounds of the present disclosure have the advantage of excellent brain penetration. The ability of a particular compound to cross the BBB and penetrate the brain can be assessed using various known methods or a combination of such methods. One in vitro method frequently used to predict a compound's in vivo brain penetration is the P-gp efflux ratio. P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) ​​and limits the penetration of its substrates into the central nervous system (CNS). Compounds that are found to be good P-gp substrates in vitro (i.e., have a high efflux ratio) are predicted to have poor in vivo brain penetration. To measure the P-gp efflux ratio, the apparent apical-to-basolateral permeability (Papp[AB]) and apparent basolateral-to-apical permeability (Papp[BA]) of Madin-Darby canine kidney cells (MDCK-MDR1 cells) overexpressing P-gp for the compound are determined. The P-gp efflux ratio is a measure of the ratio Papp[BA] / Papp[AB]. In some embodiments, compounds of the present disclosure have a P-gp efflux ratio of less than 2, less than 3, less than 4, or less than 5.

[0073] Some compounds of the present disclosure have the advantage of excellent metabolic stability. One indicator of excellent metabolic stability is high microsomal stability. Hepatic metabolism is the main route of elimination for small molecule drugs. Clearance of a compound by hepatic metabolism can be evaluated in vitro using human liver microsomes (HLMs) or human hepatocytes. Compounds are incubated with HLMs plus appropriate cofactors or human hepatocytes, and compound depletion is measured to determine the in vitro intrinsic clearance (Cl). Cl is scaled to the total body clearance (CL), and the hepatic extraction ratio (ER) is determined by dividing the CL by the standard human hepatic blood flow. Compounds with low hepatic extraction ratios are considered to have excellent metabolic stability. In some embodiments, compounds of the present disclosure have a calculated ER of <0.3, <0.4, <0.5, or <0.6. Pharmaceutical Composition Pharmaceutical compositions of the present disclosure (also referred to herein as "disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carriers or diluents and a compound of the present disclosure (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof.

[0074] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the administration and / or absorption of a formulation and / or active agent to a subject and can be included in the pharmaceutical compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (e.g., Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose or starch, hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidone, coloring agents, and the like. Such preparations can be sterilized and, if desired, can be mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents, which do not deleteriously react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds or pharmaceutically acceptable salts thereof.

[0075] The pharmaceutical compositions of the present disclosure may optionally contain one or more pharmaceutically acceptable carriers and / or diluents, such as lactose, starch, cellulose, and glucose. 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., 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 the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th ed.) and the United States Pharmacopeia: National Formulary (USP 24 NF19), published in 1999. A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not harmful to the recipient thereof. Treatment methods The present disclosure provides a method for inhibiting certain mutant forms of epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. Mutant forms of EGFR include, for example, EGFR with LRTMCS mutations (exon 19 deletion (del19) or exon 21 (L858R) substitution mutation, T790M mutation, and C797S mutation). A subject "in need of inhibiting EGFR" is one who has a disease in which a beneficial therapeutic effect can be achieved by inhibiting at least one mutant EGFR, for example, slowing progression, alleviating one or more symptoms associated with the disease, or increasing the subject's longevity in light of the disease.

[0076] In some embodiments, the present disclosure provides a method of treating a disease / condition / or cancer associated with or modified by mutant EGFR, where inhibition of mutant EGFR is therapeutically effective, including but not limited to, treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0077] In another embodiment, the present disclosure provides a method for treating a subject with cancer, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.Cancers that can be treated according to the disclosed method include lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, including metastases (particularly brain metastases) of all of the indicated cancers.Generally, the cancer is characterized by one or more EGFR mutations described herein.In certain embodiments, the cancer progresses during or after EGFR tyrosine kinase inhibitor (TKI) therapy.In certain embodiments, the disease progresses during or after first-line osimertinib administration.

[0078] In certain embodiments, the cancer to be treated is lung cancer. In further particular embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology. In another embodiment, the lung cancer is NSCLC adenocarcinoma. In another particular embodiment, the lung cancer (or non-small cell lung cancer) has metastasized to the brain. In another embodiment, the genotypes are selected from the group consisting of genotypes 1 to 17 according to the following table (del18 = exon 18 deletion, in particular, for example, del E709_T710 insD; del19 = exon 19 deletion, in particular, for example, delE746_A750 (most common), delE746_S752insV, del747_A750insP, delL747_P753insS, and delS752_I759; del20ins - Diseases / conditions / or cancers associated with or modified by mutant EGFR characterized by an exon 20 insertion, in particular an EGFR genotype selected from, for example, D761-E762insX, A763-Y764insX, Y764-V765insX, V765-M766insX, A767-S768insX, S768-D769insX, V769-D770insX, N771-P772insX, P772-H773insX, H773-V774insX, and V774-C775insX):

[0079] [Table 1-1]

[0080] [Table 1-2]

[0081] [Table 1-3]

[0082] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR, including EGFR del19.

[0083] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 T790M.

[0084] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del19 C797S.

[0085] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del19 C797X (C797G or C797N).

[0086] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 T790M C797S.

[0087] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 T790M (C797G or C797N).

[0088] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792X (L792F, L792H, or L792Y).

[0089] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 T790M L792X (L792F, L792H, or L792Y).

[0090] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 G796R (G796S).

[0091] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792R (L792V or L792P).

[0092] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del19 L718Q (L718V).

[0093] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is characterized by EGFR comprising EGFR del19 T790M G796R (G796S).

[0094] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is characterized by EGFR comprising EGFR del19 T790M L792R (L792V or L792P).

[0095] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is characterized by EGFR comprising EGFR del19 T790M L718Q (L718V).

[0096] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R.

[0097] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790M.

[0098] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R C797S.

[0099] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R C797X (797G or C797N).

[0100] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790M C797S.

[0101] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R T790M C797X (797G or C797N).

[0102] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R L792X (L792F, L792H, or L792Y).

[0103] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R L790M L792X (L792F, L792H, or L792Y).

[0104] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R G796R (G796S).

[0105] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R L792R (L792V or L792P).

[0106] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R L718Q (L718V).

[0107] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790M G796R (G796S).

[0108] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R T790M L792R (L792V or L792P).

[0109] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790M L718Q (L718V).

[0110] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR, including EGFR del18.

[0111] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719R, G719D, or G719V).

[0112] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR E709X (E709K, E709H, or E709A).

[0113] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing EGFR E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).

[0114] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.

[0115] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing EGFR ex20ins.

[0116] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing the EGFR ex20ins L718Q.

[0117] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing the EGFR ex20ins T790M.

[0118] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing the EGFR exon C797S.

[0119] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR, including EGFR S7681I.

[0120] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR, including EGFR T790M.

[0121] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR T790M C797S / G L792X (L792F, L792H, L792R, or L792Y).

[0122] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR genotype selected from genotypes 1-17.

[0123] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib.

[0124] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to afatinib.

[0125] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to dacomitinib.

[0126] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to gefitinib.

[0127] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to erlotinib.

[0128] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and afatinib.

[0129] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and dacomitinib.

[0130] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and gefitinib.

[0131] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and erlotinib.

[0132] Another embodiment is the treatment of subjects with metastatic NSCLC whose tumors harbor an activating exon 19 deletion or an L858R EGFR mutation as detected by approved molecular testing methodologies and a resistance mutation disclosed herein. Another embodiment is the disclosed compounds in combination with a first or third generation TKI indicated for the treatment of subjects with metastatic NSCLC whose tumors harbor T790M and C797S mutations as detected by an approved test, whose disease has progressed on or after at least two EGFR TKI therapies.

[0133] Another embodiment is a disclosed compound for the treatment of a subject with metastatic NSCLC, where the disease has progressed during or after any EGFR TKI with on-target EGFR resistance. In certain embodiments, the disclosed compound is used in combination with a first- or third-generation TKI indicated for the treatment of a subject with metastatic NSCLC.

[0134] Another embodiment is a disclosed compound for the treatment of a subject with metastatic EGFR C797S mutation-positive NSCLC, as detected by an approved molecular test, where the disease has progressed during or after first-line osimertinib treatment. In certain embodiments, the disclosed compound is used in combination with a first- or third-generation TKI indicated for the treatment of subjects with metastatic NSCLC.

[0135] In particular embodiments, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test. One skilled in the art can readily determine whether a subject has a particular EGFR alteration in their cells, cancer, gene, or gene product, for example, whether the subject has one or more of the mutations or deletions described herein, using detection methods known in the art, for example, selected from hybridization-based methods, amplification-based methods, microarray analysis, flow cytometry analysis, DNA sequencing, next-generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot, and Southern blot.

[0136] To detect one or more EGFR deletions and / or mutations, primary tumor samples, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and / or circulating exosomes can be collected from a subject. The samples are processed, and nucleic acids are isolated using techniques known in the art. The nucleic acids are then sequenced using methods known in the art. The sequences are then mapped to individual exons, and a measure of transcriptional expression (e.g., RPKM, or reads per kilobase per million mapped reads) is quantified. Raw sequence and exon array data are available from sources such as TCGA, ICGC, and NCBI Gene Expression Omnibus (GEO). For a given sample, individual exon coordinates are annotated with gene identifier information, and exons belonging to the kinase domain are flagged. The exon levels are then z-scored normalized across all tumor samples.

[0137] The compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein can be used to treat subjects who have become resistant to treatment with one or more other EGFR inhibitors. "Resistant" means that the subject's cancer previously responded to the drug, but subsequently shows little or no response. In some embodiments, the subject becomes resistant to one or more first-generation EGFR inhibitors, such as erlotinib, gefitinib, icotinib, or lapatinib. In some embodiments, the subject becomes resistant to treatment with one or more second-generation EGFR inhibitors, such as afatinib, dacomitinib, poziotinib, or neratinib. In some embodiments, the subject becomes resistant to treatment with one or more first-generation inhibitors and one or more second-generation inhibitors. In some embodiments, the subject becomes resistant to treatment with one or more third-generation inhibitors, such as osimertinib, nazartinib, or avitinib. In one embodiment, the subject becomes resistant to treatment with one or more first-generation EGFR inhibitors and one or more third-generation EGFR inhibitors. In some embodiments, the subject becomes resistant to treatment with one or more second-generation EGFR inhibitors and one or more third-generation EGFR inhibitors. In some embodiments, the subject becomes resistant to treatment with one or more first-generation inhibitors and one or more third-generation EGFR inhibitors. combination The compounds of the present disclosure, their pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein can be used in combination with one or more additional pharmacologically active substances.For example, the present disclosure can be used in combination with EGFR (or EGFR gene mutation) inhibitors, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST2818), almonertinib (HS10296), BBT-176, BI-4020, CH7233163, glytel. gilitertinib, JND-3229, lazertinib, nazartinib (EGF816), PCC-0208027, rezivertinib (BPI-7711), TQB3804, zorifertinib (AZ-3759), or DZD9008; EGFR antibodies, e.g., cetuximab, panitumumab, necitabine, or a bispecific EGFR and MET antibody (e.g., amivantamab ((JNJ-61186372, JNJ-372)). Treatment of cancer with a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein in combination with a first-line therapy, e.g., in the case of NSCLC, for example, a first, second, or third generation EGFR inhibitor (i.e., as an initial treatment before the cancer becomes resistant), can prevent or delay the development of resistance. Generally, the cancer is characterized by one of the EGFR genotypes described herein.

[0138] Alternatively, the compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein may be used in combination with other anti-cancer agents that are not EGFR inhibitors, such as MEK inhibitors, including mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET inhibitors, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib, glumetinib, tepotinib), and MET antibodies (emibetuzumab, telisotuzumab vedotinib). vedotin (ABBV339); mitotic phase kinase inhibitors (CDK4 / 6 inhibitors, e.g., palbociclib, ribociclib, abemaciclib, GIT38); angiogenesis inhibitors, e.g., bevacizumab, nintedanib; apoptosis inducers, e.g., Bcl-2 inhibitors, e.g., venetoclax, obatoclax, navitoclax, palcitoclax (APG-1252), and Mcl-1 inhibitors, e.g., AZD-5991, AMG-176, S-64315; mTOR inhibitors, e.g., rapamycin, temsirolimus, everolimus, ridaforolimus; RET inhibitors such as pralsetinib and selpercatinib, and PI3K inhibitors, dactolisib (BEZ235), pictilisib (GDC-0941), LY294002, idelalisib (CAL-101); JAK inhibitors (e.g., AZD4205, itacitinib), Aurora A inhibitors (e.g., alisertib); BCR / ABL and / or Src family tyrosine kinase inhibitors (e.g., dasatinib); VEGF inhibitors (e.g., MP0250; ramucirumab); multikinase protein inhibitors (e.g., anlotinib, midostaurin); PARP inhibitors (e.g., niraparib); platinum therapy (e.g., cisplatin (CDDP), carboplatin (CBDCA), or nedaplatin (CDGP)); PD-L1 inhibitors (e.g., durvalumab (MEDI4736)); HER2 / neu receptor inhibitors (e.g., trastuzumab);It can be administered in combination with anti-HER2 or anti-HER3 antibody-drug conjugates (e.g., patritumab deruxtecan (U3-1402), trastuzumab emtansine); or immunogenetic therapy (e.g., oncoprex);

[0139] A "subject" is a human in need of treatment. Method of administration and dosage form The exact amount of compound administered to provide an "effective amount" to a subject depends on the mode of administration, the type and severity of the cancer, and the subject's characteristics, such as general health, age, sex, weight, and tolerance to drugs. Those skilled in the art can determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with an anti-cancer agent, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Appropriate dosages are known for approved therapeutic agents and can be adjusted by those skilled in the art according to the subject's condition, the type of condition being treated, and the amount of compound of formula (I) being used, for example, by following dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).

[0140] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of the disease, condition, or cancer; ameliorating or improving clinical symptoms or indicators associated with the disease, condition, or cancer; delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or cancer; or reducing the likelihood of recurrence of the disease, condition, or cancer.

[0141] The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical outcomes, e.g., an amount that suppresses, inhibits, or reduces the symptoms of the condition being treated in the subject compared to the control. For example, a therapeutically effective amount can be administered in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day; or alternatively, 10 mg to 1 gram per day).

[0142] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver a composition to a desired biologically active site. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used in the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, latest edition; Pergamon; and Remington's, Pharmaceutical Sciences (latest edition), Mack Publishing Co., Easton, Pa.

[0143] Furthermore, a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure can be co-administered with another therapeutic agent. As used herein, the terms "co-administered," "administered in combination with," and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, one or more compounds of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure are co-administered with another agent. These terms encompass the administration of two or more agents to a subject such that the agents and / or their metabolites are present in the subject at the same time. These include simultaneous administration in the form of separate compositions, administration at different times in the form of separate compositions, and / or administration in the form of a composition in which both agents are present. Thus, in some embodiments, a compound described herein and another agent are administered in the form of a single composition. In some embodiments, a compound described herein and another agent are mixed in a composition.

[0144] The specific mode of administration and dosage regimen will be selected by the attending clinician, taking into account the characteristics of the case (e.g., subject, disease, involved pathology, specific treatment). Treatment may require daily or multiple daily or less-than-daily (e.g., weekly or monthly) doses over a period of several days to several months, or even years. However, those skilled in the art will readily recognize appropriate and / or equivalent doses, based on the dosages of approved compositions for treating diseases using EGFR inhibitors disclosed for guidance.

[0145] As will be understood by those skilled in the art, the compound of the present disclosure or its pharmaceutically acceptable salt can be administered to patients in various forms depending on the selected route of administration.The compound of the present teachings can be administered, for example, orally, parenterally, buccal, sublingually, nasally, rectally, by patch, pump or transdermal administration and the pharmaceutical composition formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal and topical administration modes.Parenteral administration can be by continuous infusion over a selected period of time.

[0146] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration.In one embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0147] Generally, for oral therapeutic administration, the compounds of the present disclosure or pharmaceutically acceptable salts thereof may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0148] Generally, for parenteral administration, the solution of the compound of the present disclosure or its pharmaceutically acceptable salt can be prepared in water, generally mixed with surfactant such as hydroxypropylcellulose.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, DMSO and their mixtures, with or without alcohol, and in oil.Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0149] Generally, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the compounds of the present disclosure for extemporaneous preparation of sterile injectable solutions or dispersions are suitable. The following examples are intended to be illustrative and not to limit the scope of the disclosure in any way. [Example]

[0150] Preparation of Representative Compounds definition TsOH 4-methylbenzenesulfonic acid TEA Triethylamine THF tetrahydrofuran MsCl methanesulfonyl chloride DCM dichloromethane NH4Cl Ammonium chloride MgSO4 Magnesium Sulfate NaN3 Sodium Azide DMF Dimethylformamide EA Ethyl acetate Na2SO4 Sodium Sulfate MeOH Methanol N2 nitrogen H2 Hydrogen LiAlH4 Lithium Aluminum Hydride NaHCO3 Sodium Bicarbonate CbzCl benzyl carbonochloridate PE Petroleum Ether DAST N-ethyl-N-(trifluoro-sulfanyl)ethanamine HCl Hydrochloric acid ACN Acetonitrile DIPEA Diisopropylethylamine DMSO dimethyl sulfoxide DMA Dimethylacetamide h time HPLC High Performance Liquid Chromatography min C Celsius I C 50 50% inhibitory concentration IPA Isopropyl Alcohol MTBE Methyl tert-butyl ether rt room temperature TFA trifluoroacetic acid The method for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by a person skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a person skilled in the art can select a solvent suitable for a particular reaction step.

[0151] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups.The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art.The chemical properties of protecting groups are described, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons: New Jersey (2014), which is incorporated herein by reference in its entirety.

[0152] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Analytical equipment and methods for compound characterization are as follows: LC-MS: Liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were obtained using an Agilent Model 1260 LC system equipped with an Agilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0 × 50 mm dimensions) reverse-phase column at 22.4 °C, using an Agilent 6120 mass spectrometer employing ES-API ionization. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic over the course of 4 minutes was used. The flow rate was constant at 1 mL / min.

[0153] Alternatively, liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were obtained using a Shimazu LCMS system equipped with an Agilent (Poroshel HPH-C18, 2.7 μm particle size, 3.0 × 50 mm dimensions) reverse-phase column at 22.4 °C, using a Shimazu LCMS mass spectrometer with electrospray ionization. The mobile phase consisted of a solvent mixture of 5 mM NH4HCO3 in water (or 0.05% TFA) and acetonitrile. A constant gradient of 90% aqueous / 10% organic to 5% aqueous / 95% organic over the course of 2 minutes was used. The flow rate was constant at 1.5 mL / min.

[0154] Preparative LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP® preparative system equipped with a Luna 5u C18(2) 100A, AXIA pack, 250 x 21.2 mm reverse-phase column at 22.4 °C. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant mobile phase gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic over the course of 25 minutes was used. The flow rate was constant at 20 mL / min. Reactions performed in a microwave were performed in a Biotage Initiator microwave instrument.

[0155] Alternatively, preparative HPLC was performed on a Waters preparative system equipped with an XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm. The mobile phase consisted of a solvent mixture of water (10 mmol / L NH4HCO3 + 0.05% NH3·H2O) and acetonitrile. A constant mobile phase gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic over the course of 11 minutes was used. The flow rate was constant at 60 mL / min. Reactions performed in a microwave were performed in a Biotage Initiator microwave instrument.

[0156] Silica gel chromatography: Silica gel chromatography was performed on a Teledyne Isco CombiFlash® Rf instrument, a Biotage® Isolera Four instrument or a Biotage® Isolera Prime instrument.

[0157] Proton NMR: 1 H NMR spectra were obtained using a Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds (1 second delay time); scans from 16 to 64) or an Avance 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 5.45 seconds (1 second delay time); scans from 4 to 64). Unless otherwise indicated, all protons are reported as parts per million (ppm) relative to residual DMSO (2.50 ppm) in DOMSO-d6 solvent.

[0158] SFC: Waters preparative system. Chiral HPLC was performed on an Agilent 1260 preparative system. Those skilled in the art will understand that variations in concentration gradient, column length and flow rate are possible and that some conditions may be more suitable for compound characterization than others, depending on the chemical species being analyzed. General synthetic scheme:

[0159] [ka]

[0160] In certain embodiments, an optionally substituted bicyclic heteroaromatic compound A1 (where X=C or N, and R=H, halo, optionally substituted alkyl, or -O-alkyl) is reacted with an optionally substituted azetidine 1 (where R=H, alkyl, and R=optionally substituted methyl sulfone or sulfinimide) using standard Buchwald coupling conditions to give the optionally substituted condensation product B1. The resulting species is further homologated by a second Buchwald coupling with an optionally substituted pyrimidine or triazine (where Y=C, N, O, n=0, 1, 2, and each or both of R3 and R4 is H, halo, optionally substituted alkyl, O-alkyl, or N-alkyl) to give the final product C1. Synthesis Examples Example A1: Synthesis of 3-(ethylsulfonylmethyl)azetidine trifluoroacetate

[0161] [ka]

[0162] Step I: Synthesis of tert-butyl 3-(ethylthiomethyl)azetidine-1-carboxylate: tert-Butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol, 1 equivalent) and (ethylsulfanyl)sodium (1.12 g, 13.4 mmol, 2 equivalents) were dissolved in a mixed solvent (CHCN / HO = 3:1, 20 mL). The resulting solution was stirred at 60 °C for 18 hours. The resulting solution was concentrated in vacuo. The residue was purified by chromatography using DCM / MeOH (30 / 1). This afforded 1.4 g (90%) of the title compound as an off-white solid.

[0163] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56]. Step 2: Synthesis of tert-butyl 3-(ethylsulfonylmethyl)azetidine-1-carboxylate: tert-Butyl 3-[(ethylsulfanyl)methyl]azetidine-1-carboxylate (1.4 g, 6.05 mmol, 1 equiv.) was dissolved in a mixed solvent (THF:EtOH = 1:1, 10 mL), and then pentapotassium sulfate diperoxymonosulfate hydrogen sulfate (Oxone, 11.1 g, 18.1 mmol, 3 equiv.) in 0.5 mL of water was added. The resulting solution was stirred at 0 °C for 10 minutes and then at room temperature for 2 hours. The resulting solution was concentrated in vacuo and purified by chromatography using DCM / MeOH (20:1) to give 1.3 g (81%) of the title compound as a white solid.

[0164] Analytical data: LC-MS: (ES, m / z) = 286 [M+23]. Step 3: Synthesis of 3-(ethylsulfonylmethyl)azetidine trifluoroacetate: Trifluoroacetic acid (3.36 g, 29.5 mmol) was added to a solution of tert-butyl 3-[(ethanesulfonyl)methyl]azetidine-1-carboxylate (1.3 g, 4.93 mmol) in DCM (8 mL). The resulting solution was stirred at room temperature for 3 hours. The resulting solution was concentrated in vacuo, and the residue was washed with methyl tert-butyl ether to give 800 mg of the title compound as a white solid.

[0165] Analytical data: LC-MS: (ES, m / z) = 164 [M+1]. Example A2: Synthesis of 3-(isopropylsulfonylmethyl)azetidine

[0166] [ka]

[0167] Step I: Synthesis of tert-butyl 3-(isopropylthiomethyl)azetidine-1-carboxylate: tert-Butyl 3-(iodomethyl)azetidine-1-carboxylate (200 mg, 673 μmol, 1 equiv.) and (propan-2-ylsulfanyl)sodium (66.0 mg, 673 μmol, 1 equiv.) were dissolved in ACN (3 mL). The resulting solution was stirred at 80° C. for 16 hours. The resulting solution was extracted with DCM, and the organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded 150 mg (90%) of the title compound.

[0168] Step 2: Synthesis of tert-butyl 3-(isopropylsulfonylmethyl)azetidine-1-carboxylate: tert-Butyl 3-[(propan-2-ylsulfanyl)methyl]azetidine-1-carboxylate (140 mg, 570 μmol, 1 equiv.) and pentapotassium sulfate diperoxymonosulfate hydrogen sulfate (525 mg, 855 μmol, 1.50 equiv.) were dissolved in a mixture (THF:EtOH:HO=1:1:1; 1 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched by adding sodium sulfite solution to the resulting solution, followed by extraction with EA. The organic layers were combined and concentrated in vacuo. This afforded the title compound (130 mg, 82%) as an off-white solid.

[0169] Analytical data: LC-MS: (ES, m / z) = 300 [M+23]. Step 3: Synthesis of 3-(isopropylsulfonylmethyl)azetidine trifluoroacetate: In an 8 mL tube, tert-butyl 3-[(propane-2-sulfonyl)methyl]azetidine-1-carboxylate (120 mg, 432 μmol) was placed in DCM (4 mL) / TFA (1 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo. This afforded 70 mg of the title compound as a white solid.

[0170] Analytical data: LC-MS: (ES, m / z) = 178 [M+1]. Example A3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidine

[0171] [ka]

[0172] Step 1: Synthesis of benzyl 3-((trifluoromethylthio)methyl)azetidine-1-carboxylate: A mixture of benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (100 mg, 0.450 mmol, 1 equiv.), AgSCF (420 mg, 1.8 mmol, 4.00 equiv.), and nBuNI (1725 mg, 5.4 mmol, 12 equiv.) in toluene (8 mL) was stirred at 80° C. for 12 h. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column with EA / PE (3:1). This gave 50 mg (36.4%) of the title compound as a pale yellow solid.

[0173] Analytical data: LC-MS: (ES, m / z=306 [M+1]. Step 2: Synthesis of benzyl 3-((trifluoromethylsulfonyl)methyl)azetidine-1-carboxylate: Oxone (330.5 mg, 1.97 mmol, 3 equiv.) was added to a solution of benzyl 3-[[(trifluoromethyl)sulfanyl]methyl]azetidine-1-carboxylate (200 mg, 0.66 mmol, 1 equiv.) in THF (1 mL) / EtOH (1 mL) / HO (1 mL). The resulting solution was stirred at 60 °C for 2 h. The reaction was then quenched by the addition of NaSO (1 mL) and extracted with EA (3 × 5 mL). The residue was applied onto a silica gel column with EA / PE (3:1). This gave 120 mg (54.5%) of the title compound as a pale yellow oil.

[0174] Analytical data: LC-MS: (ES, m / z) = 338 [M+1]. Step 3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidine hydrobromide: Benzyl 3-(trifluoromethanesulfonylmethyl)azetidine-1-carboxylate (50 mg, 0.148 mmol, 1 equiv.) was added to ethanecarboperoxoyl bromide (30% in AcOH, 1 mL). The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated to give 20 mg (66.4%) of 3-(trifluoromethanesulfonylmethyl)azetidine hydrobromide as a pale yellow solid. The crude product was used directly in the next step without further purification.

[0175] Analytical data: LC-MS: (ES, m / z): = 204 [M+1]. Example A4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0176] [ka]

[0177] Step 1: Synthesis of (2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate: (2R,3S)-1-Benzhydryl-2-methylazetidin-3-ol (Pharmablock, 20 g, 78.9 mmol) was dissolved in DCM (300 mL), TEA (9.55 g, 94.6 mmol) was added, and the reaction mixture was cooled in an ice bath. Mesyl chloride (9.93 g, 86.7 mmol) was added dropwise and stirred while slowly warming to room temperature and stirring overnight. The mixture was diluted with DCM, washed with water, and the organic phase was dried over sodium sulfate, filtered, and evaporated to give 26 g (98%) of the title compound as a viscous yellow oil.

[0178] Analytical data: LC-MS: (ES, m / z) = 332 [M+1]. Step 2: Synthesis of (S)-methyl 2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate: (2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (26 g, 78.4 mmol) and methyl 2-(methylsulfonyl)acetate (15.3 g, 101 mmol) were dissolved in DMF (260 mL), followed by the addition of NaH (3.75 g of a 60% dispersion in mineral oil, 6.63 mmol) and stirring for approximately 15 minutes until hydrogen evolution ceased. The reaction mixture was heated to 80° C. overnight. The reaction was cooled and then diluted with approximately 200 mL of water and extracted with EA. The combined organics were washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give the crude product. The residue was purified by chromatography (0 to 7% MeOH / DCM). Pure fractions were combined and evaporated to give 24 g (80%) of the title compound as a pale yellow foam.

[0179] Step 3: Synthesis of (2R,3S)-1-benzhydryl-2-methyl-3-(methylsulfonylmethyl)azetidine: (S)-Methyl-2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (24 g, 61.9 mmol) was dissolved in DMA (240 mL), lithium chloride (20.9 g, 495 mmol) was added, and the flask was placed in a preheated block maintained at 150 °C. LC / MS showed the starting material was consumed after 1.5 h. Cooled to room temperature, diluted with water, extracted with EA, and the combined organics were washed with water, brine, and dried over sodium sulfate. Filtration and evaporation gave the crude product, which was further purified by chromatography (0 to 5% MeOH / DCM). Pure fractions were combined and evaporated to give 19 g (93%) of the title compound as a pale yellow foam.

[0180] Analytical data: LC-MS: (ES, m / z) = 330 [M+1]. Step 4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine: To a solution of (2R,3S)-1-(diphenylmethyl)-3-(methanesulfonylmethyl)-2-methylazetidine (19 g, 57.3 mmol) in MeOH (270 mL) was added TFA (9 mL) and Pd(OH) (5.7 g), and the reaction was stirred at room temperature under an atmosphere of H. The reaction mixture was filtered and evaporated to give the crude title compound (17 g) as a light brown oil.

[0181] Analytical data: LC-MS: (ES, m / z) = 164 [M+1]. Example A5: Synthesis of 3-methyl-3-(methylsulfonylmethyl)azetidine

[0182] [ka]

[0183] Step I: Synthesis of tert-butyl 3-methyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate: Methanesulfonyl chloride (255 mg, 2.23 mmol) was added dropwise to TEA (301 mg, 2.98 mmol) and tert-butyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate (300 mg, 1.49 mmol) in DCM at 0° C. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM and washed with brine. The organic layer was dried and concentrated in vacuo to give 350 mg (95%) of the title compound as a colorless oil.

[0184] Analytical data: LC-MS: (ES, m / z) = 224 [M+1-56]. Step 2: Synthesis of tert-butyl 3-methyl-3-(methylsulfonylmethyl)azetidine-1-carboxylate: Sodium methylsulfanide (175 mg, 2.50 mmol) was added to tert-butyl 3-[(methanesulfonyloxy)methyl]-3-methylazetidine-1-carboxylate (350 mg, 1.25 mmol) in ACN (30 mL) at room temperature. The resulting mixture was heated to reflux for 16 hours. The mixture was diluted with DCM and washed with brine. The organic layer was concentrated in vacuo. The residue was purified by silica gel column using PE:EA=1:1. This gave 250 mg (75%) of the title compound as a white solid.

[0185] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56]. Step 3: Synthesis of tert-butyl 3-methyl-3-(methylsulfonylmethyl)azetidine-1-carboxylate: Oxone (362 mg, 2.16 mmol) was added to tert-butyl 3-methyl-3-[(methylsulfanyl)methyl]azetidine-1-carboxylate (250 mg, 1.08 mmol) in THF / HO / EtOH (5 / 5 / 5 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified on a silica gel column using DCM:MeOH=20:1. This afforded 200 mg (88%) of the title compound as a colorless substance.

[0186] Analytical data: LC-MS: (ES, m / z) = 208 [M+1-56]. Step 4: Synthesis of 3-methyl-3-(methylsulfonylmethyl)azetidine: TFA (5 mL) was added to tert-butyl 3-(methanesulfonylmethyl)-3-methylazetidine-1-carboxylate (150 mg, 569 μmol) in DCM (15 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give the title compound (100 mg) as a colorless oil.

[0187] Analytical data: LC-MS: (ES, m / z) = 164 [M+1]. Example A6: Synthesis of N-((azetidin-3-ylmethyl)(methyl)(oxo)-16-sulfaneilidene)benzamide

[0188] [ka]

[0189] Step 1: Synthesis of tert-butyl 3-(methylthiomethyl)azetidine-1-carboxylate: A mixture of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (5.05 g, 17 mmol, 1 equiv.) and NaSMe (3.56 g, 25.5 mmol, 1.50 equiv.) in MeCN (30 mL) and HO (10 mL) was heated to 60° C. for 18 h. After cooling to room temperature, the mixture was concentrated and the residue was diluted with EA. The organic solution was washed with water and dried over NaSO. The solution was concentrated to give the title compound (3.69 g, quantitative) as a pale yellow oil.

[0190] Step 2: Synthesis of tert-butyl 3-(methylsulfinylmethyl)azetidine-1-carboxylate: To a solution of tert-butyl 3-[(methylsulfanyl)methyl]azetidine-1-carboxylate (3.69 g, 17 mmol, 1 equiv.) in DCM (50 mL) was added mCPBA (2.92 g, 17 mmol, 1 equiv.) portionwise at 0 °C. The reaction was carried out at 0 °C for 2 h and then quenched by adding saturated NaHCO (200 mL). The mixture was extracted with DCM. The organic layers were combined and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15:1) to give the title compound (2.7 g, 68.2%) as a pale yellow syrup.

[0191] Step 3: Synthesis of tert-butyl 3-(S-methylsulfonimidoylmethyl)azetidine-1-carboxylate: A mixture of tert-butyl 3-(methanesulfinylmethyl)azetidine-1-carboxylate (2.68 g, 11.5 mmol, 1 equiv.), ammonium acetate (4.41 g, 57.4 mmol, 5.00 equiv.), and PhI(OAc) (5.53 mg, 17.2 mmol, 1.50 equiv.) in MeCN (60 mL) was stirred at 35° C. for 18 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=15:1) to give the title compound (1.5 g, 52.63%) as a pale yellow syrup.

[0192] Analytical data: LC-MS: (ES, m / z) = 249 [M+1]. Step 4: Synthesis of tert-butyl 3-((N-benzoyl-S-methylsulfonimidoyl)methyl)azetidine-1-carboxylate: tert-Butyl 3-{[imino(methyl)oxo-λ 6 To a mixture of {-sulfanyl}methyl}azetidine-1-carboxylate (372 mg, 1.50 mmol, 1 equiv.) and DMAP (366 mg, 3 mmol, 2 equiv.) in DCM (6 mL) was added BzCl (281 mg, 2 mmol, 1.33 equiv.) at 0 °C. The reaction was carried out at room temperature for 3 h and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give the title compound (440 mg, 83.3%) as a yellow syrup.

[0193] Analytical data: LC-MS: (ES, m / z) = 375 [M+23]. Step 5: Synthesis of N-((azetidin-3-ylmethyl)(methyl)(oxo)-16-sulfaneilidene)benzamide: tert-Butyl 3-((N-benzoyl-S-methylsulfonimidoyl)methyl)azetidine-1-carboxylate (440 mg, 1.25 mmol, 1 equiv.) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 4 hours. The mixture was concentrated to give the title compound trifluoroacetate (315 mg, quantitative) as a yellow syrup.

[0194] Example A7: Synthesis of (2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidine

[0195] [ka]

[0196] Step 1: Synthesis of methyl 2-(ethylthio)acetate: A solution of methyl 2-sulfanylacetate (20 g, 188 mmol), iodoethane (87.9 g, 564 mmol), and KCO (39.5 g, 282 mmol) in THF (300 mL) was refluxed for 5 h. Water was added, and the reaction mixture was extracted with EA. The organic layer was concentrated in vacuo to give the title compound (20 g) as a pale yellow oil.

[0197] Analytical data: LC-MS: (ES, m / z) = 157 [M+23]. Step 2: Synthesis of methyl 2-(ethylsulfonyl)acetate: m-CPBA (76.7 g, 446 mmol) was added to a solution of methyl 2-(ethylsulfanyl)acetate (20 g, 149 mmol) in DCM (500 mL) at 0° C., and the reaction was stirred at room temperature overnight. The reaction mixture was washed with water and concentrated in vacuo. The residue was applied onto a silica gel column with EA / PE (1:3) to give the title compound (13.5 g) as a pale yellow oil.

[0198] Step 3: Synthesis of methyl 2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(ethylsulfonyl)acetate: (2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (Step 1, Example A4, 13 g, 39.2 mmol) and methyl 2-(ethanesulfonyl)acetate were dissolved in DMF (130 mL), then NaH (1.12 g of a 60% dispersion in mineral oil, 47.0 mmol) was added and stirred for approximately 15 minutes until hydrogen evolution ceased. The reaction mixture was heated to 80° C. overnight. The reaction was cooled, then diluted with water and extracted with EA, and the combined organics were washed with water, brine, and dried over sodium sulfate. Filtration and evaporation gave the crude product. The crude product was purified by chromatography (0 to 7% MeOH / DCM) to give 8 g of the title compound as a pale yellow foam.

[0199] Analytical data: LC-MS: (ES, m / z) = 402 [M+1]. Step 4: Synthesis of (2R,3S)-1-benzhydryl-3-(ethylsulfonylmethyl)-2-methylazetidine: To a solution of methyl 2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-(ethanesulfonyl)acetate (8 g, 19.9 mmol) in DMA (150 mL) was added lithium chloride (6.74 g, 159 mmol) and heated to 150 °C for 1.5 h. Cooled to room temperature, diluted with 150 mL of water, extracted with EA (3 x), and the combined organics were washed with water (3 x), brine, and dried over sodium sulfate. Filtration and evaporation gave the crude product, which was purified by chromatography (0 to 5% MeOH / DCM) to give 6 g of the title compound as a pale yellow foam.

[0200] Analytical data: LC-MS: (ES, m / z) = 344 [M+1]. Step 5: Synthesis of (2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidine: A solution of methyl 2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-(ethanesulfonyl)acetate (6 g, 14.9 mmol) in MeOH (270 mL) / TFA (30 mL) was stirred at room temperature under an atmosphere of H. The reaction was filtered and concentrated in vacuo to give 3.8 g of the title compound (trifluoroacetate salt) as a light brown oil.

[0201] Analytical data: LC-MS: (ES, m / z) = 178 [M+1]. Example A8: Synthesis of rac-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxo)-16-sulfaneilidene)benzamide

[0202] [ka]

[0203] Step 1: Synthesis of rac-tert-butyl (trans)-3-(hydroxymethyl)-2-methylazetidine-1-carboxylate: To a solution of rac-(trans)-1-[(tert-butoxy)carbonyl]-2-methylazetidine-3-carboxylic acid (1.50 g, 7 mmol, 1 equiv.) in THF (20 mL) was added BH3 (21.0 mL, 21.0 mmol, 3 equiv., 1 M in THF) at 0 °C. The reaction was carried out at room temperature for 18 h and then quenched with 1 N HCl (10 mL). The mixture was neutralized with 10% Na2CO3. The mixture was extracted with EA (30 mL × 3). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / EA = 1:1) to give the title compound (1.2 g, 85.7%) as a colorless syrup.

[0204] Analysis data: 1H-NMR (300 MHz, CD3Cl) δ ppm 4.09 - 3.99 (m, 1H), 3.91 (t, 1H, J=8.5 Hz), 3.76 (dd, 2H, J=6.5, 5.2 Hz), 3.60 (dd, 1H, J=8.6, 6.0 Hz), 2.33 - 2.21 (m, 1H), 1.54 (t, 1H, J=5.3 Hz), 1.46 (s, 9H), 1.41 (d, 3H, J=6.3 Hz) Step 2: Synthesis of rac-(trans)-tert-butyl 2-methyl-3-(methylthiomethyl)azetidine-1-carboxylate: To a solution of rac-tert-butyl (trans)-3-(hydroxymethyl)-2-methylazetidine-1-carboxylate (1.20 g, 6 mmol, 1 equiv.) in DCM (35 mL) was added TEA (1.21 g, 12.0 mmol, 2 equiv.) followed by MsCl (889 mg, 7.80 mmol, 1.3 equiv.) at 0 °C. The reaction was carried out at 0 °C for 1 h and then quenched with saturated NaHCO (50 mL). The mixture was extracted with DCM (30 mL × 3). The organic layers were combined and concentrated. The residue was dissolved in MeCN (12 mL) and HO (3 mL). NaSMe (840 mg, 12.0 mmol, 2 equiv.) was added. The reaction was carried out at 60 °C for 18 h. After cooling to room temperature, EA (100 mL) was added. The mixture was washed with water (50 mL) and concentrated. The residue was purified by silica gel column chromatography (PE / EA=4:1) to give the title compound (1.38 g, quantitative) as a yellow oil.

[0205] Analysis data: 1H-NMR (300 MHz, CD3Cl) δ ppm 3.96 (dd, 2H, J=9.8, 7.0 Hz), 3.51 (dd, 1H, J=8.7, 6.1 Hz), 2.69 (d, 2H, J=7.8 Hz), 2.34 - 2.23 (m, 1H), 2.12 (s, 3H), 1.46 (s, 9H), 1.42 (d, 3H, J=6.2 Hz) Step 3: Synthesis of rac-(trans)-tert-butyl 2-methyl-3-(methylsulfinylmethyl)azetidine-1-carboxylate: To a solution of rac-tert-butyl (trans)-2-methyl-3-[(methylsulfanyl)methyl]azetidine-1-carboxylate (1.38 g, 6 mmol, 1 equiv.) in DCM (30 mL) was added mCPBA (1.08 g, 6.30 mmol, 1.05 equiv.) portionwise at 0 °C for 2 h, followed by quenching with saturated NaHCO (50 mL). The mixture was extracted with DCM (30 mL × 3). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 15:1) to give the title compound (1.2 g, 81.1%) as a pale yellow oil.

[0206] Analysis data: 1H-NMR (300 MHz, CD3Cl) δ ppm 4.15 - 4.02 (m, 2H), 3.66 (td, 1H, J=9.0, 6.2 Hz), 3.11 - 2.79 (m, 2H), 2.74 - 2.65 (m, 1H), 2.61 (d, 3H, J=3.9Hz), 1.51 - 1.40 (m, 12H) Step 4: Synthesis of rac-(2R,3S)-tert-butyl 2-methyl-3-(S-methylsulfonimidoylmethyl)azetidine-1-carboxylate: A mixture of rac-tert-butyl (trans)-3-(methanesulfinylmethyl)-2-methylazetidine-1-carboxylate (1.23 g, 5 mmol, 1 equiv.), PhI(OAc) (2.41 g, 7.50 mmol, 1.5 equiv.), and ammonium acetate (2.31 g, 30.0 mmol, 6 equiv.) in ACN (30 mL) was stirred at 35 °C for 18 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 15:1) to give the title compound (600 mg, 45.8%) as a pale yellow syrup.

[0207] Analytical data: LC-MS: (ES, m / z) = 263 [M+1]. Step 5: Synthesis of rac-tert-butyl (trans)-3-((N-benzoyl-S-methylsulfonimidoyl)methyl)-2-methylazetidine-1-carboxylate: rac-tert-butyl(trans)-3-{[imino(methyl)oxo-λ 6 To a mixture of {-sulfanyl]methyl}-2-methylazetidine-1-carboxylate (393 mg, 1.5 mmol, 1 equiv.) and DMAP (292 mg, 2.40 mmol, 1.6 equiv.) in DCM (5 mL) was added benzoyl chloride (274 mg, 1.95 mmol, 1.3 equiv.) at 0 °C. The reaction was carried out at 0 °C for 2 h and then quenched with saturated NaHCO (20 mL). The mixture was extracted with DCM (20 mL × 3). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / EA = 1:1) to give the title compound (400 mg, 72.9%) as a colorless syrup.

[0208] Analytical data: LC-MS: (ES, m / z) = 367 [M+1]. Step 5: Synthesis of rac-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxo)-16-sulfaneilidene)benzamide: A solution of rac-(trans)-tert-butyl 3-((N-benzoyl-S-methylsulfonimidoyl)methyl)-2-methylazetidine-1-carboxylate (732 mg, 2 mmol, 1 equiv.) in TFA (2 mL) and DCM (6 mL) was stirred at room temperature for 3 hours. The mixture was concentrated to give the title compound (370 mg, 69.6%) as a colorless syrup.

[0209] Analytical data: LC-MS: (ES, m / z) = 267 [M+1]. Example B1: Synthesis of (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol and (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol and (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol and (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol

[0210] [ka]

[0211] Step 1: Synthesis of tert-butyl 3-methyl-4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate: Trimethylsilyl trifluoromethanesulfonate (12.50 g, 56.25 mmol, 1.20 equiv) was added dropwise to a pre-cooled solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (10 g, 46.88 mmol, 1 equiv) and TEA (11.38 g, 112.5 mmol, 2.40 equiv) in toluene (100 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 4 h. The solution was quenched with water (50 mL) and extracted twice with EA. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (10.5 g, 78.5%) as a yellow oil.

[0212] Analysis data: 1H-NMR (400 MHz, 6d-DMSO) δ ppm 3.68-3.66 (m, 2H), 3.43 (t, 2H, J = 5.8 Hz), 2.05 (tq, 2H, J = 6.0, 2.0 Hz), 1.53 - 1.47 (m, 3H), 1.41 (s, 9H), 0.15 (s, 9H). Step 2: Synthesis of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate: A mixture of tert-butyl 5-methyl-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylate (10 g, 35.0 mmol, 1 equiv) and SelectFluor (13.6 g, 38.5 mmol, 1.10 equiv) in acetonitrile (100 mL) was stirred at 0 °C for 1 h. The solution was diluted with water (100 mL) and extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This afforded 8 g (98.8%) of the title compound as a pale yellow oil.

[0213] Step 3: Synthesis of tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate: A mixture of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (7 g, 30.2 mmol, 1 equiv.) and NaBH4 (1.37 g, 36.2 mmol, 1.12 equiv.) in methanol (70 mL) was stirred at room temperature for 3 hours. The solution was extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This gave 7 g (99.4%) of the title compound as a pale yellow oil.

[0214] Step 4: Synthesis of 3-fluoro-3-methylpiperidin-4-ol hydrochloride: To a reaction vessel was added tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (7 g, 30.0 mmol), DCM (70 mL), and hydrochloric acid (4 M in dioxane, 50 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction precipitate was collected by filtration to give the title compound (4.5 g) as a white solid.

[0215] Step 5: Synthesis of 1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol: A mixture of 2-chloropyrimidin-4-amine (2.7 g, 20.8 mmol, 1 equiv.), 3-fluoro-3-methylpiperidin-4-ol hydrochloride (3.86 g, 22.8 mmol, 1.10 equiv.), and TEA (6.30 g, 62.4 mmol, 3 equiv.) in isopropyl alcohol (45 mL) was stirred in a sealed vial at 130° C. for 5 hours. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated in vacuo to give the title compound (6 g) as a yellow oil.

[0216] The crude product, 1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol, was purified by HP-FLASH using the following conditions: Column: XBridge Preparative OBD C18 column 30 x 150 mm 5 μm; Mobile phase A: water (3 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 100 mL / min; Gradient: 10% B to 30% B in 35 min; 254 / 220 nm; Rt: 21.12 min. Fractions containing the desired compound were evaporated to dryness to give the cis racemate (1.3 g, 26.1%) as a white solid and the trans racemate (500 mg, 10.0%) as a white solid.

[0217] Cis-racemic (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol was separated by preparative chiral SFC-HPLC using the following conditions: Column: Phenomenex Lux 5u cellulose-3, 5 x 25 cm, 5 um; Mobile phase A: CO2:50, Mobile phase B: MEOH (0.1% DEA):50; Flow rate: 170 mL / min; 220 nm. Fractions containing the desired compound were evaporated to dryness to give (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (stereochemistry assigned by X-ray crystallography of compound 55; 500 mg, peak 1) as a white solid and (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (500 mg, peak 2) as a white solid.

[0218] Analysis data: LC-MS: (ES, m / z)=227[M+1];1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.71 (d, 1H, J = 5.6 Hz), 6.37 (s, 2H), 5.69 (d, 1H, J = 5.6 Hz), 4.93 (d , 1H, J = 6.5 Hz), 4.66 (ddd, 1H, J = 14.1, 9.1, 2.2 Hz), 4.60 - 4.50 (m, 1H), 3.44 (ddt, 1H, J = 24.8, 11.0, 5.6 Hz), 3.02 - 2.78 (m, 2H), 1.69 - 1.53 (m, 2H), 1.31 (d, 3H, J = 21.2 Hz). The trans racemate was separated by preparative chiral SFC using the following conditions (Column: CHIRALPAK AD-H-TC001 SFC, 2 x 25 cm, 5 um; Mobile phase A: CO2:70, Mobile phase B: MeOH-preparative:30; Flow rate: 40 mL / min; 220 nm). Fractions containing the desired compound were evaporated to dryness to give (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (180 mg) as a white solid (peak 1) and (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (190 mg) as a white solid (peak 2).

[0219] Analysis data: LC-MS: (ES, m / z)=227[M+1];1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H J = 5.7 Hz), 6.40 (s, 2H), 5.70 (d, 1H, J = 5.6 Hz), 5.24 (d, 1H, J = 4.5 Hz), 3.83 - 3.56 (m, 5H), 1.78 (ddt, 1H, J = 12.9, 10.0, 4.7 Hz), 1.48 - 1.36 (m, 1H), 1.24 (d, 3H, J = 22.5 Hz). Example B2: Synthesis of (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine and (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine

[0220] [ka]

[0221] Step 1: Synthesis of tert-butyl 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate: tert-Butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (2 g, 8.50 mmol, 1 equiv.), trimethylsulfoxonium iodide (5.61 g, 25.5 mmol, 3 equiv.), and t-BuOK (2.85 g, 25.5 mmol, 3 equiv.) were dissolved / suspended in t-BuOH. The mixture was stirred at 50° C. for 2 days. Water was added to the reaction mixture, and it was extracted with EA. The organic layer was concentrated in vacuo. This gave 2 g (89%) of the title compound.

[0222] Step 2: Synthesis of 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane: TFA (3 mL) was added to tert-butyl 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 7.59 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give 2.1 g of the title compound as the trifluoroacetic acid salt. The crude product was used directly in the next step.

[0223] Analytical data: LC-MS: (ES, m / z) = 164 [M+1]. Step 3: Synthesis of (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine and (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine: TEA (12.3 g, 122 mmol, 2 equiv.) was added to 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane (10 g, 61.2 mmol, 1 equiv.) and 2-chloropyrimidin-4-amine (8.41 g, 61.2 mmol, equiv.) in DMSO (100 mL). The reaction was stirred at 100° C. for 2 h. Water was added to the mixture and extracted with EA. The organic layer was washed with brine, dried, and concentrated. The residue was purified by FLASH (5% MeOH in DCM) to give the title compound (2.1 g).

[0224] 2.1 g of product was separated by preparative SFC-HPLC using the following conditions (Column: CHIRALART Amylose-SA, 2 x 25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: EtOH; Flow Rate: 40 mL / min; Gradient: 35% B; 254 nm), and the fractions containing the desired compound were evaporated to dryness to give Peak 1: (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidine-4 800 mg of Peak 1: (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine and 805 mg of Peak 2: (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine were obtained.

[0225] Peak 1: (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine: Analysis data: LC-MS: (ES, m / z)=257[M+1];1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.74 (d, 1H, J = 5.6 Hz), 6.52 (s, 2H), 5.77 (d, 1H, J = 5.7 Hz), 4.46 (t, 2H, J = 7.8 Hz), 4.23 (td, 1H, J = 14.1, 7.2 Hz), 3.93 - 3.74 (m, 2H), 3.53 (ddd, 1H, J = 13.2, 8.9, 3.5 Hz), 2.74 (dt, 1H, J = 11.4, 7.5 Hz), 2.50 - 2.39 (m, 1H), 2.10 - 1.97 (m, 1H), 1.90 (ddt, 1H, J = 13.4, 8.9, 4.3 Hz). Peak 2: (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine: Analysis data: LC-MS: (ES, m / z)=237[M+1];1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.75 (d, 1H, J = 5.7 Hz), 6.52 (s, 2H), 5.77 (d, 1H, J = 5.6 Hz), 4.46 (t, 2H, J = 7.8 Hz), 4.23 (td, 1H, J = 14.2, 7.2 Hz), 3.93 - 3.74 (m, 2H), 3.53 (ddd, 1H, J = 13.1, 8.8, 3.5 Hz), 2.74 (dt, 1H, J = 11.4, 7.5 Hz), 2.50 - 2.41 (m, 1H), 2.10 - 1.97 (m, 1H), 1.91 (ddt, 1H, J = 13.4, 8.8, 4.3 Hz). Example B3: Synthesis of 2-(4-methylpiperazin-1-yl)pyrimidin-4-amine

[0226] [ka]

[0227] A mixture of 2-chloropyrimidin-4-amine (300 mg, 2.31 mmol, 1 equiv.), 1-methylpiperazine (231 mg, 2.31 mmol, 1 equiv.), and TEA (466 mg, 4.62 mmol, 2 equiv.) in IPA (3 mL) was heated to 100° C. for 1.5 h. LCMS showed the reaction was complete. The mixture was diluted with water and extracted with EA. The organic phase was dried, concentrated, and purified by FLASH (DCM:MeOH=5%). This afforded 270 mg (60%) of the title compound as a yellow solid.

[0228] Analytical data: LC-MS: (ES, m / z) = 194 [M+1]. Example B4: Synthesis of 2-(4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0229] [ka]

[0230] A mixture of 4-methoxypiperidine (1.15 g, 10 mmol, 1.0 equiv), 2-chloropyrimidin-4-amine (1.3 g, 10 mmol, 1.0 equiv), and TEA (2.0 g, 20 mmol, 2.0 equiv) in IPA (15 mL) was stirred overnight at 100° C. The mixture was concentrated, and the residue was purified by Combi Flash (5% MeOH in DCM) to give 1.12 g (53%) of the title compound as a pale yellow solid.

[0231] Analytical data: LC-MS: (ES, m / z) = 209 [M+1]. Example B5: Synthesis of 2-morpholinopyrimidin-4-amine

[0232] [ka]

[0233] A mixture of 2-chloropyrimidin-4-amine (296 mg, 2.3 mmol, 1 equiv.), morpholine (200 mg, 2.3 mmol, 1 equiv.), and TEA (460 mg, 4.6 mmol, 2.0 equiv.) in IPA (5 mL) was stirred at 100° C. for 5 h. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative TLC to give 360 ​​mg (87%) of the title compound as a yellow solid.

[0234] Analytical data: LC-MS: (ES, m / z) = 181 [M+1]. Example B6: Synthesis of rac-2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine

[0235] [ka]

[0236] A mixture of 1-oxa-7-azaspiro[3.5]nonane (1.27 g, 10 mmol, 1 equiv.), DIPEA (2.6 g, 20 mmol, 2 equiv.) and 2-chloropyrimidin-4-amine (1.29 g, 10 mmol, 10.00 equiv.) in DMSO (12 mL) was stirred at 120° C. overnight. The mixture was cooled to room temperature and diluted with water. The suspension was extracted with EA. The organic layer was washed with brine, dried and concentrated. The residue was purified by preparative TLC to give 1.3 g (59%) of the title compound as a pale yellow solid.

[0237] Analytical data: LC-MS: (ES, m / z) = 221 [M+1]. Example B7: Synthesis of 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrimidin-4-amine

[0238] [ka]

[0239] To a solution of commercially available (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (841 mg, 6.49 mmol, 1 equiv.) in IPA, commercially available hexahydro-1H-furo[3,4-c]pyrrole (970 mg, 8.57 mmol, 1.32 equiv.) and TEA (1.30 g, 12.9 mmol, 2 equiv.) were added, heated to 100 °C, and stirred overnight. LCMS showed the reaction was complete. Water was added to the mixture, which was extracted with EA. The organic phase was concentrated and purified by FLASH (5% MeOH in DCM). This afforded 500 mg (37%) of the title compound as a pale yellow solid.

[0240] Analytical data: LC-MS: (ES, m / z) = 207 [M+1]. Example B8: Synthesis of 2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrimidin-4-amine

[0241] [ka]

[0242] 2-Chloropyrimidin-4-amine (600 mg, 4.63 mmol, 1 equiv), (3R,4S)-3,4-difluoropyrrolidine (495 mg, 4.63 mmol, 1 equiv), TEA (1.39 g, 13.8 mmol, 3 equiv) in IPA (10 mL) were added in a 20 mL sealed tube under nitrogen and warmed to 100° C. for 12 h. The reaction mixture was filtered and evaporated to give 800 mg (86%) of the title compound as a yellow solid.

[0243] Analytical data: LC-MS: (ES, m / z) = 201 [M+1]. Example B9: Synthesis of 1-(4-aminopyrimidin-2-yl)-4-methylpiperidin-4-ol

[0244] [ka]

[0245] A mixture of 4-methylpiperidin-4-ol (230 mg, 2 mmol, 1 eq.), 2-chloropyrimidin-4-amine (258 mg, 2 mmol, 1 eq.) and TEA (300 mg, 3 mmol, 1.5 eq.) in IPA (5 mL) was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was purified by preparative TLC (6% MeOH in DCM) to give 210 mg (50%) of the title compound.

[0246] Analytical data: LC-MS: (ES, m / z) = 209 [M+1]. Example B10: Synthesis of (3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol and (3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol

[0247] [ka]

[0248] Step 1: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol: A mixture of cis-4-methoxypiperidin-3-ol (1.7 g, 13 mmol, 1 equiv), 2-chloropyrimidin-4-amine (1.7 g, 13 mmol, 1 equiv), and TEA (2.6 g, 26 mmol, 2.0 equiv) in IPA (15 mL) was stirred overnight at 100° C. The mixture was concentrated, and the residue was purified by FLASH (5% MeOH in DCM) to give 2.4 g (82.7%) of the title compound as a yellow solid.

[0249] Analytical data: LC-MS: (ES, m / z) = 225 [M+1]. Step 2: Synthesis of (3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol and (3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol: 2.4 g of cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol was separated by chiral SGC under the following conditions: column name, CHIRALPAK IA (4.6 x 150 mm, 5 um); solvent, CO2 / 10% MEOH (0.1% DEA); flow rate, 4 mL / min. Fractions containing the desired compounds were evaporated to dryness to give peak 1: (3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (900 mg) and peak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (890 mg).

[0250] Example B11: Synthesis of (4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol and (4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol

[0251] [ka]

[0252] Step 1: Synthesis of cis-5-fluoro-3,3-dimethylpiperidin-4-ol: Cis-tert-butyl 5-fluoro-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (4.7 g, 19.0 mmol) was added to a solution of HCl in 1,4-dioxane (30 mL), and the resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give the title compound as a hydrochloride salt (3.6 g) as a white solid.

[0253] Step 2: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol: TEA (3.83 g, 38.0 mmol) was added to a mixture of cis-5-fluoro-3,3-dimethylpiperidin-4-ol (3.6 g, 19.0 mmol) and 2-chloropyrimidin-4-amine (2.46 g, 19.0 mmol) in iPrOH (10 mL), and the resulting mixture was stirred at 100 °C for 3 h. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC: Column: XBridge Preparative OBD C18 Column 30 × 150 mm 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 5% B to 32% B in 8 min; 254 / 220 nm; Rt: 6.92 min. Fractions containing the desired compound were evaporated to dryness to give the title compound (1.8 g, 39.4%) as a white solid.

[0254] Analytical data: LC-MS: (ES, m / z) = 241 [M+1]. Step 3: Synthesis of (4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol and (4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol: 1.8 g of the cis racemate was separated by preparative chiral HPLC on a column (EnantioPak-A1-5(02), 5 × 25 cm, 5 um; mobile phase A: CO 2 : 60, mobile phase B: EtOH 0.1% DEA; flow rate: 2 mL / min; 220 nm). Fractions containing the desired compound were evaporated to dryness to give Peak 1: (4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol or (4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol (776 mg, 43.3%) as a white solid, and Peak 2: (4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol or (4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol (700 mg, 39.1%) as a white solid.

[0255] (4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol or (4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol: Analytical data: Analytical data: LC-MS: (ES, m / z)=241[M+1];1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.69 (d, 1H, J = 5.7 Hz), 6.36 (s, 2H), 5.67 (d, 1H, J = 5.6 Hz), 5.00 (d, 1H, J = 5.4 Hz), 4.75 - 4.47 (m, 1H), 4.09 - 3.93 (m, 1H), 3.86 - 3.67 (m, 1H), 3.62 (d, 1H, J = 12.9 Hz), 3.37 (ddd, 1H, J = 22.0, 5.5, 2.9 Hz), 3.31 - 3.18 (m, 1H), 0.95 - 0.78 (m, 6H). Example B12: Synthesis of (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol and (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

[0256] [ka]

[0257] Step 1: Synthesis of rac-cis-tert-butyl 3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate: MeMgBr (9.2 mL, 27.6 mmol) was added to a solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (5 g, 2.3 mmol) in THF (50 mL) at −78° C. The mixture was stirred at room temperature overnight. The reaction mixture was carefully diluted with saturated NH4Cl (aq), then extracted with EA and washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated to give 4.8 g (crude) of the title compound as a yellow solid.

[0258] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56]. Step 2: Synthesis of rac-cis-3-fluoro-4-methylpiperidin-4-ol: Tert-butyl 3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate (4.8 g, 20 mmol) in HCl / dioxane (50 mL) was stirred at room temperature for 4 hours. The reaction mixture was evaporated to give 3-fluoro-4-methylpiperidin-4-ol (crude) 3 g as a yellow solid. The crude product was used directly in the next step.

[0259] Analytical data: LC-MS: (ES, m / z) = 134 [M+1]. Step 3: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol: A mixture of 2-chloropyrimidin-4-amine (1.5 g, 11.5 mmol), 3-fluoro-4-methylpiperidin-4-ol (3 g, crude) and DIPEA (11.9 g, 92.3 mmol) in DMSO (40 mL) was stirred at 120 °C overnight. The reaction mixture was diluted with water, extracted with EA and washed with brine. The organic layer was dried over Na SO , filtered, evaporated and purified by column chromatography (PE:EA = 1:1) to give the title compound (1.3 g) as a pale yellow solid.

[0260] Analytical data: LC-MS: (ES, m / z) = 227 [M+1]. Step 4: Synthesis of (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol and (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol: rac-cis1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol was separated by preparative SFC using the following conditions: column: CHIRAL cellulose-SJ (4.6 × 150 mm, 5 μm); mobile phase: CO / MeOH (0.1% DEA); flow rate: 4 g / min; to give peak 1: (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (450 mg, stereochemistry assigned by X-ray crystallography of compound 117) as a white solid and peak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (470 mg) as a white solid.

[0261] Peak 1: (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol: Analysis data: 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.73 (d, 1H J = 5.6 Hz), 6.40 (s, 2H), 5.72 (d, 1H, J = 5.6 Hz), 4.71 (s, 1H), 4.39 - 3.92 (m, 3H), 3.38 (dddd, 2H, J = 40.5, 13.6, 10.3, 4.6 Hz), 1.62 (q, 1H, J = 6.2 Hz), 1.42 (td, 1H, J = 13.6, 12.0, 4.3 Hz,), 1.20 (s, 3H). Peak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol Analysis data: 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.73 (d, 1H, J = 5.6 Hz), 6.40 (s, 2H), 5.72 (d, 1H, J = 5.6 Hz), 4.71 (s, 1H), 4.36 - 4.07 (m, 2H), 4.07 - 3.95 (m, 1H), 3.44 (ddd, 1H, J = 13.2, 9.4, 4.8 Hz), 3.31 (ddd, 1H, J = 13.4, 8.3, 3.2 Hz), 1.61 (ddt, 1H, J = 14.1, 7.2, 3.9 Hz), 1.41 (ddd, 1H, J = 13.9, 10.3, 4.4 Hz), 1.20 (s, 3H). Example B13: Synthesis of (S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol and (R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol

[0262] [ka]

[0263] Step 1: Synthesis of 1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol: A mixture of 3,3-difluoro-4-methylpiperidin-4-ol (300 mg, 2.0 mmol), 2-chloropyrimidin-4-amine (260 mg, 2.0 mmol), and TEA (300 mg, 3.0 mmol) in DMSO (2 mL) was stirred at 120° C. overnight. Water was added, and the mixture was extracted with EA. The organic phase was washed with brine, dried, and purified by FLASH (5% MeOH in DCM) to give 320 mg (65%) of the title compound as a white solid.

[0264] Analytical data: LC-MS: (ES, m / z) = 245 [M+1]. Step 2: Synthesis of (S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol and (R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol: 320 mg of 1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol was separated by preparative chiral SFC using the following conditions: Column: CHIRALPAK AD-3 3 x 100 mm, 3 um; Co-solvent: MeOH (0.1% DEA); Gradient (B%): 10% to 50% in 4.0 minutes, hold at 50% for 2.0 minutes; Backpressure (psi): 1500.000; Flow rate: 2 mL / min; to obtain Peak 1: (S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol or (R)- 145 mg of (R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol and 150 mg of peak 2: (R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol or (S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol were obtained, both of which are pale yellow solids.

[0265] Analysis data: 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.74 (d, 1H, J=5.6 Hz), 6.45 (s, 2H), 5.74 (d, 1H, J=5.7 Hz), 5.41 (s, 1H), 4.58 (dt, 1H, J=13.4, 9.4 Hz), 4.29 (d, 1H, J=13.3 Hz), 3.59 - 3.38 (m, 1H), 3.23 (ddd, 1H, J=13.8, 9.6, 4.7 Hz), 1.62 (q, 2H, J=5.8, 4.8 Hz), 1.22 (d, 3H, J=1.6Hz) Example B14: Synthesis of rac-(trans)-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

[0266] [ka]

[0267] To a solution of 2-chloropyrimidin-4-amine (216 mg, 1.67 mmol) in IPA, rac-(3R,4R)-4-fluoropiperidin-3-ol hydrochloride (200 mg, 1.67 mmol) and TEA (337 mg, 3.34 mmol) were added, and the mixture was heated to 100° C. and stirred overnight. LCMS showed that the reaction was complete. Water was added to the mixture, and it was extracted with EA. The organic phase was concentrated and purified by FLASH. This gave 180 mg (65%) of the title compound as a yellow solid.

[0268] Analytical data: LC-MS: (ES, m / z) = 213 [M+1]. Example B15: Synthesis of rac-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol

[0269] [ka]

[0270] Step 1: Synthesis of (1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-ol: A mixture of commercially available rac-(1R,5S,8S)-3-benzyl-3-azabicyclo[3.2.1]octan-8-ol (200 mg, 920 μmol) and Pd / C (97.9 mg, 920 μmol) in MeOH (3 mL) was stirred at room temperature for 3 h. The solid was filtered off, and the filtrate was concentrated to give the title compound (110 mg) as a yellow solid.

[0271] Analytical data: LC-MS: (ES, m / z) = 128 [M+1]. Step 2: Synthesis of rac-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol: A mixture of rac-(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-ol (100 mg, 786 μmol), 2-chloropyrimidin-4-amine (101 mg, 786 μmol), and TEA (237 mg, 2.35 mmol) in IPA (3 mL) was stirred for 16 h at 100° C. The reaction mixture was concentrated and purified by preparative TLC (10% MeOH in DCM) to give 110 mg (64%) of the crude product as a yellow solid.

[0272] Analytical data: LC-MS: (ES, m / z) = 221 [M+1]. Example B16: Synthesis of rac-1-(1-(4-aminopyrimidin-2-yl)-3-fluoropyrrolidin-3-yl)ethanol

[0273] [ka]

[0274] Step 1: Synthesis of rac-tert-butyl 3-fluoro-3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate: A solution of rac-1-[(tert-butoxy)carbonyl]-3-fluoropyrrolidine-3-carboxylic acid (1 g, 4.28 mmol), methoxy(methyl)amine (339 mg, 5.56 mmol), HATU (3.25 g, 8.56 mmol), and DIPEA (1.65 g, 12.8 mmol) in DMF (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column using EA / PE (1:6) to give 900 mg (76%) of the title compound as a pale yellow oil.

[0275] Analytical data: LC-MS: (ES, m / z) = 221 [M+1-56]. Step 2: Synthesis of rac-tert-butyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate: To a solution of rac-tert-butyl 3-fluoro-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (900 mg, 3.25 mmol) in THF (20 mL) was added bromo(methyl)magnesium (7.7 mL, 2.5 M, 16.2 mmol) at −60° C. under N. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous NH4Cl (10 mL), extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 780 mg (crude) of the title compound as a pale yellow oil.

[0276] Step 3: Synthesis of rac-tert-butyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate: To a solution of rac-tert-butyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate (780 mg, 3.37 mmol) in MeOH (10 mL) was added NaBH (191 mg, 5.05 mmol) at 0° C. and stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo, extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 700 mg of the product as a pale yellow oil.

[0277] Step 4: Synthesis of rac-1-(3-fluoropyrrolidin-3-yl)ethanol: To a solution of rac-tert-butyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (700 mg, 3 mmol) in DCM (5 mL) was added HCl / dioxane (3 mL) and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give 500 mg of the product as a pale yellow solid.

[0278] Step 5: Synthesis of rac-1-(1-(4-aminopyrimidin-2-yl)-3-fluoropyrrolidin-3-yl)ethanol: A solution of rac-1-(3-fluoropyrrolidin-3-yl)ethan-1-ol (550 mg, 4.13 mmol), 2-chloropyrimidin-4-amine (535 mg, 4.13 mmol), and TEA (1.24 g, 12.3 mmol) in IPA (6 mL) was heated to 100° C. and stirred overnight. The reaction was concentrated in vacuo and purified by TLC (DCM:MeOH=15:1) to give 800 mg of the product as a pale yellow solid.

[0279] Analytical data: LC-MS: (ES, m / z) = 227 [M+1]. Example B17: Synthesis of rac-2-(4-aminopyrimidin-2-yl)-2-aza-bicyclo[2.2.1]heptan-5-ol

[0280] [ka]

[0281] Step 1: Synthesis of rac-2-aza-bicyclo[2.2.1]heptan-5-ol: To a solution of rac-tert-butyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 2.34 mmol) in DCM (8 mL) was added TFA (226 mg, 2.34 mmol), and the mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete, and the solution was concentrated to give 450 mg of product, which was used directly in the next step.

[0282] Analytical data: LC-MS: (ES, m / z) = 114 [M+1]. Step 2: Synthesis of rac-2-(4-aminopyrimidin-2-yl)-2-aza-bicyclo[2.2.1]heptan-5-ol: A mixture of 2-chloropyrimidin-4-amine (200 mg, 1.54 mmol), rac-2-azabicyclo[2.2.1]heptan-5-ol (174 mg, crude) and TEA (311 mg, 3.08 mmol) in IPA (5 mL) was stirred at 110° C. overnight. LCMS showed the reaction was complete. Water was added to the mixture and extracted with EA. The organic phase was concentrated and purified by FLASH. This gave 180 mg of the title compound as a yellow solid.

[0283] Analytical data: LC-MS: (ES, m / z) = 207 [M+1]. Example B18: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

[0284] [ka]

[0285] Step 1: Synthesis of cis-4-fluoropiperidin-3-ol: Tert-butyl (cis)-4-fluoro-3-hydroxypiperidine-1-carboxylate (300 mg) was dissolved in dioxane (1 mL). HCl in dioxane (4 M, 2 mL) was added and stirred for 1 hour. The reaction mixture was concentrated to give the title compound as a white solid (140 mg).

[0286] Analytical data: LC-MS: (ES, m / z) = 120 [M+1]. Step 2: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol: A mixture of 2-chloropyrimidin-4-amine (129 mg), cis-4-fluoropiperidin-3-ol (118 mg), and DIPEA (384 mg) in DMSO was stirred for 12 hours at 120° C. Water was added, and the mixture was extracted with EA and purified by preparative TLC (5% MeOH in DCM) to give the title compound (95 mg) as a yellow solid.

[0287] Analytical data: LC-MS: (ES, m / z) = 213 [M+1]. Example B19: Synthesis of 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-amine

[0288] [ka]

[0289] To a solution of 2-chloropyrimidin-4-amine (1 g, 7.71 mmol) in IPA (12 mL), 1,4-dioxa-8-azaspiro[4.5]decane (1.10 g, 7.71 mmol) and TEA (1.55 g, 15.4 mmol) were added, heated to 100 °C, and stirred overnight. Water was added to the mixture, and it was extracted with EA. The organic layer was concentrated and purified by FLASH (5% MeOH in DCM). This gave 1.5 g (82.8%) of the title compound as a yellow solid.

[0290] Analytical data: LC-MS: (ES, m / z) = 237 [M+1]. Example B20: Synthesis of rac-tert-butyl 4-(4-aminopyrimidin-2-yl)-2-(difluoromethyl)piperazine-1-carboxylate

[0291] [ka]

[0292] A mixture of rac-tert-butyl 2-(difluoromethyl)piperazine-1-carboxylate (200 mg, 846 μmol), 2-chloropyrimidin-4-amine (109 mg, 846 μmol), and DIEA (326 mg, 2.53 μmol) in DMSO (5 mL) was stirred at 120° C. for 3 hours. The reaction mixture was diluted with water and extracted with EA. The organic layer was dried and purified by column chromatography (DCM:MeOH=20:1) to give the title compound (200 mg, 72%) as a yellow solid.

[0293] Analytical data: LC-MS: (ES, m / z) = 330 [M+1]. Example B21: Synthesis of (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol and (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol

[0294] [ka]

[0295] To a solution of rac-trans-3-methylpiperidin-4-ol (800 mg, 6.94 mmol) in IPA (10 mL) was added 2-chloropyrimidin-4-amine (1.34 g, 10.4 mmol) and TEA (2.1 g, 20.8 mmol). The mixture was stirred at 100° C. for 8 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash elution using the following conditions: DCM:MEOH=10:1. This afforded 1.2 g (83.3%) of the title compound as a white solid.

[0296] rac-trans-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol (1.2 g, 5.76 mmol) was purified using the following conditions: Column: CHIRALPAK AD-H-TC001 SFC, 2 x 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MEOH (2 mM Further separation by chiral preparative HPLC using NH-MEOH; flow rate: 40 mL / min; gradient: 25% B; 220 nm afforded 500 mg of peak 1: (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol and 460 mg of peak 2: (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as white solids.

[0297] Analytical data: LC-MS: (ES, m / z) = 209 [M+1]. Example B22: Synthesis of rac-(cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol and rac-(trans)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol

[0298] [ka]

[0299] Step 1: Synthesis of tert-butyl 3-fluoro-4-hydroxy-3,4-dimethylpiperidine-1-carboxylate: LiMe (27 mL, 43.2 mmol) was added to a mixture of rac-tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (5 g, 21.6 mmol, from Step 2 of Example B1) in THF at 0° C. The reaction was stirred at 0° C. for 1 hour. The reaction was quenched with HO and extracted with EA. The organic layer was evaporated in vacuo to give a colorless oil (6 g, 24.2 mmol), which was used directly in the next step.

[0300] Step 2: Synthesis of 3-fluoro-3,4-dimethylpiperidin-4-ol: rac-tert-Butyl 3-fluoro-4-hydroxy-3,4-dimethylpiperidine-1-carboxylate (6 g, 24.2 mmol) was added to DCM / TFA (50 mL / 15 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation to give 6 g of crude product.

[0301] Step 3: Synthesis of rac-(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol and rac-(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol: DIPEA (7.85 g, 60.9 mmol) was added to 3-fluoro-3,4-dimethylpiperidin-4-ol (3 g, crude) and 2-chloropyrimidin-4-amine (2.62 g, 20.3 mmol) in DMSO (20 mL). The mixture was stirred at 100 ° C for 16 hours. Water was added, and the suspension was extracted with EA. The organic phase was concentrated, and the residue was purified by FLASH (50% EA in PE) to give the title compound (1.5 g) as a pale yellow solid.

[0302] 1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol (1.5 g, 6.24 mmol) was separated by SFC HPLC: column: CHIRALPAK IC-3, 3 × 100 mm 3 um; mobile phase A: mobile phase B: MeOH (0.1% DEA); flow rate: 2 mL / min; gradient: 10% B; 220 nm; to give peak 1: rac-cis-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol (identified as cis by 2D NMR, 400 mg) as a white solid, and peak 2: rac-trans-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol (identified as trans by 2D NMR, 300 mg) as a white solid.

[0303] Analytical data: LC-MS: (ES, m / z) = 241 [M+1]. Example B23: Synthesis of rac-(cis)-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol and rac-(trans)-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol

[0304] [ka]

[0305] Step 1: Synthesis of rac-tert-butyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate: To a solution of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate (7.95 g, 35 mmol, 1 equiv.) in DMF (35 mL) was added TEA (7.07 g, 70.0 mmol, 2 equiv.) followed by TMSCl (5.67 g, 52.5 mmol, 1.50 equiv.) at room temperature. The reaction was carried out at 120 °C for 18 h and then quenched with saturated NaHCO3. The mixture was extracted with MTBE. The organic layers were combined and concentrated. The residue was dissolved in DMF (70 mL), and Selectfluor (12.3 g, 35 mmol, 1 equiv.) was added at 0 °C. The mixture was stirred at room temperature for 2 h and then quenched with brine. The mixture was extracted with EA. The organic layers were combined and concentrated to give a mixture of tert-butyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate, tert-butyl 3-ethyl-5-fluoro-4-oxopiperidine-1-carboxylate and tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate as a yellow oil (6.5 g).

[0306] Step 2: Synthesis of rac-(9H-fluoren-9-yl)methyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate: A solution of tert-butyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate (6.5 g, 26.4 mmol, 1 equiv.) in TFA (20 mL) and DCM (60 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and redissolved in DCM (120 mL), and TEA (13.3 g, 132 mmol, 5.00 equiv.) was added, followed by (9H-fluoren-9-yl)methyl carbonochloridate (10.2 g, 39.5 mmol, 1.50 equiv.). The reaction was carried out at room temperature for 2 hours. Saturated NaHCO3 was added. The mixture was extracted with DCM. The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / EA=30:1) to give the title compound (3.7 g, 30.53% over two steps) as a colorless syrup.

[0307] Analytical data: LC-MS: (ES, m / z) = 390 [M+23]. Step 3: Synthesis of rac-cis-(9H-fluoren-9-yl)methyl 3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate and rac-trans-(9H-fluoren-9-yl)methyl 3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate: In a 25 mL round-bottom flask, 9H-fluoren-9-ylmethyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate (500 mg, 1.361 mmol, 1 equivalent), methanol (10 mL), and NaBH (102.97 mg, 2.722 mmol, 2 equivalents) were placed. The resulting solution was stirred at 0 °C for 1 hour. The reaction was then quenched by adding 1 mL of water. The resulting mixture was concentrated. The residue was applied to a silica gel column using EA / PE (1:1). This gave 200 mg of Peak 1: rac-cis-(9H-fluoren-9-yl)methyl 3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate (identified as cis by 2D NMR) and 100 mg of Peak 2: rac-trans-(9H-fluoren-9-yl)methyl 3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate (identified as trans by 2D NMR).

[0308] Analytical data: LC-MS: (ES, m / z) = 370 [M+1]. Step 4: Synthesis of rac-cis-3-ethyl-3-fluoropiperidin-4-ol and rac-trans-3-ethyl-3-fluoropiperidin-4-ol: Diethylamine (3 mL) was added to a solution of rac-cis-(9H-fluoren-9-yl)methyl 3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate (200.0 mg, 0.54 mmol) in methanol (15 mL). The resulting solution was stirred at 0° C. for 2 hours. The resulting mixture was concentrated. This afforded 60 mg (75%) of the title compound as a pale yellow oil.

[0309] Analytical data: LC-MS: (ES, m / z) = 148 [M+1]. Step 5: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol and rac-trans-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol: A mixture of rac-cis-3-ethyl-3-fluoropiperidin-4-ol (1 g, 6.794 mmol, 1 equiv.), 2-chloropyrimidin-4-amine (0.88 g, 6.794 mmol, 1 equiv.), and TEA (2.06 g, 20.38 mmol, 3 equiv.) in IPA (10.00 mL) was stirred at 100° C. for 12 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column using DCM / MeOH (5:1). This afforded rac-cis-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol 1 g (61.3%) as a pale yellow solid.

[0310] Analysis data: LC-MS: (ES, m / z)=241[M+1];1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J=5.6 Hz), 6.35 (s, 2H), 5.69 (d, 1H, J=5.6 Hz), 4.88 (d, 1H, J=6.5 Hz), 4.62 (ddd, 1H, J=14.0, 9.0, 1.9 Hz), 4.52 - 4.40 (m, 1H), 3.63 - 3.42 (m, 1H), 3.08 - 2.86 (m, 2H), 1.84 (ddt, 1H, J=15.1, 9.4, 7.5 Hz), 1.75 - 1.49 (m, 3H), 0.92 (t, 3H, J=7.6 Hz) A mixture of rac-trans-3-ethyl-3-fluoropiperidin-4-ol (900 mg, 6.114 mmol, 1 equiv.), 2-chloropyrimidin-4-amine (792.12 mg, 6.114 mmol, 1 equiv.), and TEA (1856.15 mg, 18.343 mmol, 3 equiv.) in IPA (10.00 mL) was stirred at 100° C. for 12 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column using DCM / MeOH (5:1). This afforded 500 mg (34.03%) of rac-trans-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol as a pale yellow solid.

[0311] Analytical data: LC-MS: (ES, m / z) = 241 [M+1]. Example B24: Synthesis of (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol and (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol

[0312] [ka]

[0313] A mixture of 2-chloropyrimidin-4-amine (700 mg, 5.42 mmol), rac-(3R,4S)-3-methylpiperidin-4-ol (900 mg, 5.42 mmol), and TEA (1.7 g, 16.8 mmol) in IPA (10 mL) was stirred at 100° C. for 2 hours. The mixture was concentrated, and the residue was purified by preparative TLC using DCM / MeOH (20:1). This afforded 700 mg (56%) of rac-(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a yellow solid. rac-(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol was purified under the following conditions (column: CHIRALPAK Purification by preparative HPLC using ID-3, 4.6 x 100 mm, 3 μm; mobile phase A:, mobile phase B: IPA (0.1% DEA; flow rate: 4 mL / min; gradient: 10% B; 220 nm) and evaporation of fractions containing the desired compound to dryness gave peak 1: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a yellow solid (200 mg, 33%), and peak 2: (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a light yellow solid (200 mg, 33%).

[0314] Analytical data: LC-MS: (ES, m / z) = 209 [M+1]. Example B25: Synthesis of 2-(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-4-amine

[0315] [ka]

[0316] A mixture of 2-chloropyrimidin-4-amine (80 mg, 617 μmol), 1,4-dioxa-9-azaspiro[5.5]undecane (97.0 mg, 617 μmol), and TEA (186 mg, 1.85 mmol) in IPA (2 mL) was stirred at 100° C. for 3 hours. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried, evaporated, and purified by preparative TLC (DCM:MeOH=20:1) to give the title compound (85 mg, 55%) as a yellow solid.

[0317] Analytical data: LC-MS: (ES, m / z) = 251 [M+1]. Example B26: Synthesis of (3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol

[0318] [ka]

[0319] Step 1: Synthesis of rac-tert-butyl 5-fluoro-5-methyl-4-(triethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate: To a solution of rac-tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (4.7 g, 20.3 mmol) in THF (30 mL) was added LiHDMS (30.4 mL, 30.4 mmol) at -70 °C and stirred at -30 °C to -20 °C for 1 h. TESCl (6.11 g, 40.6 mmol) was then added and stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EA. The organic layer was dried and concentrated. The residue was purified on a silica column using 10% EtOAc in PE to give the title compound (6.2 g, 88%) as a colorless oil.

[0320] Step 2: Synthesis of rac-tert-butyl 3,5-difluoro-3-methyl-4-oxopiperidine-1-carboxylate: To a solution of rac-tert-butyl 3-fluoro-3-methyl-4-[(triethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylate (6.2 g, 17.9 mmol) in DMF (30 mL) was added SelectFluor (12.6 g, 35.8 mmol) at 10° C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EA. The organic layer was dried and concentrated. The residue was purified on a silica gel column using 30% EtOAc in PE to give the title compound (3 g, 67%) as a pale yellow oil.

[0321] Step 3: Synthesis of rac-tert-butyl 3,5-difluoro-4-hydroxy-3-methylpiperidine-1-carboxylate: To a solution of rac-tert-butyl 3,5-difluoro-3-methyl-4-oxopiperidine-1-carboxylate (3.5 g, 14.0 mmol) in MeOH was added NaBH4 (1.06 g, 28 mmol) in an ice cream bath. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with EA, and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 2.9 g (82.6%) of the title compound as a colorless oil.

[0322] Analytical data: LC-MS: (ES, m / z) = 196 [M+1-56]. Step 4: Synthesis of rac-3,5-difluoro-3-methylpiperidin-4-ol: rac-tert-butyl 3,5-difluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (1.6 g, 6.36 mmol) was added to a mixture of DCM (20 mL) and TFA (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the title compound as a salt (1.6 g).

[0323] Analytical data: LC-MS: (ES, m / z) = 152 [M+1]. Step 5: Synthesis of (3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol: Three 40 mL sealed tubes were charged with 3,5-difluoro-3-methylpiperidin-4-ol (900 mg, 5.95 mmol), 2-chloropyrimidin-4-amine (1.6 g, crude, TFA salt), and DIEA (3.07 g, 23.8 mmol) in DMSO (10 mL). The resulting solution was stirred at 120 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with water, extracted with EA, and concentrated in vacuo. The residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7B to 20B in 7 min; 254 nm; 220 nm. This gave 380 mg of (3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol, as well as 350 mg of (3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol as white solids. The isomers were further separated by SFC to give peak 1: (3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol or (3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol 150 mg and peak 2: (3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol or (3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol 150 mg.The second mixture was further separated by SFC to give 140 mg of peak 1: (3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol or (3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and 140 mg of peak 2: (3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol or (3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol.

[0324] Analytical data: LC-MS: (ES, m / z) = 245 [M+1]. Example B27: Synthesis of rac-2-(6-fluoro-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-amine

[0325] [ka]

[0326] Step 1: Synthesis of benzyl 1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate: To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (500 mg, 3.49 mmol) and TEA (386 mg, 3.83 mmol) in THF (10 mL) was added benzyl carbonochloridate (386 mg, 3.83 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with EA and saturated brine. The organic layer was dried over Na2SO4, filtered, evaporated, and purified by column chromatography (PE:EA = 1:1) to give the benzyl title compound (800 mg) as a yellow oil.

[0327] Analytical data: LC-MS: (ES, m / z) = 278 [M+1]. Step 2: Synthesis of rac-benzyl 6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate: H2SO4 (14.1 mg, 144 μmol) was added to a mixture of benzyl 1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (800 mg, 2.88 mmol) and SelectFluor (2.04 g, 5.76 mmol) in ACN (10 mL) at room temperature, and the mixture was stirred at 50 °C for 1 h. Ethylene glycol (886 mg, 14.3 mmol) was added and the mixture was stirred for 2 h. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried over Na2SO4, filtered, evaporated, and purified by column chromatography (PE:EA = 1:1) to give the title compound (620 mg) as a yellow oil.

[0328] Analytical data: LC-MS: (ES, m / z) = 296 [M+1]. Step 3: Synthesis of rac-6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane: A mixture of rac-benzyl 6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (600 mg, 2.03 mmol) and Pd / C (239 mg, 2.03 mmol) in MeOH (20 mL) was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered and evaporated to give the title compound (340 mg) as a brown oil.

[0329] Analytical data: LC-MS: (ES, m / z) = 162 [M+1]. Step 4: Synthesis of rac-2-(6-fluoro-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-amine: A mixture of 2-chloropyrimidin-4-amine (180 mg, 1.38 mmol), rac-6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane (333 mg, 2.07 mmol), and TEA (418 mg, 4.14 mmol) in IPA (5 mL) was stirred at 100° C. for 4 hours. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried over NaSO, filtered, evaporated, and purified by column chromatography (DCM:MeOH=30:1) to give the title compound (200 mg) as a yellow solid.

[0330] Analytical data: LC-MS: (ES, m / z) = 255 [M+1]. Example B28: Synthesis of (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol and (3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol

[0331] [ka]

[0332] 2-Chloropyrimidin-4-amine (987 mg, 7.62 mmol) was added to trans-(3S,4S)-4-methoxypiperidin-3-ol (1.0 g, 7.62 mmol) and TEA (2.30 g, 22.8 mmol) in IPA (20 mL) at room temperature. The mixture was stirred at 100 °C for 16 hours. The mixture was concentrated in vacuo, and the residue was purified on a silica gel column using DCM:MeOH = 20:1. This gave 1.2 g of trans-(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a colorless oil. trans-(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (1.2 g, 5.35 mmol) was purified by chiral SFC using the following conditions: column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: CO, mobile phase B: EtOH (8 mmol / L NH MeOH)-HPLC; flow rate: 40 mL / min; gradient: 25% B; 254 nm. This gave 450 mg of Peak 1: (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a white solid, and 460 mg of Peak 2: (3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a white solid.

[0333] Analytical data: LC-MS: (ES, m / z) = 225 [M+1]. Example B29: Synthesis of 2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethanamine

[0334] [ka]

[0335] Step 1: Synthesis of tert-butyl 3-((2-hydroxyethylthio)methyl)azetidine-1-carboxylate: In a 50 mL flask, tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (3 g, 10.0 mmol) dissolved in THF (10 mL) was added. To this was added 2-sulfanylethan-1-ol (781 mg, 10.0 mmol) and K2CO3 (4.20 g, 30.0 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EA. The organic layer was dried and concentrated to give the title compound (2.8 g) (crude) as a brown oil.

[0336] Analytical data: LC-MS: (ES, m / z) = 248 [M+1]. Step 2: Synthesis of tert-butyl 3-((2-hydroxyethylsulfonyl)methyl)azetidine-1-carboxylate: In a 50 mL flask, tert-butyl 3-{[(2-hydroxyethyl)sulfanyl]methyl}azetidine-1-carboxylate (2.7 g, 1.2 mmol) dissolved in THF / EtOH / HO (10 mL) was added. To this was added oxone (744 mg, 1.2 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EA. The organic layer was dried and concentrated to give the title compound (2.4 g, crude) as a yellow solid.

[0337] Step 3: Synthesis of tert-butyl 3-(vinylsulfonylmethyl)azetidine-1-carboxylate: Methanesulfonyl chloride (1.8 g) was added to a solution of tert-butyl 3-[(2-hydroxyethanesulfonyl)methyl]azetidine-1-carboxylate (2.2 g) and TEA (2.5 g) in DCM (10 mL) at 0° C. The mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with EA. The organic layer was dried and concentrated to give the title compound (1.8 g) as a brown solid.

[0338] Analytical data: LC-MS: (ES, m / z) = 206 [M+1-56]. Step 4: Synthesis of tert-butyl 3-((2-(dimethylamino)ethylsulfonyl)methyl)azetidine-1-carboxylate: In a 50 mL flask, tert-butyl 3-[(ethenesulfonyl)methyl]azetidine-1-carboxylate (1.8 g) dissolved in DCM (10 mL) was added. Dimethylamine hydrochloride (1.2 g) and TEA (2.3 g) were added. The mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with DCM. The organic layers were combined and purified with DCM / MeOH (20 / 1) to give the title compound (1.5 g) as a brown solid.

[0339] Analytical data: LC-MS: (ES, m / z) = 307 [M+1]. Step 5: Synthesis of 2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethanamine: tert-Butyl 3-((2-(dimethylamino)ethylsulfonyl)methyl)azetidine-1-carboxylate (1.5 g, 4.9 mmol) was added to a solution of TFA (5 mL) in DCM (15 mL). The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the title compound as the trifluoroacetic acid salt 1.2 g (crude) as a yellow solid.

[0340] Analytical data: LC-MS: (ES, m / z) = 207 [M+1]. Example B30: Synthesis of 3-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1,2,4-triazin-5-amine

[0341] [ka]

[0342] Step 1: Synthesis of 3,5-dichloro-1,2,4-triazine: To a solution of 2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione (5.0 g, 44.2 mmol) in toluene (20 mL) was added DIEA (17.1 g, 132.7 mmol) and POCl (27.1 g, 176.8 mmol) at room temperature. The solution was then heated at 120 °C for 3 h. Excess POCl and toluene were removed under reduced pressure, and the residue was diluted with EA and water. The organic layer was washed with brine, dried over Na SO and concentrated to dryness to give the crude product, which was used in the next step without further purification (200 mg, crude).

[0343] Step 2: Synthesis of 3-chloro-1,2,4-triazin-5-amine: To a solution of 3,5-dichloro-1,2,4-triazine (200 mg, 1.33 mmol) in THF (5 mL) was added NH3 / MeOH (20 mL, 7.0 M), and the resulting mixture was stirred at room temperature for 30 min; LC-MS showed the reaction was complete. Evaporation to dryness and purification by preparative HPLC gave the title compound (50 mg, 20% yield for two steps).

[0344] Analytical data: LC-MS: (ES, m / z) = 131 [M+1]. Step 3: Synthesis of 3-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1,2,4-triazin-5-amine: To a solution of 3-chloro-1,2,4-triazin-5-amine (30 mg, 229 μmol) and DIPEA (88.4 mg, 686 μmol) in DMSO (1 mL) was added 1-oxa-7-azaspiro[3.5]nonane (29.1 mg, 229 μmol) at room temperature. The mixture was stirred at 120° C. for 2 hours. Water was added, and the mixture was extracted with EA. The organic layers were combined and dried over Na2SO4. The organic layer was concentrated, and the residue was purified by preparative TLC using DCM / MeOH (20:1). This gave 30 mg (59%) of the title compound as a pale yellow solid.

[0345] Analytical data: LC-MS: (ES, m / z) = 222 [M+1]. Example B31: Synthesis of 3-(4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

[0346] [ka]

[0347] To a solution of 3-chloro-1,2,4-triazin-5-amine (30 mg, 229 μmol) and DIEA (59 mg, 458 μmol) in DMSO (1 mL) was added 4-methoxypiperidine (26.3 mg, 229 μmol) at room temperature. The mixture was stirred at 120° C. for 2 hours. Water was added, and the mixture was extracted with EA. The organic layers were combined and dried over Na2SO4. The organic layers were concentrated, and the residue was purified by preparative TLC using PE / EA (5:1). This gave 30 mg (62%) of the title compound as a pale yellow solid.

[0348] Analytical data: LC-MS: (ES, m / z) = 210 [M+1]. Example B32: Synthesis of 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0349] [ka]

[0350] Step 1: Synthesis of (3R,4S)-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate: To a solution of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (700 mg, 3.19 mmol) in THF (5 mL) was added NaH (152 mg, 3.82 mmol) at 0° C. MeI (497 mg, 3.5 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water, extracted with EA, and washed with brine. The organic layer was dried over NaSO, filtered, and evaporated to give the title compound (750 mg, crude) as a yellow oil.

[0351] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56]. Step 2: Synthesis of (3R,4S)-3-fluoro-4-methoxypiperidine: To a solution of tert-butyl (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylate (750 mg, 3.21 mmol) in DCM (10 mL), TFA (2 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was evaporated to give the title compound (700 mg, crude) as a brown oil.

[0352] Step 3: Synthesis of 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine: A mixture of (3R,4S)-3-fluoro-4-methoxypiperidine (700 mg, 5.25 mmol), 2-chloropyrimidin-4-amine (488 mg, 3.76 mmol), and DIPEA (1.44 g, 11.2 mmol) in DMSO (5 mL) was stirred at 100° C. for 2 hours. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried over NaSO, filtered, evaporated, and purified by column chromatography (50% EA in PE) to give the title compound (550 mg) as a yellow solid.

[0353] Example B33: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0354] [ka]

[0355] Step 1: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate: Sodium hydride (218.90 mg, 9.122 mmol, 4 equiv.) was added to tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.280 mmol, 1 equiv.) in THF (10 mL) at 0° C. After stirring for 20 minutes, methyl iodide (1294.73 mg, 9.122 mmol, 4 equiv.) was added. The resulting solution was stirred for an additional hour at 0° C. The reaction was then quenched by the addition of 10 mL of water. The solid was filtered off. The resulting solution was extracted with EA and concentrated in vacuo. This gave 500 mg (94.1%) of the title compound as a pale yellow oil.

[0356] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56]. Step 2: Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine: A solution of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate (500 mg, 2.143 mmol, 1 equivalent) in TFA / DCM (3 / 10 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to give 500 mg of the title compound (crude) as a solid.

[0357] Step 3: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine: A mixture of (3S,4R)-3-fluoro-4-methoxypiperidine (3 g, 22.528 mmol, 1 equiv), 2-chloropyrimidin-4-amine (2.33 g, 0.018 mmol, 0.8 equiv), and TEA (6.84 g, 0.068 mmol, 3 equiv) in IPA (3 mL) was stirred for 12 h at 100° C. The solvent was removed in vacuo, and the residue was purified by FLASH (5% MeOH in DCM) to give 3.3 g (66%) of the title compound as a pale yellow solid.

[0358] Analytical data: LC-MS: (ES, m / z)=227[M+1]. 1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J=5.6 Hz), 6.39 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.83 (d, 1H, J=49.3 Hz), 4.60 - 4.49 (m, 1H), 4.29 (d, 1H, J=13.3 Hz), 3.55 - 3.42 (m, 1H), 3.28 (d, 1H, J=13.3 Hz), 3.20 - 3.04 (m, 1H), 1.76 - 1.48 (m, 2H) Example B34: Synthesis of 2-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)pyrimidin-4-amine

[0359] [ka]

[0360] A mixture of 8-oxa-3-aza-bicyclo[3.2.1]octane (226 mg, 2.0 mmol), 2-chloropyrimidin-4-amine (260 mg, 2.0 mmol) and TEA (300 mg, 3.0 mmol) in IPA (5 mL) was stirred overnight at 100° C. The solvent was removed and the residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (300 mg, 73.8%) as a yellow solid.

[0361] Analytical data: LC-MS: (ES, m / z) = 207 [M+1]. Example B35: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol

[0362] [ka]

[0363] Step 1: Synthesis of rac-tert-butyl 4-hydroxy-2,4-dimethylpiperidine-1-carboxylate: Methyllithium (822 mg, 37.4 mmol) was added dropwise to rac-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (4 g, 18.7 mmol) in THF at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with water / ice and extracted with EA. The combined organic layers were concentrated in vacuo. This gave 4.2 g (98.1%) of the title compound as a yellow solid.

[0364] Analytical data: LC-MS: (ES, m / z) = 230 [M+1]. Step 2: Synthesis of rac-2,4-dimethylpiperidin-4-ol: To a stirred solution of rac-tert-butyl 4-hydroxy-2,4-dimethylpiperidine-1-carboxylate (4 g, 17.4 mmol) in DCM was added TFA (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo. The crude product was used directly in the next step.

[0365] Analytical data: LC-MS: (ES, m / z) = 130 [M+1]. Step 3: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol: To a stirred solution of rac-2,4-dimethylpiperidin-4-ol (2 g, 15.4 mmol) and 2-chloropyrimidin-4-amine (2.18 g, 16.9 mmol) in NMP was added DIEA (3.97 g, 30.8 mmol). The mixture was stirred at 150 °C overnight. After cooling to room temperature, the reaction mixture was extracted with DCM / MeOH (10:1). The residue was purified by preparative TLC using DCM / MeOH (10:1). This gave 0.2 g of the title compound as a white solid.

[0366] Analytical data: LC-MS: (ES, m / z) = 223 [M+1]. Example B36: Synthesis of rac-2-(6-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)pyrimidin-4-amine

[0367] [ka]

[0368] A mixture of 2-chloropyrimidin-4-amine (100 mg, 0.7719 mmol), rac-6-oxa-3-azabicyclo[3.2.1]octane hydrochloride (115 mg, 0.7719 mmol), and TEA (233 mg, 2.31 mmol) in IPA (3 mL) was stirred for 3 h at 100° C. The solution was concentrated, and the residue was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (100 mg) as a white solid.

[0369] Analytical data: LC-MS: (ES, m / z) = 207 [M+1]. Example B37: Synthesis of tert-butyl 3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate

[0370] [ka]

[0371] Step 1: Synthesis of benzyl 3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate: In a 100 mL round-bottom flask, benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.2 g, 5.42 mmol), TEA (822 mg, 8.13 mmol), and methanesulfonyl chloride (620 mg, 5.42 mmol) were placed in DCM (20 mL). The resulting solution was stirred at room temperature for 6 hours. The solution was washed with water and purified by preparative TLC (20% EA in PE). This afforded 1.0 g of the title compound as a white solid.

[0372] Analytical data: LC-MS: (ES, m / z) = 300 [M+1]. Step 2: Synthesis of tert-butyl 3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylthio)azetidine-1-carboxylate: A mixture of benzyl 3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate (530 mg, 1.77 mmol), tert-butyl 3-sulfanylazetidine-1-carboxylate (335 mg, 1.77 mmol), and CsCO (1.15 g, 3.54 mmol) in DMF (2 mL) was stirred at 100° C. for 2 hours. Water was added, and the mixture was extracted with EA. The organic phase was concentrated to give 480 mg of the title compound as a white solid.

[0373] Analytical data: LC-MS: (ES, m / z) = 293 [M+1-100]. Step 3: Synthesis of tert-butyl 3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylsulfonyl)azetidine-1-carboxylate: Oxone (4.21 g, 6.86 mmol) was added to a solution of benzyl 3-[({1-[(tert-butoxy)carbonyl]azetidin-3-yl}sulfanyl)methyl]azetidine-1-carboxylate (900 mg, 2.29 mmol) in EtOH / THF / HO (3 / 3 / 3 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting solution was extracted with EA and purified by preparative TLC using DCM / MeOH (100:1) to give 680 mg of the title compound as a white solid.

[0374] Analytical data: LC-MS: (ES, m / z) = 325 [M+1-100]. Step 4: Synthesis of tert-butyl 3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate: Benzyl 3-[({1-[(tert-butoxy)carbonyl]azetidin-3-yl}sulfonyl)methyl]azetidine-1-carboxylate (660 mg, 1.55 mmol) and Pd / C (199 mg, 1.55 mmol) in MeOH (12 mL) were stirred at room temperature under an atmosphere of hydrogen for 4 hours. The solid was filtered off and the mother liquor solvent was concentrated under reduced pressure to give the title compound (480 mg) as a white solid.

[0375] Analytical data: LC-MS: (ES, m / z) = 291 [M+1]. Example B38: Synthesis of rac-1-(4-aminopyrimidin-2-yl)azepan-4-ol

[0376] [ka]

[0377] A mixture of rac-azepan-4-ol hydrochloride (150 mg, 0.9892 mmol), 2-chloropyrimidin-4-amine (128 mg, 0.989 mmol), and TEA (199 mg, 1.97 mmol) in IPA (15 mL) was stirred for 3 hours at 100° C. The reaction mixture was concentrated and purified by preparative TLC (DCM:MeOH=5:1) to give the title compound (90 mg) as a yellow solid.

[0378] Analytical data: LC-MS: (ES, m / z) = 209 [M+1]. Example B39: Synthesis of (S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine and (R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0379] [ka]

[0380] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-methoxypiperidine-1-carboxylate: NaH (20.23 mg, 0.843 mmol, 2 equiv.) was added to tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (100 mg, 0.422 mmol, 1 equiv.) in DMF (5 mL) at 0° C. After stirring for 30 min, MeI (89.74 mg, 0.632 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with EA and concentrated. This gave 150 mg of the title compound (crude) as a pale yellow solid.

[0381] Analytical data: LC-MS: (ES, m / z) = 252 [M+1]. Step 2: Synthesis of 3,3-difluoro-4-methoxypiperidine: A solution of tert-butyl 3,3-difluoro-4-methoxypiperidine-1-carboxylate (300 mg, 1.194 mmol) in 4 M HCl / dioxane (5 mL) and DCM (15 mL) was stirred at room temperature for 12 hours. The resulting mixture was concentrated to give 280 mg (crude) of the title compound as the HCl salt as a pale yellow solid.

[0382] Analytical data: LC-MS: (ES, m / z) = 152 [M+1]. Step 3: Synthesis of (S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine and (R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine: A mixture of 3,3-difluoro-4-methoxypiperidine (1.5 g, 9.923 mmol, 1 equiv.), 2-chloropyrimidin-4-amine (1.29 g, 9.923 mmol, 1 equiv.), and TEA (3.01 g, 29.77 mmol, 3 equiv.) in IPA (10 mL) was stirred at 100° C. for 3 h. The resulting mixture was concentrated. The residue was applied to a silica gel column with EA / PE (1:1). This gave 1.1 g (45.4%) of the title compound as a yellow solid.

[0383] 2-(3,3-Difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine was separated by preparative chiral SFC using the following conditions: Column name: CHIRALCEL OJ-3, 4.6 x 50 mm, 3 um; Co-solvent: MeOH (0.1% DEA) gradient (B%): 10% to 50% in 4.0 min, hold at 50% for 2.0 min; Back pressure (psi): 1500.000; Flow rate (mL / min) to obtain Peak 1: (S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine or (R)-2- (3,3-Difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (500 mg) was obtained as a pale yellow solid, and Peak 2: (R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine or (S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (500 mg) was obtained as a pale yellow solid.

[0384] Analytical data: LC-MS: (ES, m / z) = 245 [M+1]. Example B40: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-5,5-dimethylpiperidin-4-ol

[0385] [ka]

[0386] Step 1: Synthesis of rac-tert-butyl 5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylate: To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (7.5 g, 32.9 mmol) and TEA (13.2 g, 131 mmol) in toluene was added TMSOTf (14.6 g, 65.8 mmol) at 0 °C under a N atmosphere. The mixture was stirred at room temperature for 2 h. The mixture was extracted with EA and water. The organic layer was dried over NaSO and concentrated in vacuo. The crude product was used directly in the next step.

[0387] To a solution of tert-butyl 3,3-dimethyl-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylate (1.2 g, 4.0 mmol) in ACN was added Selectfluor (1.55 g, 4.4 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Water was added, and the mixture was extracted with EA. The organic layers were combined and dried over Na2SO4. The organic layers were concentrated, and the residue was purified by flash using PE / EA (5:1). This gave 500 mg (51%) of the title compound as a pale yellow solid.

[0388] Analytical data: LC-MS: (ES, m / z) = 246 [M+1]. Step 2: Synthesis of tert-butyl 3,3-difluoro-5,5-dimethyl-4-oxopiperidine-1-carboxylate: To a solution of rac-tert-butyl 5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylate (100 mg, 407 μmol) in THF was added LiHMDS (46.4 mg, 814 μmol) at −78° C. under a N atmosphere. The mixture was stirred at −78° C. for 10 minutes, and NFSI (117 mg, 610 μmol) was added. The resulting mixture was stirred for 2 hours. The mixture was extracted with EA and water. The organic layer was concentrated, and the residue was purified by preparative TLC using PE / EA (5:1). This afforded 60 mg (56%) of the title compound as a pale yellow solid.

[0389] Analytical data: LC-MS: (ES, m / z) = 208 [M+1-56]. Step 3: Synthesis of rac-tert-butyl 3,3-difluoro-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate: To a solution of tert-butyl 3,3-difluoro-5,5-dimethyl-4-oxopiperidine-1-carboxylate (80 mg, 303 μmol) in MeOH was added NaBH4 (45.9 mg, 1.21 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA and water. The organic layer was concentrated in vacuo. 75 mg of the crude product was used directly in the next step.

[0390] Analytical data: LC-MS: (ES, m / z) = 210 [M+1-56]. Step 4: Synthesis of rac-3,3-difluoro-5,5-dimethylpiperidin-4-ol: rac-tert-Butyl 3,3-difluoro-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate (75 mg, 282 μmol) was added to DCM / TFA (5 mL / 2 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give the title compound (40 mg, 86%) as a brown liquid.

[0391] Analytical data: LC-MS: (ES, m / z) = 166 [M+1]. Step 5: Synthesis of rac-tert-butyl 2-(3,3-difluoro-4-hydroxy-5,5-dimethylpiperidin-1-yl)pyrimidin-4-ylcarbamate: A mixture of rac-3,3-difluoro-5,5-dimethylpiperidin-4-ol (100 mg, 605 μmol), tert-butyl N-(2-bromopyrimidin-4-yl)-N-[(tertbutoxy)carbonyl]carbamate (226 mg, 605 μmol), CuI (57.3 mg, 302 μmol), L-proline (6.95 mg, 60.5 μmol), and KPO (383 mg, 1.81 mmol) in DMSO was stirred at 100 °C under a N atmosphere for 2 h. Water was added, and the mixture was extracted with EA. The organic phase was concentrated, and the residue was purified by preparative TLC using DCM / MeOH (20:1). This afforded 100 mg (36%) of the product as a yellow solid.

[0392] Analytical data: LC-MS: (ES, m / z) = 359 [M+1]. Step 6: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-5,5-dimethylpiperidin-4-ol: rac-tert-butyl-N-[(tert-butoxy)carbonyl]-N-[2-(3,3-difluoro-4-hydroxy-5,5-dimethylpiperidin-1-yl)pyrimidin-4-yl]carbamate (200 mg, 436 μmol) in DCM / TFA (10 / 3 mL) was stirred at room temperature for 2 hours. The solvent was concentrated in vacuo to give the title compound (100 mg, 90%) as a brown solid.

[0393] Analytical data: LC-MS: (ES, m / z) = 259 [M+1]. Example B41: Synthesis of rac-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol

[0394] [ka]

[0395] To a solution of 3-chloro-1,2,4-triazin-5-amine (280 mg, 2.14 mmol) and TEA (648 mg, 6.42 mmol) in IPA (5 mL) was added 3-fluoro-3-methylpiperidin-4-ol (Step 4, B1; 284 mg, 2.14 mmol) at room temperature. The mixture was stirred at 100 °C for 2 hours. The solvent was removed, and the residue was purified by preparative TLC using PE / EA (5:1). This gave 260 mg (53%) of 1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol as a yellow solid. The product was purified using an XBridge Shield RP18 OBD column, 30 x 150 mm, 5 µm; mobile phase A: water (0.05% NH3HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5B to 10B in 7 min; 254 / 220 nm. This afforded 90 mg of rac-cis-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol and 30 mg of rac-trans-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol. Both were yellow solids.

[0396] Analytical data: LC-MS: (ES, m / z) = 228 [M+1]. Example B42: Synthesis of rac-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-ol and rac-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol

[0397] [ka]

[0398] Step 1: Synthesis of rac-(cis)-tert-butyl 3,4-dihydroxy-3-methylpiperidine-1-carboxylate: To a mixture of tert-butyl 5-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate (200 mg, 1012 μmol), NMO (142.2 mg, 1214 μmol) in acetone (6 mL) and water (2 mL) was added KOsO·2H O (37.4 mg, 101.2 μmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with EA. The organic layer was dried over NaSO. Filtration and concentration to dryness afforded the title compound (180 mg) as a dark yellow oil.

[0399] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56]. Step 2: Synthesis of rac-(cis)-tert-butyl 3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylate: Mel (367 mg, 2.59 mmol) was added to a mixture of AgO (399 mg, 1.72 mmol) and tert-butyl (cis)-3,4-dihydroxy-3-methylpiperidine-1-carboxylate (200 mg, 864 μmol) in DMF (20 mL) at room temperature. The mixture was stirred at room temperature for 2 days. The solid was filtered off, and the filtrate was diluted with EA and washed with HO. The organic layer was dried over NaSO and concentrated in vacuo to give 160 mg of rac-tert-butyl (cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylate mixed with rac-(cis)-tert-butyl 4-hydroxy-3-methoxy-3-methylpiperidine-1-carboxylate as a colorless oil, which was used in the next step without further purification.

[0400] Analytical data: LC-MS: (ES, m / z) = 190 [M+1-56]. Step 3: Synthesis of rac-(cis)-4-methoxy-3-methylpiperidin-3-ol: TFA (5 mL) was added dropwise to rac-tert-butyl (cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylate mixed with rac-(cis)-tert-butyl 4-hydroxy-3-methoxy-3-methylpiperidine-1-carboxylate (160 mg, 652 μmol) in DCM (15 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 100 mg of rac-(cis)-4-methoxy-3-methylpiperidin-3-ol mixed with rac-(cis)-3-methoxy-3-methylpiperidin-4-ol as a colorless oil.

[0401] Analytical data: LC-MS: (ES, m / z) = 146 [M+1]. Step 4: Synthesis of rac-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-ol and rac-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol: 2-Chloropyrimidin-4-amine (100 mg, 771 μmol) was added to rac-(cis)-4-methoxy-3-methylpiperidin-3-ol (111 mg, 771 μmol) / rac-(cis)-3-methoxy-3-methylpiperidin-4-ol in TEA (388 mg, 385 mmol) and IPA at room temperature. The mixture was heated to 100° C. for 16 hours. The mixture was concentrated in vacuo. The residue was purified by preparative TLC using DCM:MeOH=25:1. This gave 120 mg of rac-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-ol mixed with rac-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol as a brown oil.

[0402] Analytical data: LC-MS: (ES, m / z) = 239 [M+1]. Example B43: Synthesis of 3-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

[0403] [ka]

[0404] To a solution of (3R,4S)-3-fluoro-4-methoxypiperidine (60 mg, 450 μmol) and DIEA (174 mg, 1.35 mmol) in DMSO (2 mL) was added 3-chloro-1,2,4-triazin-5-amine (64.6 mg, 495 μmol) at room temperature. The mixture was stirred at 120° C. for 2 hours. Water was added, and the mixture was extracted with EA. The organic layer was concentrated and purified by preparative TLC using PE / EA (5:1). This gave 40 mg (39%) of the title compound as a yellow solid.

[0405] Analytical data: LC-MS: (ES, m / z) = 228 [M+1]. Example B44: Synthesis of 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethanol

[0406] [ka]

[0407] A mixture of 2-chloropyrimidin-4-amine (400 mg, 3.08 mmol), 2-(piperidin-4-yloxy)ethan-1-ol (447 mg, 3.08 mmol), and TEA (933 mg, 9.24 mmol) in IPA (10 mL) was stirred at 100° C. for 12 hours. The reaction mixture was diluted with water and extracted with EA. The organic layer was dried over NaSO, filtered, evaporated, and purified by column chromatography (DCM:MeOH=20:1) to give the title compound (270 mg) as a yellow solid.

[0408] Analytical data: LC-MS: (ES, m / z) = 239 [M+1]. Example B45: Synthesis of rac-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol

[0409] [ka]

[0410] Step 1: Synthesis of rac-1-tert-butyl 3-methyl 4-methoxypiperidine-1,3-dicarboxylate: NaH (1.3 g, 34.5 mmol) was added to a solution of rac-1-tert-butyl 3-methyl 4-hydroxypiperidine-1,3-dicarboxylate (6.0 g, 23.0 mmol) in DMF (50 mL) at 0° C. After stirring for 10 min, iodomethane (4.8 g, 34.5 mmol) was added. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EA. The organic phase was washed with water, dried, and concentrated. The residue was purified by FLASH (20% EA in PE) to give 3.0 g (47%) of the title compound as a colorless oil.

[0411] Analytical data: LC-MS: (ES, m / z) = 274 [M+1]. Step 2: Synthesis of rac-tert-butyl 3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate: LiBH4 (2 M in THF, 15 mmol) was added to a solution of rac-1-tert-butyl 3-methyl 4-methoxypiperidine-1,3-dicarboxylate (2 g, 7.3 mmol) in THF (40 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EA. The organic phase was washed with water, dried and concentrated to give 1.2 g (67%) of the title compound as a colorless oil.

[0412] Analytical data: LC-MS: (ES, m / z) = 246 [M+1]. Step 3: Synthesis of rac-(4-methoxypiperidin-3-yl)methanol: 1.2 g of rac-tert-butyl 3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate was added to a solution of TFA / DCM (20 mL / 6 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give 700 mg of the title compound trifluoroacetate as a yellow oil.

[0413] Analytical data: LC-MS: (ES, m / z) = 146 [M+1]. Step 4: Synthesis of rac-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol: A mixture of rac-(4-methoxypiperidin-3-yl)methanol (700 mg), 2-chloropyrimidin-4-amine (376 mg, 2.89 mmol) and TEA (578 mg, 5.78 mmol) in IPA was stirred overnight at 100° C. The solvent was removed and the residue was purified by preparative TLC (5% MeOH in DCM) to give 400 mg of rac-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol as a pale yellow solid.

[0414] Analytical data: LC-MS: (ES, m / z) = 239 [M+1]. Example B46: Synthesis of (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol

[0415] [ka]

[0416] Step 1: Synthesis of (4-methoxypiperidin-4-yl)methanol: To a solution of 4-methoxypiperidine-4-carboxylic acid hydrochloride (200 mg, 1.02 mmol) in THF (25 mL) was added LiAlH (116 mg, 3.06 mmol). The mixture was stirred at 60° C. for 16 hours. The reaction mixture was quenched with ice water. The resulting mixture was washed with EA. The aqueous layer was filtered and concentrated to dryness to give the title compound (400 mg, crude) as a colorless oil.

[0417] Analytical data: LC-MS: (ES, m / z) = 146 [M+1]. Step 2: Synthesis of (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol: A mixture of (4-methoxypiperidin-4-yl)methanol (400 mg, crude), 4-chloropyrimidin-2-amine (130 mg, 1.01 mmol), TEA (306 mg, 3.03 mmol) in IPA (25 mL) was stirred for 2 h at 100° C. The mixture was concentrated, and the residue was purified on preparative TLC (EA:PE=2:1) ​​to give the title compound (35 mg) as a pale yellow solid.

[0418] Analytical data: LC-MS: (ES, m / z) = 239 [M+1]. Example B47: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-2-methylpiperidin-4-ol

[0419] [ka]

[0420] A mixture of rac-2-methylpiperidin-4-ol (575 mg, 5.0 mmol), 2-chloropyrimidin-4-amine (645 mg, 5.0 mmol), and TEA (1000 mg, 10 mmol) in IPA (5 mL) was stirred at 100° C. overnight. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (5% MeOH in DCM) to give 200 mg of the title compound as a yellow solid.

[0421] Analytical data: LC-MS: (ES, m / z) = 209 [M+1]. Example B48: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate

[0422] [ka]

[0423] Step 1: Synthesis of tert-butyl 2-(piperidin-4-yloxy)ethylcarbamate: A mixture of tert-butyl 2-(pyridin-4-yloxy)ethylcarbamate (200 mg, 0.84 mmol) and PtO (30 mg) in AcOH (5 mL) was stirred overnight at 50 °C under a 5 atm H atmosphere. The solvent was removed under reduced pressure, and the residue was diluted with MeOH. The solid was filtered off, and the filtrate was concentrated to give 250 mg of the crude title compound as a colorless oil.

[0424] Analytical data: LC-MS: (ES, m / z) = 245 [M+1]. Step 2: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate: A mixture of crude tert-butyl 2-(piperidin-4-yloxy)ethylcarbamate (250 mg), 2-chloropyrimidin-4-amine (129 mg, 1.0 mmol), and TEA (200 mg, 2.0 mmol) in DMSO (1 mL) was stirred at 120° C. overnight. Water was added, and the mixture was extracted with EA. The organic phase was washed, concentrated, and purified by preparative TLC (5% MeOH in DCM) to give 70 mg of the title compound as a yellow oil.

[0425] Analytical data: LC-MS: (ES, m / z) = 338 [M+1]. Example B49: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile and rac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile

[0426] [ka]

[0427] Step 1: Synthesis of rac-tert-butyl 3-carbamoyl-4-methoxypiperidine-1-carboxylate: A solution of rac-1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-3-carboxylic acid (500 mg, 1.92 mmol), DIPEA (744 mg, 5.76 mmol), aqueous ammonia (10 mL), and HATU (1.09 g, 2.88 mmol) in DCM (30 mL) was stirred at room temperature for 1 h. The mixture was extracted with DCM, dried, and concentrated to give the title compound (500 mg) as a colorless oil.

[0428] Analytical data: LC-MS: (ES, m / z) = 259 [M+1]. Step 2: Synthesis of rac-tert-butyl 3-cyano-4-methoxypiperidine-1-carboxylate: TFAA (810 mg, 3.86 mmol) was added to a solution of rac-tert-butyl 3-carbamoyl-4-methoxypiperidine-1-carboxylate (500 mg, 1.93 mmol) and TEA (585 mg, 5.79 mmol) in DCM (25 mL). The mixture was stirred at room temperature for 2 hours. The resulting solution was washed with water and dried over Na2SO4. This gave the title compound (400 mg) as a colorless oil.

[0429] Analytical data: LC-MS: (ES, m / z) = 185 [M+1-56]. Step 3: Synthesis of rac-4-methoxypiperidine-3-carbonitrile: To a solution of rac-tert-butyl 3-cyano-4-methoxypiperidine-1-carboxylate (400 mg, 1.66 mmol) in DCM (10 mL) was added TFA (5 mL). After 1 hour, the solvent was removed by concentration to give the title compound (500 mg) as a pale yellow oil.

[0430] Analytical data: LC-MS: (ES, m / z) = 141 [M+1]. Step 4: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile and rac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile: A mixture of 2-chloropyrimidin-4-amine (461 mg, 3.56 mmol), rac-4-methoxypiperidine-3-carbonitrile (500 mg, 3.56 mmol), and DIPEA (1.37 g, 10.6 mmol) in DMSO (20 mL) was stirred for 3 hours at 120° C. The reaction mixture was purified on preparative HPLC: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (0.05% NH H O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 13B to 23B in 7 min; 254 / 220 nm. This gave rac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile (35 mg) as a colorless oil and rac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile (50 mg) as a colorless oil.

[0431] rac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile: Analysis data: LC-MS: (ES, m / z)=234[M+1];1H-NMR (300 MHz, 3d-CD3Cl) δ ppm 7.94 (d, 1H, J=5.6 Hz), 5.81 (d, 1H, J=5.7 Hz), 4.68 (s, 2H), 4.37 (dd, 1H, J=13.4, 7.0 Hz), 4.14 - 4.00 (m, 1H), 3.85 (dd, 1H, J=13.1, 3.6 Hz), 3.68 - 3.57 (m, 2H), 3.49 (s, 3H), 3.04 (dtd, 1H, J=6.7, 3.8, 2.0 Hz), 1.99 - 1.71 (m, 2H) rac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile: Analysis data: LC-MS: (ES, m / z)=234[M+1];1H-NMR (300 MHz, 3d-CD3Cl) δ ppm 7.93 (d, 1H, J=5.6 Hz), 5.82 (d, 1H, J=5.6 Hz), 4.78 - 4.71 (m, 1H), 4.69 (s, 2H), 4.51 - 4.37 (m, 1H), 3.61 - 3.51 (m, 1H), 3.49 (s, 3H), 3.40 (dd, 1H, J=13.4, 9.5 Hz), 3.19 (ddd, 1H, J=13.6, 10.4, 3.1 Hz), 2.64 (td, 1H, J=9.1, 4.0 Hz), 2.21 - 2.07 (m, 1H), 1.53 - 1.34 (m, 1H) Example B50: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-3-methoxypiperidin-4-ol

[0432] [ka]

[0433] Step 1: Synthesis of rac-tert-butyl 4-hydroxy-3-methoxypiperidine-1-carboxylate: NaBH4 (395 mg, 10.4 mmol) was added to a solution of rac-tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate (2 g, 8.72 mmol) in THF (50 mL) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (2 g, crude) as a yellow semi-solid.

[0434] Analytical data: LC-MS: (ES, m / z) = 232 [M+1]. Step 2: Synthesis of rac-3-methoxypiperidin-4-ol: A solution of rac-tert-butyl 4-hydroxy-3-methoxypiperidine-1-carboxylate (1 g, 4.32 mmol) in HCl / dioxane (50 mL) was stirred at room temperature for 3 hours. The reaction mixture was evaporated to give the title compound (700 mg, crude) as a yellow semi-solid.

[0435] Analytical data: LC-MS: (ES, m / z) = 132 [M+1]. Step 3: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-3-methoxypiperidin-4-ol: A mixture of rac-2-chloropyrimidin-4-amine (200 mg, 1.54 mmol), 3-methoxypiperidin-4-ol (700 mg, 5.33 mmol), and TEA (1.24 g, 12.3 mmol) in IPA (8 mL) was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (100 mL), extracted with EA (150 mL×3), and washed with brine (50 mL). The organic layer was dried over NaSO, filtered, evaporated, and purified by column chromatography (EA) to give the title compound (220 mg) as a yellow solid.

[0436] Analytical data: LC-MS: (ES, m / z) = 225 [M+1]. Example B51: Synthesis of 2-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

[0437] [ka]

[0438] Step 1: Synthesis of (3R,4S)-tert-butyl 3-fluoro-4-(2-hydroxyethoxy)piperidine-1-carboxylate: NaH (455 mg, 11.4 mmol) was added to tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1.0 g, 4.56 mmol) in 10 mL of DMF at 0° C. After stirring for 20 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (3.25 g, 13.6 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash using PE:EA=10:1 to give 1.1 g of the title compound as a colorless oil.

[0439] Step 2: Synthesis of 2-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol: TFA (5 mL) was added to tert-butyl (3R,4S)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoropiperidine-1-carboxylate (1.1 g, 2.91 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was mixed with 2-chloropyrimidin-4-amine (317 mg, 2.45 mmol) and DIEA (1.26 mg, 9.80 mmol) in DMSO (10 mL). The mixture was heated to 100° C. and stirred for 16 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash using MeOH:EA=1:15 to give 450 mg of the title compound as a yellow solid.

[0440] Analysis data: LC-MS: (ES, m / z)=257[M+1];1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J=5.6 Hz), 6.41 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.91 - 4.73 (m, 1H), 4.67 - 4.50 (m, 2H), 4.34 (d, 1H, J=13.0 Hz), 3.69 - 3.46 (m, 5H), 3.30 - 3.17 (m, 1H), 3.06 (d, 1H, J=11.3 Hz), 1.80 - 1.54 (m, 2H). Example B52: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

[0441] [ka]

[0442] Step 1: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-(2-hydroxyethoxy)piperidine-1-carboxylate: NaH (1.35 g, 33.9 mmol) was added batchwise to tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (3.0 g, 13.6 mmol) in DMF (10 mL) at 0° C. The mixture was stirred at 0° C. for 20 min. (2-Bromoethoxy)(tert-butyl)dimethylsilane (9.76 g, 40.8 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash using PE:EA=10:1 to give 3.0 g of the title compound as a colorless oil.

[0443] Step 2: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol: TFA (15 mL) was added to tert-butyl (3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoropiperidine-1-carboxylate (3.0 g, 7.94 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was mixed with 2-chloropyrimidin-4-amine (873 mg, 6.74 mmol) and DIEA (629 mg, 4.88 mmol) in DMSO (10 mL). The mixture was stirred at 100° C. overnight. The mixture was diluted with EA (50 mL), washed with brine, and the organic layer was dried over Na SO and concentrated in vacuo. The residue was purified by flash using MeOH:EA=1:15 to give 1.1 g of the title compound as a yellow solid.

[0444] Analysis data: LC-MS: (ES, m / z)=257[M+1];1H-NMR (400 MHz, 6d-DMSO) δ ppm7.72 (d, 1H, J=5.6 Hz), 6.41 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.94 - 4.69 (m, 1H), 4.67 - 4.52 (m, 2H), 4.34 (d, 1H, J=13.3 Hz), 3.72 - 3.45 (m, 5H), 3.31 - 3.19 (m, 1H), 3.07 (t, 1H, J=11.4 Hz), 1.77 - 1.44 (m, 2H). Example B53: Synthesis of rac-cis-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate and rac-trans-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate

[0445] [ka]

[0446] Step 1: Synthesis of rac-1-(tert-butoxycarbonyl)-4-methoxypiperidine-3-carboxylic acid: A mixture of rac-1-tert-butyl 3-methyl 4-methoxypiperidine-1,3-dicarboxylate (3 g, 10.9 mmol), NaOH (871 mg, 21.8 mmol) in MeOH (25 mL) and water (10 mL) was stirred at 80° C. for 1 h. The mixture was extracted with EA. The organic layer was dried over NaSO and concentrated to dryness to give the title compound (2.7 g, 95%) as a pale yellow oil.

[0447] Analytical data: LC-MS: (ES, m / z) = 282 [M+23]. Step 2: Synthesis of rac-4-methoxypiperidine-3-carboxylic acid: To a solution of rac-1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-3-carboxylic acid (1.5 g, 5.78 mmol) in DCM (20 mL) was added TFA (7 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration to dryness to give the title compound (1.5 g, crude) as a pale yellow oil.

[0448] Analytical data: LC-MS: (ES, m / z) = 160 [M+1]. Step 3: Synthesis of rac-1-(benzyloxycarbonyl)-4-methoxypiperidine-3-carboxylic acid: To a solution of rac-4-methoxypiperidine-3-carboxylic acid (1.5 g, crude) and NaOH (931 mg, 23.3 mmol) in water (20 mL) was added CbzCl (1.49 g, 8.74 mmol). After 1 h, the resulting mixture was washed with EA. The aqueous layer was acidified with 1 N HCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to dryness to give the title compound (1.2 g, 70% for two steps) as a colorless oil.

[0449] Analytical data: LC-MS: (ES, m / z) = 294 [M+1]. Step 4: Synthesis of rac-benzyl 3-(tert-butoxycarbonylamino)-4-methoxypiperidine-1-carboxylate: To a solution of rac-1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-3-carboxylic acid (1.2 g, 4.09 mmol) and TEA (1.23 g, 12.2 mmol) in tBuOH (40 mL) was added DPPA (1.49 g, 6.13 mmol). The mixture was stirred at 100° C. for 3 hours. The solvent was removed by concentration, and the residue was purified on a silica gel column using 60% EtOAc in PE to give the title compound (300 mg) as a colorless oil.

[0450] Analytical data: LC-MS: (ES, m / z) = 387 [M+23]. Step 5: Synthesis of rac-tert-butyl 4-methoxypiperidin-3-ylcarbamate: A mixture of rac-benzyl 3-{[(tert-butoxy)carbonyl]amino}-4-methoxypiperidine-1-carboxylate (300 mg, 823 μmol) and Pd / C (87.5 mg, 82.3 μmol) in MeOH (20 mL) was stirred at room temperature under an H atmosphere for 2 hours. The solid was filtered off, and the filtrate was concentrated to dryness to give the title compound (100 mg) as a colorless oil.

[0451] Analytical data: LC-MS: (ES, m / z) = 231 [M+1]. Step 6: Synthesis of rac-cis-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate and rac-trans-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate: A mixture of rac-tert-butyl N-(4-methoxypiperidin-3-yl)carbamate (100 mg, 434 μmol), 2-chloropyrimidin-4-amine (56.2 mg, 434 μmol), and DIEA (168 mg, 1.30 mmol) in DMSO (8 mL) was stirred for 3 hours at 100° C. The resulting mixture was purified by preparative HPLC to give peak 2: rac-cis-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate (18 mg) as an off-white solid and peak 1: rac-trans-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate (55 mg) as an off-white solid.

[0452] Analytical data: LC-MS: (ES, m / z) = 324 [M+1]. Example B54: Synthesis of (3R,4R)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol and (3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol

[0453] [ka]

[0454] Step 1: Synthesis of tert-butyl 5,5-difluoro-5,6-dihydropyridine-1(2H)-carboxylate: To a solution of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (355 mg, 1.5 mmol, 1 equiv) in DCM (6 mL) was added DMAP (274 mg, 2.25 mmol, 1.5 equiv) followed by trifluoromethanesulfonyl trifluoromethanesulfonate (550 mg, 1.95 mmol, 1.3 equiv) at 0 °C. The reaction was carried out at 0 °C for 1 hour and then quenched with saturated NaHCO3 (30 mL). The mixture was extracted with DCM (10 mL × 3). The organic layers were combined and concentrated. The residue was dissolved in toluene (5 mL). DBU (569 mg, 3.75 mmol, 2.5 equiv) was added. The reaction was carried out at 70 °C for 18 hours. After cooling to room temperature, the mixture was diluted with MTBE (50 mL). The mixture was washed with water (10 mL). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (PE / EA=10:1) to give the title compound (260 mg, 79.3%) as a pale yellow oil.

[0455] Analysis data: 1H-NMR (400 MHz, CD3Cl) δ ppm 6.23 - 6.17 (m, 1H), 5.98 - 5.92 (m, 1H), 4.06 - 4.00 (m, 2H), 3.91 - 3.65 (m, 2H), 1.51 (s, 9H). Step 2: Synthesis of tert-butyl cis-3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylate: To a mixture of tert-butyl 3,3-difluoro-1,2,3,6-tetrahydropyridine-1-carboxylate (153 mg, 700 μmol, 1 equiv.) in acetone (4 mL) and HO (1 mL) was added KOsO·2HO (12.8 mg, 35 μmol, 0.05 equiv.) and NMO (244 mg, 2.1 mmol, 3 equiv.) at room temperature. The reaction was carried out at 40 °C for 18 h. After cooling to room temperature, the mixture was diluted with EA (50 mL) and washed with 10% NaSO solution (10 mL) and water (10 mL). The organic layer was concentrated, and the residue was purified by silica gel column chromatography (DCM / EA = 2:1) to give the title compound (71 mg, 40.1%) as a white solid.

[0456] Analysis data: 1H-NMR (400 MHz, 6d-DMSO) δ ppm 5.88 (d, 1H, J=5.1 Hz), 5.18 (d, 1H, J=5.9 Hz), 3.96 - 3.60 (m, 3H), 3.60 - 3.44 (m, 1H), 3.34 - 3.19 (m, 1H), 3.10 - 2.76 (m, 1H), 1.40 (s, 9H). Step 3: Synthesis of tert-butyl cis-3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate: To a solution of tert-butyl cis-3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylate (69.6 mg, 275 μmol, 1 equiv.) in THF (2 mL) was added NaH (10.9 mg, 275 μmol, 1 equiv., 60%) at 0° C. After 30 min, MeI (39.0 mg, 275 μmol, 1 equiv.) was added. The reaction was carried out at 0° C. for 1 h and at room temperature for 18 h. After quenching with saturated NH4Cl (10 mL), the mixture was extracted with EA (5 mL × 3). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / EA = 2:1) to give the title compound (22 mg, 30%) as a colorless syrup.

[0457] Step 4: Synthesis of cis-5,5-difluoro-4-methoxypiperidin-3-ol: A solution of tert-butyl cis-3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate (240 mg, 900 μmol, 1 equiv) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 3 h and concentrated to give the title compound (220 mg, crude) as a colorless oil.

[0458] Analytical data: LC-MS: (ES, m / z) = 168 [M+1]. Step 5: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol and (3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol: 220 mg of cis-5,5-difluoro-4-methoxypiperidin-3-ol was dissolved in IPA (2 mL). 2-Chloropyrimidin-4-amine (116 mg, 900 μmol, 1 eq.) was added, followed by TEA (454 mg, 4.50 mmol, 5 eq.). The reaction was carried out at 100° C. for 18 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (DCM / MeOH=20:1) to give (3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol (50 mg, 21.36%) as a white solid. The compound was purified under the following conditions: CHIRAL Cellulose-SB 4.6×100 mm Separation by preparative chiral HPLC using 3 μm; mobile phase: Hex (0.1% DEA): IPA = 70:30; flow rate: 1.0 mL / min gave peak 1: (3R,4R)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol or (3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol (20 mg) as a pale yellow solid, and peak 2: (3R,4R)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol or (3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol (20 mg) as a pale yellow solid.

[0459] Analysis data: LC-MS: (ES, m / z)=261[M+1];1H-NMR (300 MHz, 3d-CD3Cl) δ ppm 7.95 (d, 1H, J=5.6 Hz), 5.82 (d, 1H, J=5.6 Hz), 4.87 - 4.70 (m, 1H), 4.67 - 4.48 (m, 3H), 3.91 (s, 1H), 3.67 (d, 3H, J=1.0 Hz), 3.67 - 3.60 (m, 1H), 3.51 (ddd, 1H, J=29.0, 14.0, 1.8 Hz), 3.12 (dd, 1H, J=12.9, 10.1 Hz), 2.41 (s, 1H). Example B55: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

[0460] [ka]

[0461] Step 1: Synthesis of rac-cis-tert-butyl 3,4-dihydroxy-4-methylpiperidine-1-carboxylate: To a solution of tert-butyl 4-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate (300 mg, 1.52 mmol) in THF (3 mL) and HO (1 mL), KOsO 2HO (50.4 mg, 152 μmol) and NMO (533 mg, 4.56 mmol) were added at room temperature and stirred for 12 h. The reaction mixture was diluted with saturated aqueous NaSO and extracted with EA and brine. The organic layer was dried over NaSO, filtered, and evaporated to give the title compound (350 mg, crude) as a yellow solid.

[0462] Analytical data: LC-MS: (ES, m / z) = 254 [M+23]. Step 2: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol: To a solution of rac-tert-butyl cis-3,4-dihydroxy-4-methylpiperidine-1-carboxylate (350 mg, crude) in DCM (6 mL), TFA (2 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was evaporated, the residue was dissolved in IPA (3 mL), 2-chloropyrimidin-4-amine (160 mg, 1.23 mmol) and TEA (621 mg, 6.15 mmol) were added, and the mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried over Na SO , filtered, and evaporated. The residue was purified by column chromatography (DCM:MeOH=20:1) to give the title compound (200 mg, 72.7%) as a yellow solid.

[0463] Analytical data: LC-MS: (ES, m / z) = 225 [M+1]. Example B56: Synthesis of rac-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

[0464] [ka]

[0465] Step 1: Synthesis of tert-butyl 6-methyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate: To a solution of tert-butyl 4-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate (500 mg, 2.53 mmol) in DCM (20 mL) was added m-CPBA (870 mg, 5.06 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA and water. The organic layer was concentrated and purified by FLASH (30% EA in PE) to give 460 mg of the title compound as a colorless oil.

[0466] Analytical data: LC-MS: (ES, m / z) = 214 [M+1]. Step 2: Synthesis of rac-tert-butyl trans-3,4-dihydroxy-4-methylpiperidine-1-carboxylate: To a solution of rac-tert-butyl 6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (100 mg, 468 μmol) in HO (5 mL) was added KOH (448 mg, 8.00 mmol) and the solution was stirred at 75° C. for 15 h. The mixture was extracted with EA, dried and concentrated to give 180 mg of the title compound as a yellow oil.

[0467] Analytical data: LC-MS: (ES, m / z) = 232 [M+1]. Step 2: Synthesis of rac-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol: To a solution of rac-tert-butyl trans-3,4-dihydroxy-4-methylpiperidine-1-carboxylate (300 mg, 1.29 mmol) in DCM (10 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure. The residue was dissolved in IPA (2 mL), and 2-chloropyrimidin-4-amine (88.8 mg, 686 μmol) and DIEA (441 mg, 3.42 mmol) were added, and the solution was heated to 120° C. for 10 hours. The mixture was extracted with EA and water. The organics were concentrated and purified by FLASH (50% MeOH in DCM) to give 80 mg of the title compound as a pale yellow solid.

[0468] Analytical data: LC-MS: (ES, m / z) = 225 [M+1]. Example B57: Synthesis of rac-tert-butyl 1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-ylcarbamate

[0469] [ka]

[0470] A mixture of rac-tert-butyl N-(3,3-difluoropiperidin-4-yl)carbamate (200 mg, 0.85 mmol, 1 equiv.), 2-chloropyrimidin-4-amine (109.67 mg, 0.847 mmol, 1 equiv.), and TEA (256.98 mg, 2.540 mmol, 3 equiv.) in IPA (3 mL) was stirred at 100° C. for 3 hours. The mixture was concentrated, and the residue was applied to a silica gel column using DCM / MeOH (20:1). This gave 100 mg (35.9%) of the title compound as a pale yellow solid.

[0471] Analytical data: LC-MS: (ES, m / z) = 330 [M+1]. Example B58: Synthesis of rac-cis-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-4-methylpiperidin-4-ol

[0472] [ka]

[0473] A mixture of 3-chloro-1,2,4-triazin-5-amine (200 mg, 1.53 mmol), cis-3-fluoro-4-methylpiperidin-4-ol (243 mg, 1.83 mmol), and TEA (309 mg, 3.06 mmol) in IPA (5 mL) was stirred at 100° C. for 2 h. Water was added, and the reaction was extracted with EA. The organic layer was purified by preparative TLC (DCM:MeOH=10:1). This afforded 300 mg (34.4%) of the title compound as a gray solid.

[0474] Analytical data: LC-MS: (ES, m / z) = 228 [M+1]. Example B59: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine and 2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine and 2-((3R,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine and 2-((3S,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine

[0475] [ka]

[0476] Step 1: Synthesis of rac-tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate: rac-tert-Butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (Step 3, Example B1; 4 g, 17 mmol) was dissolved in DMF (40 mL), and sodium hydride (820 mg, 34.2 mmol) was added at 0° C. The mixture was stirred at room temperature for 1 h. Iodomethane (4.82 g, 34.2 mmol) was added, and the reaction was stirred at room temperature for an additional 2 h. The reaction was quenched with water / ice, extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 5.1 g of tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate as a colorless oil.

[0477] Step 2: Synthesis of rac-2-(3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine: rac-tert-Butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate (5.1 g) was dissolved in HCl / dioxane (4 M, 50 mL). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was mixed with 2-chloropyrimidine-4- (4.21 g, 32.5 mmol) and TEA (5.47 g, 54.2 mmol) in IPA (30 mL). The mixture was stirred at 100 °C and stirred for 16 hours. The reaction was concentrated in vacuo, and the residue was purified by FLASH (DCM:MeOH = 10:1). This gave 1.6 g of the title compound as a white solid, which was further separated into four isomers using the following conditions: Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[0478] Column name: CHIRAL ND(2) 4.6 x 100 mm, 3 um; cosolvent: MeOH (0.1% DEA); gradient (%): 10% to 50% in 4.0 min, hold at 50% for 2.0 min; flow rate (mL / min) to give 2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine or 2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (490 mg) and 2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine or 2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (440 mg). Both are pale yellow solids.

[0479] Column name: CHIRAL ND(2) 4.6 x 100 mm, 3 um; cosolvent: MeOH (0.1% DEA); gradient (%): 10% to 50% in 4.0 min, hold at 50% for 2.0 min; flow rate (mL / min) to give 2-((3R,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine or 2-((3S,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (81 mg) and 2-((3S,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine or 2-((3R,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (123 mg). Both are pale yellow solids.

[0480] Example B60: Synthesis of rac-tert-butyl 2-(azetidin-3-yl)-2-(methylsulfonyl)ethylcarbamate

[0481] [ka]

[0482] Step 1: Synthesis of rac-benzyl 3-(1-(methylsulfonyl)prop-2-ynyl)azetidine-1-carboxylate: Cs2CO3 (544 mg, 1.67 mmol) was added to 2-methanesulfonylacetonitrile (1 g, 8.39 mmol) and benzyl 3-iodoazetidine-1-carboxylate (3.96 g, 12.5 mmol) in DMF (5 mL) at room temperature. The resulting mixture was stirred at 80 °C for 8 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column using PE:EA = 5:1 to give 1.2 g of the title compound as a colorless oil.

[0483] Analytical data: LC-MS: (ES, m / z) = 308 [M+1]. Step 2: Synthesis of rac-benzyl 3-(2-amino-1-(methylsulfonyl)ethyl)azetidine-1-carboxylate: rac-Benzyl 3-[cyano(methanesulfonyl)methyl]azetidine-1-carboxylate (1.2 g, 3.89 mmol) and Raney Ni (10 mg) in EtOH (4 mL) were stirred at room temperature under an H atmosphere for 8 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give 600 mg of the title compound as a colorless oil.

[0484] Analytical data: LC-MS: (ES, m / z) = 313 [M+1]. Step 3: Synthesis of rac-benzyl 3-(2-(tert-butoxycarbonylamino)-1-(methylsulfonyl)ethyl)azetidine-1-carboxylate: (Boc)2O (829 mg, 3.84 mmol) was added to Na2CO3 (407 mg, 3.84 mmol), rac-benzyl 3-(2-amino-1-methanesulfonylethyl)azetidine-1-carboxylate (600 mg, 1.92 mmol) in dioxane / HO (10 mL / 3 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column using PE:EA = 5:1 to give 650 mg of the title compound as a colorless oil.

[0485] Analytical data: LC-MS: (ES, m / z) = 413 [M+1]. Step 4: Synthesis of rac-tert-butyl 2-(azetidin-3-yl)-2-(methylsulfonyl)ethylcarbamate: A mixture of rac-benzyl-3-(2-amino-1-methanesulfonylethyl)azetidine-1-carboxylate (600 mg, 1.92 mmol) and Pd(OH) / C (300 mg, 2.14 mmol) in MeOH (50 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (300 mg) as a colorless oil.

[0486] Analytical data: LC-MS: (ES, m / z) = 279 [M+1]. Example B61: Synthesis of rac-cis-2-(hexahydrofuro[3,4-b]pyrrol-1-yl)pyrimidin-4-amine

[0487] [ka]

[0488] A mixture of 2-chloropyrimidin-4-amine (370 mg, 2.85 mmol), rac-cis-hexahydro-1H-furo[3,4-b]pyrrole (322 mg, 2.85 mmol), and DIPEA (1.10 g, 8.55 mmol) in DMSO (8 mL) was stirred at 120° C. for 12 h. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried over NaSO, filtered, evaporated, and purified by column chromatography (DCM:MeOH=20:1) to give the title compound (410 mg, 69.8%) as a yellow solid.

[0489] Analytical data: LC-MS: (ES, m / z) = 207 [M+1]. Example B62: Synthesis of tert-butyl (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methylcarbamate

[0490] [ka]

[0491] Step 1: Synthesis of 1-tert-butyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate: To a solution of 1-tert-butyl 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate (1.5 g, 5.78 mmol) in THF (40 mL) was added NaH (346 mg, 8.67 mmol) at 0 °C. After 10 min, MeI (1.23 g, 8.67 mmol) was added and stirred for 2 h. The mixture was quenched with ice water and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified on a silica gel column using 10% EA in PE to give 1-tert-butyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate (1.3 g) as a pale yellow oil.

[0492] Analytical data: LC-MS: (ES, m / z) = 296 [M+23]. Step 2: Synthesis of 1-benzyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate: To a solution of 1-tert-butyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate (1.3 g, 4.75 mmol) in DCM (20 mL) was added TFA (8 mL). The mixture was stirred at room temperature for 1 hour. The reaction was concentrated. The residue was dissolved in dioxane (20 mL) and water (10 mL), and K2CO3 (1.94 g, 14.1 mmol) and CbzCl (1.60 g, 9.42 mmol) were added at room temperature and stirred for 2 hours. The reaction was extracted with EA, dried over Na2SO4, and concentrated to dryness to give the title compound (1.2 g) as a colorless oil.

[0493] Analytical data: LC-MS: (ES, m / z) = 309 [M+1]. Step 3: Synthesis of 1-(benzyloxycarbonyl)-4-methoxypiperidine-4-carboxylic acid: To a mixture of 1-benzyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate (1.1 g, 3.57 mmol) in MeOH (20 mL) and water (5 mL) was added NaOH (285 mg, 7.14 mmol). The mixture was stirred at 70° C. for 2 hours. After cooling to room temperature, the pH was adjusted to 5 with 1N HCl and extracted with EA. The organic layer was dried over NaSO, filtered, and concentrated to dryness to give the title compound (1 g) as a colorless oil.

[0494] Analytical data: LC-MS: (ES, m / z) = 294 [M+1]. Step 4: Synthesis of benzyl 4-carbamoyl-4-methoxypiperidine-1-carboxylate: A mixture of 1-[(benzyloxy)carbonyl]-4-methoxypiperidine-4-carboxylic acid (950 mg, 3.23 mmol), DIEA (834 mg, 6.46 mmol), ammonia (1.82 g, 37.4 mmol), and HATU (1.84 g, 4.84 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. The organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified on a silica gel column using 60% EtOAc in PE to give the title compound (900 mg) as a colorless oil.

[0495] Analytical data: LC-MS: (ES, m / z) = 293 [M+1]. Step 5: Synthesis of benzyl 4-(aminomethyl)-4-methoxypiperidine-1-carboxylate: To a solution of benzyl 4-carbamoyl-4-methoxypiperidine-1-carboxylate (600 mg, 2.05 mmol) in THF (20 mL) was added NaBH (310 mg, 8.20 mmol) followed by BF EtO (1.16 g, 8.20 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA. The organic layer was dried over NaSO, filtered, and concentrated to dryness to give the title compound (1.4 g, crude) as a colorless oil.

[0496] Analytical data: LC-MS: (ES, m / z) = 279 [M+1]. Step 6: Synthesis of benzyl 4-((tert-butoxycarbonylamino)methyl)-4-methoxypiperidine-1-carboxylate: A solution of benzyl 4-(aminomethyl)-4-methoxypiperidine-1-carboxylate (1.4 g, crude) and BocO (1.21 g, 5.58 mmol) in DCM (20 mL) was stirred at room temperature for 1 h. Water was added, and the organic layer was separated and purified on a silica gel column with 60% EA in PE to give the title compound (250 mg) as a colorless oil.

[0497] Analytical data: LC-MS: (ES, m / z) = 401 [M+23]. Step 7: Synthesis of tert-butyl (4-methoxypiperidin-4-yl)methylcarbamate: A mixture of benzyl 4-({[(tert-butoxy)carbonyl]amino}methyl)-4-methoxypiperidine-1-carboxylate (240 mg, 634 μmol) and Pd / C (100 mg, 95.1 μmol) in MeOH (20 mL) was stirred at room temperature under H pressure for 1 hour. The solid was filtered off. The filtrate was concentrated to dryness to give the title compound (130 mg) as a colorless oil.

[0498] Analytical data: LC-MS: (ES, m / z) = 245 [M+1]. Step 8: Synthesis of tert-butyl (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methylcarbamate: A mixture of 1-(4-methoxypiperidin-4-yl)methanamine (120 mg, 832 μmol), 2-chloropyrimidin-4-amine (107 mg, 832 μmol), and TEA (167 mg, 1.66 mmol) in iPrOH (20 mL) was stirred for 2 hours at 80° C. The mixture was concentrated, and the residue was purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (95 mg) as an off-white solid.

[0499] Analytical data: LC-MS: (ES, m / z) = 338 [M+1]. Example B63: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yloxy)ethanol

[0500] [ka]

[0501] HCl (6 M, 5 mL) was added to 2-[(3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine (600 mg, 930 μmol, from Step 2 of Example B70) in EtOH (5 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated in vacuo to give 200 mg of the title compound as a colorless oil.

[0502] Analytical data: LC-MS: (ES, m / z) = 271 [M+1]. Example B64: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate

[0503] [ka]

[0504] Step 1: Synthesis of benzyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate: To a solution of ACN (1.73 g, 42.1 mmol) in THF (80 mL) was added n-BuLi (23.5 mL, 58.9 mmol, 2.5 M) at −78° C. The mixture was stirred at −78° C. for 30 minutes. Then, a solution of benzyl 4-oxopiperidine-1-carboxylate (10.3 g, 44.2 mmol) in THF (20 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with H2O (30 mL), extracted with EA, and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column silica-CS (PE:EA = 10:1 to 3:2). This afforded 1 g (90.9%) of the title compound as a pale yellow solid.

[0505] Analytical data: LC-MS: (ES, m / z) = 275 [M+1]. Step 2: Synthesis of benzyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate: To a solution of benzyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (250 mg, 911 μmol) and iodomethane (283 mg, 2 mmol) in DMF (30 mL) was added NaH (216 mg, 5.45 mmol) at 0 °C. The mixture was then stirred at room temperature for 13 h. The mixture was quenched with HO (4 mL), extracted with EA, and washed with brine. The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by flash column silica-CS (PE:EA = 1:1). This gave 940 mg of benzyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate as a pale yellow gum.

[0506] Analytical data: LC-MS: (ES, m / z) = 311 [M+23]. Step 3: Synthesis of benzyl 4-(2-aminoethyl)-4-methoxypiperidine-1-carboxylate: To a solution of benzyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate (840 mg, 2.91 mmol) in THF (30 mL) was added BH3-THF (8.73 mL, 8.73 mmol, 1 M) at 0 °C. The mixture was then stirred at room temperature for 5 hours. The reaction was quenched with MeOH (8 mL) and concentrated to give the crude title compound (900 mg).

[0507] Analytical data: LC-MS: (ES, m / z) = 293 [M+1]. Step 4: Synthesis of benzyl 4-(2-(tert-butoxycarbonylamino)ethyl)-4-methoxypiperidine-1-carboxylate: To a solution of benzyl 4-(2-aminoethyl)-4-methoxypiperidine-1-carboxylate (850 mg, 2.90 mmol) in DCM (30 mL) was added TEA (586 mg, 5.80 mmol) and di-tert-butyl dicarbonate (949 mg, 4.35 mmol). The mixture was then stirred at room temperature for 10 hours. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by flash column silica-CS (PE:EA = 10:1 to 3:2). This afforded 900 mg (79.6%) of the title compound as a pale yellow gum.

[0508] Analytical data: LC-MS: (ES, m / z) = 415 [M+23]. Step 5: Synthesis of tert-butyl 2-(4-methoxypiperidin-4-yl)ethylcarbamate: To a solution of benzyl 4-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methoxypiperidine-1-carboxylate (420 mg, 1.07 mmol) in MeOH (25 mL) was added Pd / C (200 mg). The mixture was then hydrogenated under a hydrogen balloon at room temperature for 2 hours. The reaction mixture was filtered through a celite bed, washed with MeOH (100 mL), and the filtrate was concentrated to give the title compound (250 mg), which was used directly in the next step.

[0509] Analytical data: LC-MS: (ES, m / z) = 259 [M+1]. Step 6: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate: To a solution of tert-butyl N-[2-(4-methoxypiperidin-4-yl)ethyl]carbamate (260 mg, 1 mmol) in IPA (16 mL) were added 2-chloropyrimidin-4-amine (116 mg, 900 μmol) and DIPEA (323 mg, 2.50 mmol). The mixture was stirred at 120° C. for 13 hours. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH=10:1). This afforded 280 mg (79.7%) of the title compound as a pale yellow solid.

[0510] Analytical data: LC-MS: (ES, m / z) = 352 [M+1]. Example B65: Synthesis of 1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0511] [ka]

[0512] Step 1: Synthesis of (3R,4S)-tert-butyl 3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate: NaH (175.12 mg, 7.297 mmol, 8 equiv) was added to a mixture of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (200 mg, 0.912 mmol, 1 equiv) and 2,2-dimethyloxirane (526.19 mg, 7.297 mmol, 8 equiv) in DMF (5 mL) at 0° C. The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of 10 mL of water. The resulting solution was extracted with EA, washed with brine, and concentrated to give 100 mg (37.63%) of the title compound as a pale yellow oil.

[0513] Analytical data: LC-MS: (ES, m / z) = 292 [M+1]. Step 2: Synthesis of 1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol: tert-Butyl (3R,4S)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate (100.00 mg, 0.343 mmol) was added to a solution of TFA (1 mL) in DCM (3 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo, and the residue was mixed with 2-chloropyrimidin-4-amine (50 mg, 0.386 mmol, 1 equiv.) and TEA (117.16 mg, 1.158 mmol, 3 equiv.) in IPA (2 mL). The resulting solution was stirred at 100° C. for 12 hours. The mixture was concentrated in vacuo, and the residue was applied to a silica gel column using DCM / MeOH (15:1). This afforded 20 mg (18.22%) of the title compound as a pale yellow oil.

[0514] Analytical data: LC-MS: (ES, m / z) = 285 [M+1]. Example B66: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0515] [ka]

[0516] Step 1: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate: NaH (262.68 mg, 10.946 mmol, 6 equiv) was added to a solution of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (400.00 mg, 1.824 mmol, 1 equiv) and 2,2-dimethyloxirane (1315.49 mg, 18.244 mmol, 10 equiv) in DMF (20.00 mL). The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with EA and concentrated in vacuo. This gave 200 mg (37.63%) of the title compound as a yellow oil.

[0517] Analytical data: LC-MS: (ES, m / z) = 292 [M+1]. Step 2: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol: tert-Butyl (3S,4R)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate (200.00 mg, 0.686 mmol, 1 equiv.) was added to DCM / TFA (8.00 mL / 4.00 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was mixed with 2-chloropyrimidin-4-amine (67.74 mg, 0.523 mmol, 1 equiv.) and TEA (158.73 mg, 1.569 mmol, 3.0 equiv.) in IPA (3 mL) at 100° C. and stirred for 3 hours. The solvent was removed, and the residue was applied to a silica gel column using DCM / MeOH (15:1). This gave 55 mg (37%) of the title compound as a pale yellow oil.

[0518] Analytical data: LC-MS: (ES, m / z) = 285 [M+1]. Example B67: Synthesis of 2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine

[0519] [ka]

[0520] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate: NaH (218 mg, 9.08 mmol) was added to tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1000 mg, 4.56 mmol) in DMF (20 mL, 22.6 mmol) at 0° C. After stirring for 20 min, CD3I (3.30 g, 22.8 mmol) was added, and the solution was stirred at room temperature for 16 h. The reaction was quenched by adding 5 mL of water. The solid was filtered off. The resulting solution was extracted with EA, washed with brine, and concentrated. This gave 1140 mg of the title compound as a pale yellow oil.

[0521] Step 2: Synthesis of 2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine: TFA (2 mL) was added to tert-butyl (3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate (1140 mg, 4.82 mmol) in DCM (6 mL), and the solution was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was dissolved in IPA (20 mL), followed by 2-chloropyrimidine-4- (496 mg, 3.83 mmol) and TEA (0.6 mL). The mixture was stirred at 100 ° C. overnight. The mixture was concentrated, and the residue was purified by FLASH (5% MeOH in EA) to give 425 mg of the title compound as a pale yellow solid.

[0522] Analytical data: LC-MS: (ES, m / z) = 230 [M+1]. Example B68: Synthesis of 2-((3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

[0523] [ka]

[0524] Step 1: Synthesis of (3R,4S)-tert-butyl 3-fluoro-4-(vinyloxy)piperidine-1-carboxylate: A mixture of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1 equiv.), ethenyl acetate (515 mg, 5.99 mmol, 5 equiv.), Ir(COD)2Cl2 (80.3 mg, 120 μmol, 0.1 equiv.), and Na2CO3 (127 mg, 1.20 mmol, 1 equiv.) in toluene (1.5 mL) was heated to 100 °C for 3 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated. The residue was purified by preparative TLC (PE / EA = 4:1) to give the title compound (200 mg, 68%) as a colorless syrup.

[0525] Step 2: Synthesis of 2-((3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine: To a solution of diiodomethane (1.17 g, 4.39 mmol, 5.5 equiv.) in DCM (2 mL) was added diethylzinc (3.59 mL, 3.59 mmol, 4.5 equiv., 1 M in heptane) at 0° C. The mixture was stirred at 0° C. for 1 hour. A solution of tert-butyl (3R,4S)-4-(ethenyloxy)-3-fluoropiperidine-1-carboxylate (196 mg, 800 μmol, 1 equiv.) in DCM (2 mL) was added. The reaction was carried out at room temperature for 2 hours and then concentrated. The residue was suspended in TFA (1 mL) and DCM (3 mL) and stirred at room temperature for 2 hours. The mixture was concentrated. To the residue was added TEA (404 mg, 4.00 mmol, 5 equivalents), 2-chloropyrimidin-4-amine (72.5 mg, 560 μmol, 0.7 equivalents), and IPA (2 mL). The mixture was heated to 100° C. for 18 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (DCM / MeOH=25:1) to give 2-[(3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl]pyrimidin-4-amine (80 mg, 40%) as a white solid.

[0526] Analysis data: 1H-NMR (400 MHz, 3d-CD3Cl) δ ppm 7.94 (d, 1H, J=5.6 Hz), 5.78 (d, 1H, J=5.6 Hz), 4.83 (ddt, 1H, J=48.3, 5.7, 2.7 Hz), 4.68 - 4.59 (m, 1H), 4.58 (s, 2H), 4.32 (dddd, 1H, J=13.4, 5.7, 4.0, 1.5 Hz), 3.84 - 3.71 (m, 1H), 3.61 - 3.42 (m, 2H), 3.35 (dddd, 1H, J=13.2, 9.3, 3.6, 1.7 Hz), 2.05 - 1.91 (m, 1H), 1.89 - 1.74 (m, 1H), 0.72 - 0.63 (m, 2H), 0.58 - 0.49 (m, 2H). Example B69: Synthesis of rac-2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol

[0527] [ka]

[0528] Step 1: Synthesis of rac-tert-butyl 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,3-difluoropiperidine-1-carboxylate: To a solution of rac-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (3 g, 12.6 mmol) in DMF (20 mL) was added NaH (1.25 g, 31.5 mmol, 60%) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then (2-bromoethoxy)(tert-butyl)dimethylsilane (9.04 g, 37.8 mmol) was added. The mixture was stirred at room temperature for 13 h. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by flash column silica-CS (PE:EA = 1:0 to 10:1). This gave 3.8 g (76.3%) of the title compound as a yellow oil.

[0529] Step 2: Synthesis of rac-2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol: To a solution of rac-tert-butyl 4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3,3-difluoropiperidine-1-carboxylate (3.7 g, 9.35 mmol) in DCM (10 mL) was added HCl / dioxane (20 mL) at 0 °C. The mixture was then stirred at room temperature for 2 h. The reaction was concentrated, and the residue was dissolved in IPA (4 mL), followed by TEA (278 mg, 2.75 mmol) and 2-chloropyrimidin-4-amine (84.7 mg, 654 μmol). The mixture was stirred at 120 °C for 13 h. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by flash column silica-CS (DCM:MeOH=10:1). This afforded 2 g (79.6%) of the title compound as a pale yellow solid.

[0530] Analytical data: LC-MS: (ES, m / z) = 275 [M+1]. Example B70: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine

[0531] [ka]

[0532] Step 1: Synthesis of 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine: tert-Butyl(chloro)dimethylsilane (5.98 g, 39.7 mmol) was added batchwise to 1H-imidazole (3.60 g, 53.0 mmol) and chirally pure (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (from Example B1, Step 7, 6.0 g, 26.5 mmol) in DMF at 0 °C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with EA (500 mL) and washed with brine, and the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash using PE:EA = 2:1 to give 7.5 g of the title compound as a colorless oil.

[0533] Analytical data: LC-MS: (ES, m / z) = 341 [M+1]. Step 2: Synthesis of 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-3-methylpiperidin-1-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine: A mixture of [2-(chloromethoxy)ethyl]trimethylsilane (11.0 g, 66.0 mmol), DIEA (8.51 g, 66 mmol), and 2-[(3S,4R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-3-methylpiperidin-1-yl]pyrimidin-4-amine (7.5 g, 22.0 mmol) in DCM (200 mL) was stirred at reflux for 3 hours. The mixture was diluted with EA (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash using PE:EA = 5:1 to give 10.0 g of the title compound as a colorless oil.

[0534] Analytical data: LC-MS: (ES, m / z) = 601 [M+1]. Step 3: Synthesis of (3S,4R)-1-(4-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol: TBAF (83 mL, 83 mmol) was added to 2-[(3S,4R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine (10.0 g, 16.6 mmol) in THF. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum. The residue was purified by preparative TLC using PE:EA=4:1 to give 6.5 g of the title compound as a colorless oil.

[0535] Analytical data: LC-MS: (ES, m / z) = 487 [M+1]. Step 4: Synthesis of 2-((3S,4R)-4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-fluoro-3-methylpiperidin-1-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine: NaH (310 mg, 7.75 mmol) was added to 2-[(3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine (2 g, 3.10 mmol) in DMF at 0° C. The mixture was stirred at 0° C. for 10 minutes. (2-Bromoethoxy)(tert-butyl)dimethylsilane (2.22 g, 9.30 mmol) was added to the mixture, and the resulting solution was stirred at room temperature for 16 hours. The mixture was diluted with EA (100 mL) and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column with PE:EA=5:1 to give 2.1 g of the title compound as a colorless oil.

[0536] Analytical data: LC-MS: (ES, m / z) = 645 [M+1]. Step 5: Synthesis of 2-((3S,4R)-1-(4-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yloxy)ethanol: TBAF (10 mL, 10 mmol) was added to 2-[(3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine (600 mg, 930 μmol) in THF (10 mL) at room temperature. The mixture was stirred at reflux for 1 hour. The mixture was concentrated under vacuum. The residue was purified by silica gel column using PE:EA=2:1. This gave 200 mg of the title compound as a colorless oil.

[0537] Analytical data: LC-MS: (ES, m / z) = 531 [M+1]. Step 6: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine: (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (456 mg, 2.26 mmol) was added dropwise to a mixture of PPh3 (885 mg, 3.38 mmol), {[azido(phenoxy)phosphoryl]oxy}benzene (930 mg, 3.38 mmol), and 2-{[(3S,4R)-3-fluoro-3-methyl-1-[4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidin-2-yl]piperidin-4-yl]oxy}ethan-1-ol (600 mg, 1.13 mmol) in THF at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA (100 mL) and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative TLC using PE:EA=5:1 to give 280 mg of the title compound as a yellow solid.

[0538] Analytical data: LC-MS: (ES, m / z) = 556 [M+1]. Step 7: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine: HCl (6M, 5 mL) was added to 2-[(3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine (260 mg, 467 μmol) in EtOH at room temperature. The mixture was stirred at reflux for 1 hour. The mixture was concentrated in vacuo to give 120 mg of 2-[(3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl]pyrimidin-4-amine as a colorless oil.

[0539] Analytical data: LC-MS: (ES, m / z) = 296 [M+1]. Example B71: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol

[0540] [ka]

[0541] Step 1: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-(oxiran-2-ylmethoxy)piperidine-1-carboxylate: To a solution of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.28 mmol) in DMF was added NaH (109 mg, 4.56 mmol) at 0° C., and the mixture was stirred at 0° C. for 20 minutes. Then, 2-(bromomethyl)oxirane (936 mg, 6.84 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA and water. The organic layers were combined and dried over Na2SO4. The organic layers were concentrated, and 600 mg (95%) of the crude title compound was used as a brown solid.

[0542] Analytical data: LC-MS: (ES, m / z) = 220 [M+1-56]. Step 2: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylate: To a solution of tert-butyl (3S,4R)-3-fluoro-4-[(oxiran-2-yl)methoxy]piperidine-1-carboxylate (750 mg, 2.72 mmol) in THF was added LiBHEt (1 M solution in THF) at 0 °C under a N atmosphere. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA and water. The organic layers were combined and dried over NaSO. The organic layer was concentrated to give 600 mg (80%) of the title compound as a yellow solid.

[0543] Analytical data: LC-MS: (ES, m / z) = 222 [M+1-56]. Step 3: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol: To a solution of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylate (600 mg, 2.16 mmol) in DCM was added HCl (4 M solution in dioxane) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMSO (3 mL), followed by 2-chloropyrimidin-4-amine (380 mg, 2.93 mmol) and DIEA (1.13 g, 8.79 mmol). The mixture was stirred at 120° C. for 2 hours. The mixture was extracted with EA and water. The organic layers were combined and dried over Na2SO4. The organic layer was concentrated, and the residue was purified by preparative TLC using DCM / MeOH (15:1). This gave 210 mg of the title compound as a yellow solid.

[0544] Analytical data: LC-MS: (ES, m / z) = 271 [M+1]. Example B72: Synthesis of 2-((3S,4R)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

[0545] [ka]

[0546] Step 1: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-(vinyloxy)piperidine-1-carboxylate: A mixture of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1 equiv.), ethenyl acetate (515 mg, 5.99 mmol, 5 equiv.), Ir(COD)2Cl2 (80.3 mg, 120 μmol, 0.1 equiv.), and Na2CO3 (127 mg, 1.20 mmol, 1 equiv.) in toluene (1.5 mL) was heated to 100 °C for 3 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated. The residue was purified by preparative TLC (PE / EA = 4:1) to give the title compound (200 mg, 68%) as a colorless syrup.

[0547] Step 2: Synthesis of 2-((3S,4R)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine: To a solution of diiodomethane (1.17 g, 4.39 mmol, 5.5 equiv.) in DCM (2 mL) was added diethylzinc (3.59 mL, 3.59 mmol, 4.5 equiv., 1 M in heptane) at 0° C. The mixture was stirred at 0° C. for 1 hour. A solution of tert-butyl (3S,4R)-4-(ethenyloxy)-3-fluoropiperidine-1-carboxylate (196 mg, 800 μmol, 1 equiv.) in DCM (2 mL) was added. The reaction was carried out at room temperature for 2 hours and then concentrated. The residue was suspended in TFA (1 mL) and DCM (3 mL) and stirred at room temperature for 2 hours. The mixture was concentrated. To the residue, triethylamine (404 mg, 4.00 mmol, 5 equiv.), 2-chloropyrimidin-4-amine (72.5 mg, 560 μmol, 0.7 equiv.), and IPA (2 mL) were added. The mixture was heated to 100° C. for 18 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (DCM / MeOH=25:1) to give the title compound (80 mg, 40%) as a white solid.

[0548] Analysis data: 1H-NMR (400 MHz, 3d-CD3Cl) δ ppm 7.94 (d, 1H, J=5.6 Hz), 5.78 (d, 1H, J=5.6 Hz), 4.84 (ddd, 1H, J=48.1, 5.8, 2.8 Hz), 4.66 - 4.59 (m, 1H), 4.57 (s, 2H), 4.39 - 4.27 (m, 1H), 3.85 - 3.69 (m, 1H), 3.62 - 3.43 (m, 2H), 3.35 (dddd, 1H, J=13.3, 9.4, 3.6, 1.7 Hz), 1.98 (dddd, 1H, J=13.4, 6.8, 5.4, ​​3.2 Hz), 1.83 (ddd, 1H, J=9.6, 7.8, 4.6 Hz), 0.72 - 0.64 (m, 2H), 0.57 - 0.47 (m, 2H). Example B73: Synthesis of 3-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

[0549] [ka]

[0550] A solution of (3S,4R)-3-fluoro-4-methoxypiperidine (60 mg, 450 μmol, from Step 2 of Example B33), DIPEA (174 mg, 1.35 mmol), and 3-chloro-1,2,4-triazin-5-amine (64.6 mg, 495 μmol, from Step 2 of Example B30) in DMSO (2 mL) was stirred at 120° C. for 2 hours. The mixture was extracted with EA and water. The organic layer was dried and concentrated, and the residue was purified by preparative TLC using PE / EA (5:1). This gave 40 mg (39%) of the title compound as a yellow solid.

[0551] Analytical data: LC-MS: (ES, m / z) = 228 [M+1]. Example B74: Synthesis of rac-(all cis)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxypiperidin-3-ol

[0552] [ka]

[0553] Step 1: Synthesis of rac-trans-6-(hydroxymethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one: In a 100 mL round-bottom flask, rac-cis-3,4-dihydroxy-trans-5-(hydroxymethyl)tetrahydrofuran-2-one (3 g, 20.2 mmol, 1 equiv.), TsOH·HO (385 mg, 2.03 mmol, 0.100 equiv.), and anhydrous acetone (60 mL) were added, followed by the addition of 2,2-dimethoxypropane (2.53 g, 24.3 mmol, 1.20 equiv.) over 5 min at 0 °C. The resulting solution was stirred at 25 °C for 2 h. Solid sodium bicarbonate (255 mg, 3.04 mmol, 0.150 equiv.) was then added to the mixture and stirred for 5 min. The reaction mixture was filtered and concentrated in vacuo. This afforded 3.8 g (100%) of the title compound as a white solid.

[0554] Step 2: Synthesis of rac-((cis)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol-trans-4-yl)methyl methanesulfonate: In a 100 mL round-bottom flask, rac-trans-6-(hydroxymethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (3.81 g, 20.3 mmol, 1 equiv.), TEA (4.10 g, 40.5 mmol, 2 equiv.), and THF (70 mL) were placed, and then MsCl (2.78 g, 24.3 mmol, 1.20 equiv.) was added dropwise at 0 °C. The resulting solution was stirred at 25 °C for 1 h. The mixture was diluted with DCM (20 mL) and washed with saturated aqueous NH4Cl (20 mL × 3). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. This afforded 5.0 g (93%) of the title compound as an orange oil, which was used directly in the next step without further purification.

[0555] Analysis data: LC-MS: (ES, m / z): RT=0.274 min, LCMS: m / z=267[M+1], 1 H NMR (400 MHz, CDCl3) δ 4.89-4.73 (m, 3H), 4.54-4.41 (m, 2H), 3.06 (s, 3H), 1.49 (s, 3H), 1.41 (s, 3H). Step 3: Synthesis of rac-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one: In a 100 mL round-bottom flask were placed rac-((cis)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol-trans-4-yl)methyl methanesulfonate (5.00 g, 18.8 mmol, 1 equiv.), NaN (3.66 g, 56.3 mmol, 3 equiv.), and DMF (60 mL). The resulting solution was stirred in an oil bath at 75 °C for 3 h. The reaction mixture was diluted with EA (150 mL) and washed with brine (50 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo. This afforded 3.2 g (80%) of the title compound as a red oil.

[0556] Analysis data: 1 H NMR (400 MHz, CDCl3) δ 4.85 (d, J= 5.6 Hz, 1H), 4.71-4.58 (m, 2H), 3.83-3.74 (m, 1H), 3.70-3.62 (m, 1H), 1.48 (s, 3H), 1.39 (s, 3H). Step 4: Synthesis of rac-(all cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridin-4(3aH)-one: In a 100 mL round-bottom flask, rac-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (3.20 g, 15.0 mmol, 1 equiv.), Pd / C (300 mg, 10% purity), and MeOH (30 mL) were placed under a N atmosphere. The resulting solution was stirred at 25 °C under a H atmosphere (50 psi) for 3 h. The mixture was filtered and concentrated in vacuo. This afforded 2.7 g (93%) of the title compound as a colorless oil.

[0557] Analysis data: 1H NMR (400 MHz, CDCl3) δ 7.03-6.83 (m, 1H), 4.58-4.47 (m, 2H), 4.12-4.04 (m, 1H), 3.49-3.40 (m, 1H), 3.28-3.20 (m, 1H), 1.54 (s, 3H), 1.42 (s, 3H). Step 5: Synthesis of rac-(all cis)-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-7-ol: A 100 mL round-bottom flask was charged with rac-(all cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridin-4(3aH)-one (2.55 g, 13.6 mmol, 1 equiv.) and LiAlH (2.58 g, 68.1 mmol, 5.00 equiv.) in THF (50 mL) and stirred at 70 °C under a N atmosphere for 6 h. The reaction mixture was quenched with HO (3 mL). The reaction mixture was diluted with EA / MeOH (100 mL, v / v = 20 / 1), dried over NaSO, filtered, and concentrated in vacuo. This afforded 2.4 g (crude) of the title compound as a white solid.

[0558] Analytical data: LC-MS: (ES, m / z): RT=0.086 min, LCMS: m / z=174 [M+1]. Step 6: Synthesis of rac-(all cis)-benzyl 7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate: A 100 mL round-bottom flask was charged with rac-(all cis)-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-7-ol (2.36 g, 13.6 mmol, 1 equiv.), NaHCO (3.43 g, 40.9 mmol, 3 equiv.), CbzCl (2.56 g, 15.0 mmol, 1.10 equiv.), and THF (50 mL). The resulting solution was stirred in an oil bath at 50 °C for 2 h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO, PE / EA = 3 / 1 and DCM / MeOH = 20 / 1). This afforded 2.3 g (53%) of the title compound as a white solid.

[0559] Analysis data: LC-MS: (ES, m / z): RT=0.665 min, LCMS: m / z=308[M+1], 1 H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 5.15 (s, 2H), 4.45-4.35 (m, 2H), 4.04-3.82 (m, 1H), 3.76-3.62 (m, 2H), 3.58-3.49 (m, 1H), 3.30-3.20 (m, 1H), 2.30 (s, 1H), 1.49 (s, 3H), 1.38 (s, 3H). Step 7: Synthesis of rac-(all cis)-benzyl 7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate: In a 50 mL round-bottom flask, rac-(all cis)-benzyl-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate (500 mg, 1.63 mmol, 1 equiv.) and dry DCM (8 mL) were added. DAST (786 mg, 4.88 mmol, 3 equiv.) was added at 0-10 °C. The resulting solution was stirred at 0-10 °C for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 until the pH reached approximately 8 and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EA = 3 / 1 and EA / MeOH = 20 / 1). This afforded 0.38 g (75%) of the title compound as a colorless oil.

[0560] Analytical data: LC-MS: (ES, m / z): RT=0.741 min, LCMS: m / z=310 [M+1]. 1 H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 5H), 5.16 (s, 2H), 4.92-4.64 (m, 1H), 4.48-4.30 (m, 2H), 3.80-3.58 (m, 4H), 1.51 (s, 3H), 1.39 (s, 3H). Step 8: Synthesis of rac-(all cis)-benzyl 3-fluoro-4,5-dihydroxypiperidine-1-carboxylate: In a 50 mL round-bottom flask was placed rac-(all cis)-benzyl-7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate (383 mg, 1.24 mmol, 1 equiv.) and HCl / MeOH (10.1 mL, 32.6 equiv., 4 mol / L). The resulting solution was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo. This afforded 0.28 g (84%) of the title compound as a white solid.

[0561] Analysis data: 1H NMR (400 MHz, CDCl3) δ 7.42-7.31 (m, 5H), 5.16 (s, 2H), 4.73-4.52 (m, 1H), 4.02-3.51 (m, 6H). Step 9: Synthesis of rac-(all cis)-benzyl 3-fluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate and (3R,4S,5S)-benzyl 3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylate: A 25 mL round-bottom flask was charged with rac-(all cis)-benzyl 3-fluoro-4,5-dihydroxypiperidine-1-carboxylate (110 mg, 409 μmol, 1 equiv.), AgO (94.7 mg, 409 μmol, 1 equiv.), MeI (145 mg, 1.02 mmol, 2.50 equiv.), and DMF (3 mL). The resulting solution was stirred at 25 °C for 24 h. The mixture was filtered, diluted with EA (30 mL), washed with brine (30 mL × 3), and the combined organic phase was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC; mobile phase: water (10 mmol / L NHHCO) and ACN (from 18.0% ACN to 38.0% in 10 min); detector: UV 254 / 220 nm. This gave 20 mg (17%) of the title compound as a colorless oil.

[0562] Analysis data: LC-MS: (ES, m / z): RT=0.689 min, LCMS: m / z=284[M+1], 1 H NMR (400 MHz, CDCl) δ 7.43-7.30 (m, 5H), 5.20-5.10 (m, 2H), 4.65-4.43 (m, 1H), 4.10-4.05 (m, 1H), 3.86-3.82 (m, 1H), 3.76-3.29 (m, 7H), 2.68 (s, 1H). 32 mg (28%) of the title compound B was obtained as a colorless oil.

[27] LC-MS: (ES, m / z): RT = 0.705 min, LCMS: m / z = 284 [M+1]. 1H NMR (400 MHz, CDCl3) δ = 7.43-7.29 (m, 5H), 5.20-5.09 (m, 2H), 4.76-4.51 (m, 1H), 3.89-3.61 (m, 5H), 3.59 (s, 3H), 3.40-3.30 (m, 1H), 2.50 (s, 1H). Step 10: Synthesis of rac-(all cis)-5-fluoro-4-methoxypiperidin-3-ol: In a 25 mL round-bottom flask were placed rac-(all cis)-benzyl 3-fluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate and rac-(all cis)-benzyl 3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylate (5.00 mg, 17.7 μmol, 1 equiv.), Pd / C (5 mg, 10% purity), and THF (1 mL). The resulting solution was stirred under H (15 psi) at 25° C. for 2 hours. The mixture was filtered and concentrated in vacuo. This afforded 2.6 mg (100%) of the title compound as a yellow solid.

[0563] Step 11: Synthesis of rac-(all cis)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxypiperidin-3-ol: In a 250 mL round-bottom flask, 2-chloropyrimidin-4-amine (2.28 mg, 17.6 μmol, 1 equiv.), rac-(all cis)-5-fluoro-4-methoxy-piperidin-3-ol (2.63 mg, 17.6 μmol, 1 equiv.), DIEA (4.56 mg, 35.3 μmol, 2 equiv.), and DMSO (1 mL) were placed. The resulting solution was stirred at 100° C. for 12 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel preparative TLC (PE:EA=1:2). This afforded 3.5 mg (81%) of the title compound.

[0564] Analytical data: LC-MS: (ES, m / z): RT=0.077 min, LCMS: m / z=243 [M+1]. Example B75: Synthesis of rac-(all cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol:

[0565] [ka]

[0566] Step 1: Synthesis of rac-(all cis)-3-fluoro-5-methoxypiperidin-4-ol: In a 25 mL round-bottom flask was placed rac-(all cis)-benzyl 3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylate (50.0 mg, 176 μmol, 1 equivalent), Pd / C (15.0 mg, 10% purity), and THF (3 mL). The resulting solution was stirred under H (15 psi) at 25° C. for 2 hours. The reaction was filtered and concentrated in vacuo to give the title compound. This afforded 28 mg (100%) of the title compound as a colorless oil.

[0567] Analysis data: 1 H NMR (400 MHz, CDCl3) δ 7.03-6.83 (m, 1H), 4.58-4.47 (m, 2H), 4.12-4.04 (m, 1H), 3.49-3.40 (m, 1H), 3.28-3.20 (m, 1H), 1.54 (s, 3H), 1.42 (s, 3H). Step 2: Synthesis of rac-(all cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol: A 25 mL round-bottom flask was charged with rac-(all cis)-3-fluoro-5-methoxypiperidin-4-ol (28.0 mg, 188 μmol, 1 equiv.), 2-chloropyrimidin-4-amine (36.5 mg, 282 μmol, 1.50 equiv.), DIEA (60.6 mg, 469 μmol, 2.50 equiv.), and CsF (28.5 mg, 188 μmol, 1 equiv.) in DMSO (1 mL). The resulting solution was stirred at 100° C. for 36 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC; mobile phase: water (10 mmol / L NH4HCO3) and ACN (from 0% ACN to 20.0% in 10 min); detector: UV 254 / 220 nm. This afforded 15 mg (33%) of the title compound as a yellow solid.

[0568] Analysis data: 1 H NMR (400 MHz, CDCl3) 7.93 (d, J = 5.6 Hz, 1H), 5.79 (d, J = 5.6 Hz, 1H), 4.73 (s, 1H), 4.60 (s, 2H), 4.33-4.14 (m, 3H), 3.89-3.83 (m, 1H), 3.70-3.60 (m, 1H), 3.49 (s, 3H), 3.40-3.30 (m, 1H). Example B76: Synthesis of rac-2-((all cis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine

[0569] [ka]

[0570] Step I: Synthesis of rac-(3S,4R,5R)-3-fluoro-4,5-dimethoxypiperidine: A 25 mL round-bottom flask was charged with rac-benzyl-(all cis)-3-fluoro-4,5-dimethoxy-piperidine-1-carboxylate (resulting from the excess alkylation in Example B74, Step 9; 30.0 mg, 101 μmol, 1 equivalent), Pd / C (10.0 mg, 101 μmol, 10% purity), and THF (2 mL). The resulting solution was stirred under an atmosphere of H (15 psi) at 25° C. for 2 hours. The mixture was filtered and concentrated in vacuo. This afforded 16 mg (100%) of the title compound as a colorless oil.

[0571] Step 2: Synthesis of rac-2-((all cis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine: A 25 mL round-bottom flask was charged with rac-(all cis)-3-fluoro-4,5-dimethoxy-piperidine (16 mg, 98.1 μmol, 1 equiv.), 2-chloropyrimidin-4-amine (25.4 mg, 196 μmol, 2 equiv.), DIEA (38.0 mg, 294 μmol, 51.2 μL, 3 equiv.), CsF (29.8 mg, 196 μmol, 2 equiv.), and DMSO (1 mL). The resulting solution was stirred at 120 °C for 72 h. The mixture was diluted with EA (20 mL) and washed with HO (5 mL × 3). The combined aqueous phases were concentrated in vacuo. The residue was purified by preparative HPLC using water (10 mmol / L NH4HCO3) and ACN (from 0% ACN to 30.0% in 10 min); UV detection at 254 / 220 nm. This gave 8.0 mg (32%) of the title compound as a colorless oil.

[0572] Analytical data: LC-MS: (ES, m / z): RT=1.141 min, LCMS: m / z=257 [M+1]. Example B77: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol:

[0573] [ka]

[0574] Step 1: Synthesis of rac-benzyl 3,3-difluoro-5-hydroxy-4-methoxy-piperidine-1-carboxylate: To a solution of rac-benzyl 3,3-difluoro-4,5-dihydroxy-piperidine-1-carboxylate (170 mg, 591 μmol, 1 equiv., as prepared from Example 54, Step 2 (Boc-protection)) and AgO (137 mg, 591 μmol, 1 equiv.) in DMF (5 mL) was added MeI (210 mg, 1.48 mmol, 92.1 μL, 2.50 equiv.) dropwise, and the mixture was stirred at 25° C. for 16 h while protected from light. The mixture was diluted with water (60 mL) and extracted with EA (40 mL × 3), and the combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC [column: Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 31% to 51%, 10 min] to give 110 mg (61%) of the title compound as a colorless oil.

[0575] Analysis data: 1H NMR (400MHz, CDCl3) δ 7.44-7.30 (m, 5H), 5.17 (s, 2H), 4.32-3.99 (m, 2H), 3.91-3.81 (m, 1H), 3.65 (s, 3H), 3.63 (d, J = 3.6 Hz, 1H), 3.53-3.27 (m, 1H), 3.07-2.88 (m, 1H), 2.37 (s, 1H). Step 2: Synthesis of rac-5,5-difluoro-4-methoxy-piperidin-3-ol: To a solution of rac-benzyl 3,3-difluoro-5-hydroxy-4-methoxy-piperidine-1-carboxylate (100 mg, 331 μmol, 1 equiv.) in THF (5 mL) was added Pd / C (10 mg, 10% purity) under N. The mixture was stirred at 25° C. under H (15 psi) for 1 h. The mixture was filtered, and the filtrate was concentrated. The reaction mixture was filtered, and the filtrate was concentrated. This gave 50 mg (90%) of the title compound as a colorless oil, which was used directly in the next step.

[0576] Step 3: Synthesis of rac-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol: To a solution of rac-5,5-difluoro-4-methoxy-piperidin-3-ol (50.0 mg, 299 μmol, 1 equiv.) and DIEA (77.3 mg, 598 μmol, 2 equiv.) in DMSO (1 mL), 2-chloropyrimidin-4-amine (50.3 mg, 388 μmol, 1.30 equiv.) was added, and the mixture was stirred at 120 °C for 16 h. The reaction mixture was purified by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5% to 38%, 10 min]. This afforded 25 mg (32%) of the title compound as a colorless oil.

[0577] Analysis data: 1H NMR (400MHz, CD3OD) δ 7.72 (d, J = 6.0 Hz, 1H), 5.85 (d, J = 6.0 Hz, 1H), 4.75-4.66 (m, 1H), 4.58 (s, 1H), 4.47 (dd, J = 4.8, 12.8, Hz, 1H), 3.75 (dd, J = 10.4, 4.4 Hz, 1H), 3.60 (s, 4H), 3.36 (d, J = 13.6 Hz, 1H), 3.03 (dd, J = 12.4, 11.2 Hz, 1H). Example B78: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[0578] [ka]

[0579] Step 1: Synthesis of rac-cis-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol: To a solution of rac-cis-piperidine-3,4-diol (0.500 g, 3.26 mmol, 1 eq., HCl salt) and DIEA (1.68 g, 13.0 mmol, 2.27 mL, 4.00 eq.) in DMSO (5 mL), 2-chloro-4-methylsulfanyl-pyrimidine (784 mg, 4.88 mmol, 1.50 eq.) was added, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (120 mL) and extracted with EA (70 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA = 2:1). This afforded 0.68 g (96%) of the title compound as an off-white solid.

[0580] Analysis data: 1H NMR (400MHz, CDCl3) δ 7.95 (d, J = 5.2 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.24-4.17 (m, 1H), 4.16-4.07 (m, 1H), 3.96-3.86 (m, 2H), 3.73 (dd, J = 13.6, 3.2 Hz, 1H), 3.64-3.52 (m, 1H), 2.50 (s, 3H), 1.94-1.73 (m, 2H). Step 2: Synthesis of rac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol: To a solution of rac-cis-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol (470 mg, 1.95 mmol, 1 equiv.), NaI (29.2 mg, 194 μmol, 0.100 equiv.) in ACN (10 mL), 2-methoxyethyl 4-methylbenzenesulfonate (897 mg, 3.90 mmol, 2 equiv.) and CsCO (1.90 g, 5.84 mmol, 3 equiv.) were added, and the mixture was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC [column: Phenomenex Luna C18 150 × 40 mm × 15 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 1%–25%, 9 min]. This gave 0.18 g (30%) of the title compound as a yellow solid.

[0581] Analysis data: 1H NMR (400MHz, CDCl3) δ 7.95 (d, J = 5.2 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 4.07-4.02 (m, 1H), 3.97-3.79 (m, 4H), 3.71-3.65 (m, 1H), 3.61-3.47 (m, 3H), 3.42-3.38 (m, 3H), 2.50 (s, 3H), 2.01-1.89 (m, 1H), 1.78-1.66 (m, 1H). Step 3: Synthesis of rac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol: To a solution of [8]rac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol (160 mg, 534 μmol, 1 equiv.) in THF (8 mL) and HO (2 mL), oxone (1.64 g, 2.67 mmol, 5.00 equiv.) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was washed with saturated aqueous NaSO (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (EA). This afforded 85 mg (48%) of the title compound as a colorless oil.

[0582] Analysis data: 1H NMR (400MHz, CDCl3) δ 8.58 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 4.08-3.94 (m, 3H), 3.93-3.85 (m, 2H), 3.84-3.80 (m, 1H), 3.75-3.63 (m, 2H), 3.60-3.49 (m, 3H), 3.42-3.38 (m, 3H), 3.18 (s, 3H), 2.01-1.90 (m, 1H), 1.79-1.69 (m, 1H). Step 4: Synthesis of rac-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol: A solution of rac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol (80.0 mg, 241 μmol, 1 equiv.) in NH / THF (8 mL) was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (10 mM NHHCO)-ACN]; B%: 1% to 30%, 10 min]. This afforded 5.0 mg (7%) of the title compound as a colorless oil as a mixture of enantiomers.

[0583] Analysis data: 1H NMR (400MHz, CDCl3) δ 7.91 (d, J = 5.6 Hz, 1H), 5.73 (d, J = 5.6 Hz, 1H), 4.57 (s, 2H), 4.00-3.93 (m, 1H), 3.91-3.82 (m, 2H), 3.82-3.72 (m, 3H), 3.71-3.60 (m, 3H), 3.59-3.56 (m, 1H), 3.40 (s, 3H), 2-1.90 (m, 1H), 1.73-1.67 (m, 1H). Example B79: Synthesis of trans racemic (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[0584] [ka]

[0585] Step 1: Synthesis of rac-trans-tert-butyl-3,4-dihydroxypiperidine-1-carboxylate: To a solution of racemic tert-butyl 7-oxa-4-azabicyclo[4.1.0]heptane-4-carboxylate (2 g, 10.0 mmol, 1 equiv.) in dioxane (30 mL) was added a solution of KOH (1.13 g, 20.0 mmol, 2 equiv.) in water (15 mL), and the mixture was stirred at 100° C. for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was diluted with water (200 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with brine (80 mL), dried, and concentrated in vacuo. This afforded 2 g (90%) of the title compound as a colorless oil, which was used directly in the next step.

[0586] Step 2: Synthesis of (3S,4S)-piperidine-3,4-diol: A solution of rac-trans-tert-butyl-3,4-dihydroxypiperidine-1-carboxylate (2 g, 9.21 mmol, 1 equiv.) in HCl / dioxane (5 mL, 4 mol / L) was stirred at 25° C. for 30 minutes. The mixture was concentrated in vacuo. This gave 1.40 g (100%) of the title compound as a yellow solid, which was used directly in the next step.

[0587] Step 3: Synthesis of rac-trans-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol: To a solution of rac-trans-piperidine-3,4-diol (1.20 g, 7.81 mmol, 1 equiv., HCl salt) and DIEA (5.05 g, 39.1 mmol, 6.80 mL, 5.00 equiv.) in DMSO (12 mL), 2-chloro-4-methylsulfanyl-pyrimidine (1.25 g, 7.81 mmol, 1 equiv.) was added, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (150 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA = 2:1). This afforded 1.30 g (69%) of the title compound as an off-white solid, which was used directly in the next step.

[0588] Step 4: Synthesis of rac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol: To a solution of rac-trans-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol (700 mg, 2.90 mmol, 1 equiv.), NaI (43.4 mg, 290 μmol, 0.100 equiv.) in ACN (10 mL), 2-methoxyethyl 4-methylbenzenesulfonate (1.34 g, 5.80 mmol, 2 equiv.) and CsCO (2.84 g, 8.70 mmol, 3 equiv.) were added, and the mixture was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC [Column: Waters Xbridge C18 150 × 50 mm × 10 μm; Mobile phase: [water (10 mM NHHCO)-ACN]; B%: 20%–50%, 11.5 min]. This gave 300 mg (34%) of the title compound as a yellow solid.

[0589] Analysis data: 1H NMR (400MHz, CDCl3) δ 8.00-7.93 (m, 1H), 6.46-6.39 (m, 1H), 5.03-4.83 (m, 1H), 4.81-4.62 (m, 1H), 4.02-3.88 (m, 1H), 3.74-3.57 (m, 5H), 3.42 (s, 3H), 3.38-3.14 (m, 1H), 3.03-2.65 (m, 2H), 2.50 (s, 3H), 2.08-2.01 (m, 1H), 1.56-1.46 (m, 1H). Step 5: Synthesis of rac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol: To a solution of rac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol (300 mg, 1 mmol, 1 equiv.) in THF (10 mL) and HO (3 mL) was added oxone (1.85 g, 3.01 mmol, 3 equiv.), and the mixture was stirred at 25 °C for 3 h. The mixture was washed with saturated aqueous NaSO (60 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (EA). This afforded 120 mg (36%) of the title compound as a colorless oil.

[0590] Step 6: Synthesis of rac-trans-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol: A solution of rac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol (120 mg, 362 μmol, 1 equiv.) in NH3 / THF (8 mL) was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC [Column: Xtimate C18 150 × 40 mm × 10 μm; Mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 10% to 20%, 10 min]. This afforded 10.0 mg (10%) of the title compound as a colorless oil as a mixture of enantiomers.

[0591] Analysis data: 1H NMR (400MHz, CDCl3) δ 7.90 (d, J = 5.6 Hz, 1H), 5.74 (d, J = 5.6 Hz, 1H), 4.74-4.64 (m, 3H), 4.57-4.49 (m, 1H), 3.90-3.84 (m, 1H), 3.70-3.65 (m, 1H), 3.60-3.55 (m, 3H), 3.40 (s, 3H), 3.39-3.29 (m, 1H), 3.01-2.94 (m, 1H), 2.88 (dd, J = 13.2, 9.6 Hz, 1H), 2.03-2 (m, 1H), 1.53-1.43 (m, 1H). Example C1: Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine

[0592] [ka]

[0593] Step 1: Synthesis of 6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one: To a solution of 6-chloro-1,2-dihydro-2,7-naphthyridin-1-one (50 g, 0.276 mol) in DMF (300 mL) was added NIS (74 g, 0.33 mol) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed with water and evaporated to dryness to give the title compound (60 g, 70%) as a pale yellow solid.

[0594] Analytical data: LC-MS: (ES, m / z)=307[M+1]. 1H NMR (300 MHz, DMSO-d6) δ 12 (s, 1H), 9.02 (s, 1H), 7.89 (d, 1H, J = 6.0 Hz), 7.44 (s, 1H). Step 2: Synthesis of 1,6-dichloro-4-iodo-2,7-naphthyridine: A mixture of 6-chloro-4-iodo-1,2-dihydro-2,7-naphthyridin-1-one (60 g, 0.196 mol) in POCl (320 mL) was stirred at 100 °C for 1.5 h. LCMS showed that the starting material had been consumed. The mixture was concentrated and neutralized with cold saturated aqueous NaHCO. The mixture was extracted with EA (3 × 300 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 53 g (84%) of 1,6-dichloro-4-iodo-2,7-naphthyridine as a yellow solid.

[0595] Analytical data: LC-MS: (ES, m / z) = 325 [M+1]. Step 3: Synthesis of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine: To a solution of 1,6-dichloro-4-iodo-2,7-naphthyridine (30 g, 92.5 mmol) in 1,4-dioxane / HO (300 / 70 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15 g, 93 mmol), KCO (37.8 g, 276 mmol), and PdAMPhosCl / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3 g, 4.2 mmol). The resulting solution was stirred at 50 °C for 0.5 h. LCMS indicated the reaction was complete. The mixture was cooled to room temperature and diluted with 200 mL of water. The resulting solution was extracted with EA (2 × 300 mL), and the organic layers were combined. The resulting mixture was washed with 200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by chromatography using EA:PE (1:10). This gave 15 g (68.1%) of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine as a white solid.

[0596] Analytical data: LC-MS: (ES, m / z) = 239 [M+1]. Step 4: Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine: To a solution of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine (4 g, 16.8 mmol) in EA (300 mL) was added PtO (5 g, 22 mmol). The resulting mixture was stirred under H atmosphere at 25 °C for 24 h. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography (EA:PE = 1:8) to give 1,6-dichloro-4-(propan-2-yl)-2,7-naphthyridine 3 g (75%) as a white solid.

[0597] Analytical data: LC-MS: (ES, m / z)=241[M+1]. 1H NMR (300 MHz, DMSO-d6) δ 9.47 (d, 1H, J = 0.8 Hz), 8.47 (d, 1H, J = 0.7 Hz), 8.26 (d, 1H, J = 0.8 Hz), 3.64 (p, 1H, J = 6.8 Hz), 1.33 (d, 6H, J = 6.9 Hz). Example C2: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine

[0598] [ka]

[0599] Step 1: Synthesis of 5-bromo-N-tert-butyl-2-chloroisonicotinamide: In a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 5-bromo-2-chloropyridine-4-carboxylic acid (4 g, 16.9 mmol), 2-methylpropan-2-amine (1.47 g, 20.2 mmol), EDC HCl (4.85 g, 25.3 mmol), and HOBT (3.41 g, 25.3 mmol) in DMF (30 mL) were placed. The resulting solution was stirred overnight at room temperature. Water was added to the resulting solution, and the suspension was extracted with EA. The organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by FLASH using PE / EA (2:1). This afforded 3 g (60.9%) of 5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide as a white solid.

[0600] Analytical data: LC-MS: (ES, m / z)=293[M+1]; 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.30 (s, 1H), 7.58 (s, 1H), 1.36 (s, 9H). Step 2: Synthesis of (E)-N-tert-butyl-2-chloro-5-(2-ethoxyvinyl)isonicotinamide: In a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide (2 g, 6.85 mmol), 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.49 g, 7.53 mmol), CsCO (4.46 g, 13.7 mmol), and Pd(dppf)Cl (501 mg, 685 μmol) were placed in dioxane (30 mL) and HO (6 mL). The resulting solution was stirred at 80 °C for 2 h. The resulting solution was diluted with water and extracted with EA. The organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash elution with PE / EA (2:1). This gave 1.2 g (62.1%) of N-tert-butyl-2-chloro-5-[(E)-2-ethoxyethenyl]pyridine-4-carboxamide as a yellow solid.

[0601] Analysis data: LC-MS: (ES, m / z)=283[M+1];1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.20 (s, 1H), 7.35 (d, 1H, J = 13.0 Hz), 7.28 (s, 1H), 5.79 (d, 1H, J = 13.0 Hz), 3.90 (q, 2H, J = 7.0 Hz), 1.35 (s, 9H), 1.26 (t, 3H, J = 7.0 Hz). Step 3: Synthesis of 7-chloro-2,6-naphthyridin-1(2H)-one: In a 20 mL vial, N-tert-butyl-2-chloro-5-[(E)-2-ethoxyethenyl]pyridine-4-carboxamide (1.2 g, 4.24 mmol) was placed in TFA (20 mL). The resulting solution was stirred at 100 °C overnight. The resulting mixture was concentrated in vacuo. This afforded 600 mg (91.5%) of 7-chloro-1,2-dihydro-2,6-naphthyridin-1-one as a red solid. The crude product was used directly in the next step without any further purification.

[0602] Analytical data: LC-MS: (ES, m / z) = 181 [M+1]. Step 4: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1(2H)-one: In a 250 mL round-bottom flask, 7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (3 g, 16.6 mmol) and NBS (3.54 g, 19.9 mmol) were placed in DCM (40 mL). The resulting solution was stirred at room temperature for 1 hour. The solid was collected by filtration. This afforded 3 g (69.7%) of the title compound as a white solid.

[0603] Analytical data: LC-MS: (ES, m / z)=261[M+1];H NMR (300 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.93 (s, 1H), 8.04 (s, 1H), 7.70 (d, 1H, J = 6.0 Hz). Step 5: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate: In a 50 mL three-neck bottle, 4-bromo-7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (1 g, 3.85 mmol) and TEA (777 mg, 7.70 mmol) were placed in DCM (15 mL). The resulting mixture was cooled to -78 °C, and then TfO (4.34 g, 15.4 mmol) was added dropwise over 10 min. The resulting solution was stirred at -78 °C for 0.5 h. The mixture was then warmed to room temperature and stirred at this temperature for 0.5 h. The reaction was then quenched by the addition of 2 mL of water / ice and extracted with DCM. The organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column using EA / PE (0-10%). This afforded 1 g (66.6%) of the title compound as a white solid.

[0604] Analytical data: LC-MS: (ES, m / z)=393[M+1]; 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.78 (s, 1H), 8.14 (d, 1H, J = 0.9 Hz). Step 6: Synthesis of 4-bromo-7-chloro-1-iodo-2,6-naphthyridine: Into a 50 mL three-neck bottle were placed 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate (500 mg, 1.27 mmol) and NaI (952 mg, 6.35 mmol) in ACN (9 mL). The resulting mixture was cooled to 0 °C, and trifluoromethanesulfonic acid (381 mg, 2.54 mmol) in ACN (1 mL) was added dropwise over 10 min. The mixture was then stirred at room temperature for 1.5 h. After this time, the resulting solution was extracted with EA, and the organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded 500 mg of the title compound as a dark solid. The crude compound was used directly in the subsequent step without further purification.

[0605] Analytical data: LC-MS: (ES, m / z) = 369 [M+1]. Step 7: Synthesis of 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine: In a 25 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-bromo-7-chloro-1-iodo-2,6-naphthyridine (500 mg, 1.35 mmol) was placed in dioxane (5 mL) and HO (1 mL) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (226 mg, 1.35 mmol), KCO (372 mg, 2.7 mmol), and Pd(dppf)Cl (0.99 mg, 0.135 mmol) were added. The resulting solution was stirred at 80 °C for 2 h. The resulting solution was extracted with EA, and the organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC using PE / EA (8:1). This gave 200 mg (52.3%) of the title compound as a pale yellow oil.

[0606] Analytical data: LC-MS: (ES, m / z) = 285 [M+1]. Step 8: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine: In a 25 mL round-bottom flask purged and maintained with an inert atmosphere of hydrogen, 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine (160 mg, 564 μmol) and PtO (166 mg, 733 μmol) in EA (6 mL) were placed. The resulting solution was stirred at room temperature for 3 hours. The solid was filtered off. The resulting mixture was concentrated in vacuo. This afforded 100 mg (62.1%) of the title compound as a yellow solid.

[0607] Analytical data: LC-MS: (ES, m / z) = 287 [M+1]. Example C3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine

[0608] [ka]

[0609] Step 1: Synthesis of 6-chloro-4-isobutyrylnicotinic acid: To a stirred solution of n-BuLi (100 mL) in THF was added TMP (40.1 g, 285 mmol) dropwise at −78° C. The mixture was warmed to 0° C., stirred for 1 h, and then cooled back to −78° C. A solution of 6-chloropyridine-3-carboxylic acid (15 g, 95.2 mmol) in THF was then added dropwise, and the reaction was stirred for 1.5 h. N-Methoxy-N,2-dimethylpropanamide (37.3 g, 285 mmol) was then added, and the reaction mixture was warmed to room temperature and stirred for 4 h. The mixture was quenched with aqueous NH4Cl, the pH was adjusted to 5-6 with citric acid, and then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target product as a yellow oil, which was not further purified.

[0610] Analytical data: LC-MS: (ES, m / z) = 228 [M+1]. Step 2: Synthesis of 7-chloro-1-isopropylpyrido[3,4-d]pyridazin-4(3H)-one: To a solution of 6-chloro-4-(2-methylpropanoyl)pyridine-3-carboxylic acid (11 g, 48.3 mmol) in IPA, NH2NH2·HO (3.62 g, 72.4 mmol) was added, and the mixture was stirred at 70 °C for 3 h. The mixture was filtered, the solid collected, and the filtrate was concentrated to 10 mL and then filtered. The solids were combined to give the target product as a yellow solid (6 g, crude).

[0611] Analytical data: LC-MS: (ES, m / z) = 224 [M+1]. Step 3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine: To a solution of POCl (5 mL) was added 7-chloro-1-(propan-2-yl)-3H,4H-pyrido[3,4-d]pyridazin-4-one (100 mg, 447 μmol). The mixture was stirred at 100° C. overnight. The mixture was concentrated, and the product was used directly without further purification.

[0612] Analytical data: LC-MS: (ES, m / z) = 242 [M+1]. Example C4: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline

[0613] [ka]

[0614] Step 1: Synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate: Trifluoromethanesulfonyl trifluoromethanesulfonate (45.7 g, 162 mmol) was added dropwise to 8-bromo-3-chloroisoquinolin-5-ol (14 g, 54.1 mmol) and TEA (21.8 g, 216 mmol) in DCM (400 mL) at −60° C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was purified by silica gel column using PE:EA=5:1 to give the title compound 18 g (85%) as a white solid.

[0615] Analytical data: LC-MS: (ES, m / z)=392[M+1];1H NMR (400 MHz, DMSO-d6) δ 9.46 (d, 1H, J = 0.8 Hz), 8.20 (d, 1H, J = 8.3 Hz), 8.02 (d, 1H, J = 8.4 Hz), 7.93 (d, 1H, J = 0.7 Hz). Step 2: Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline: A mixture of K2CO3 (6 g, 43.5 mmol), 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (17 g, 43.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.30 g, 43.5 mmol), and Pd(dppf)Cl2·CHCl2 (2.83 g, 3.48 mmol) in dioxane / HO (200 / 20 mL) was stirred at 45 °C for 3 h. The mixture was diluted with EA (500 mL) and washed with brine (200 mL × 2). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using PE:EA = 20:1 to give the title compound (8.0 g, 67%) as an off-white solid.

[0616] Analytical data: LC-MS: (ES, m / z) = 282 [M+1]. Step 3: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline: PtO (1.7 g, 7.04 mmol) and 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (7.1 g, 25.1 mmol) in EA (300 mL) were stirred at room temperature under an atmosphere of H balloon and stirred for 1 h. The solid was filtered off. The mother liquor solvent was concentrated in vacuo. The crude product was purified on a silica gel column with PE:EA=10:1 to give 6.7 g (93%) of the title compound as a brown solid.

[0617] Analytical data: LC-MS: (ES, m / z) = 284 [M+1]. Example C5: Synthesis of rac-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol

[0618] [ka]

[0619] Step 1: Synthesis of 2-(8-bromo-3-chloroisoquinolin-5-yl)prop-2-en-1-ol: To a solution of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (5 g, 12.8 mmol, from Step 1 of Example C4) in 1,4-dioxane / HO was added 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (2.35 g, 12.8 mmol), KCO (1.76 g, 12.8 mmol), and Pd(dPPf)Cl (467 mg, 0.641 mmol). The resulting solution was stirred at 60 °C for 2 h. The resulting solution was diluted with 100 mL of water and extracted with EA (2 × 100 mL). The organic phase was washed with brine, dried, and concentrated. The residue was purified by flash using PE:EA (1:1). This gave 2.1 g (54.9%) of the title compound as a white solid.

[0620] Analytical data: LC-MS: (ES, m / z) = 298 [M+1]. Step 2: Synthesis of rac-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol: A mixture of 2-(8-bromo-3-chloroisoquinolin-5-yl)prop-2-en-1-ol (2 g, 6.69 mmol) and PtO (454 mg, 0.05 mmol) in EA (50 mL) was stirred at room temperature under an H atmosphere for 2 hours. The resulting mixture was filtered. The filtrate was concentrated in vacuo. The product was purified by flash elution with PE:EA (10:1). This afforded 1.8 g (90%) of the title compound as a yellow solid.

[0621] Analytical data: LC-MS: (ES, m / z) = 300 [M+1]. Example C6: Synthesis of 8-bromo-3-chloro-5-methylisoquinoline

[0622] [ka]

[0623] A mixture of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (500 mg, 1.28 mmol, from Step 1 of Example C1), trimethyl-1,3,5,2,4,6-trioxatriborinane (64.2 mg, 512 μmol), Pd(dppf)Cl (46.9 mg, 64.0 μmol), and KCO (176 mg, 1.28 mmol) in a mixed solvent (dioxane:HO = 5:1, 4.8 mL) was stirred at 40 °C for 16 hours under a N atmosphere. The resulting solution was concentrated in vacuo. The residue was purified by preparative TLC using DCM / MeOH (20 / 1) to give 100 mg of the title compound as an off-white solid.

[0624] Analytical data: LC-MS: (ES, m / z) = 258 [M+1]. Example C7: Synthesis of 8-bromo-3-chloroisoquinoline

[0625] [ka]

[0626] A mixture of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (100.00 mg, 0.256 mmol, 1 equiv., from Step 1 of Example C4), [3-(diphenylphosphanyl)propyl]diphenylphosphane (2.11 mg, 0.005 mmol, 0.02 equiv.), (acetyloxy)paradioacetate (1.15 mg, 0.005 mmol, 0.02 equiv.), and triethylsilane (74.43 mg, 0.640 mmol, 2.5 equiv.) in DMF (3 mL) was stirred at 60 °C under a N atmosphere for 1 h. Water was added, extracted with EA, and concentrated. The residue was applied on preparative TLC using DCM / MeOH (10:1). This afforded 50 mg (80.5%) of the title compound as a pale yellow solid.

[0627] Analytical data: LC-MS: (ES, m / z) = 242 [M+1]. Example C8: Synthesis of rac-3-chloro-5-(1-fluoropropan-2-yl)-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[0628] [ka]

[0629] Step 1: Synthesis of rac-2-{3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]isoquinolin-5-yl}propan-1-ol: To a solution of rac-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol (150 mg, 0.4990 mmol, from Example C5) in 1,4-dioxane under nitrogen, 3-(methanesulfonylmethyl)azetidine (74.4 mg, 0.499 mmol), CsCO (325 mg, 0.998 mmol), and XantPhos Pd G (44.3 mg, 49.9 mmol) were added. The mixture was stirred at 100 °C for 3 h. The resulting solution was diluted with 20 mL of water and extracted with EA (2 × 20 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The crude product was purified by preparative TLC (DCM:MeOH = 10:1). This afforded 100 mg (54.3%) of the title compound as a yellow solid.

[0630] Analytical data: LC-MS: (ES, m / z) = 369 [M+1]. Step 2: Synthesis of rac-bn 3-chloro-5-(1-fluoropropan-2-yl)-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: To a solution of 2-{3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]isoquinolin-5-yl}propan-1-ol (100 mg, 0.2710 mmol) in DCM was added DAST (87.3 mg, 0.542 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction solution was quenched with water and extracted with EA (2 × 20 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The crude product was purified by preparative TLC (DCM:MeOH = 15:1). This afforded 80 mg (79.9%) of the title compound as a yellow solid.

[0631] Analytical data: LC-MS: (ES, m / z) = 371 [M+1]. Example C9: Synthesis of 8-bromo-3-chloro-5-ethoxyisoquinoline

[0632] [ka]

[0633] Step 1: Synthesis of 8-bromo-3-chloro-5-methoxyisoquinoline: To a mixture of 3-chloro-5-methoxyisoquinoline (2 g, 10.3 mmol) in AcOH (20 mL) was added a solution of bromine (1.80 g, 11.3 mmol) dissolved in AcOH (10 mL) over 10 min. The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was slowly poured into a solution of KCO (5 g in HO (100 mL)) with rapid stirring. The mixture was then extracted with DCM and concentrated under reduced pressure to give 2.5 g (89.2%) of the title compound as a yellow solid.

[0634] Analytical data: LC-MS: (ES, m / z)=272[M+1]. 1H-NMR (300 MHz, 6d-DMSO) δ ppm 9.21 (s, 1H), 8.09 -7.81 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H). Step 2: Synthesis of 8-bromo-3-chloroisoquinolin-5-ol: To a solution of 8-bromo-3-chloro-5-methoxyisoquinoline (2 g, 7.33 mmol) in DCM was added tribromoborane (5.48 g, 21.9 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was slowly poured into ice water with rapid stirring. The precipitate was collected by filtration. This afforded 1.8 g (89%) of the title compound as a yellow solid.

[0635] Analytical data: LC-MS: (ES, m / z) = 258 [M+1]. Step 3: Synthesis of 8-bromo-3-chloro-5-ethoxyisoquinoline: To a solution of 8-bromo-3-chloroisoquinolin-5-ol (900 mg, 3.48 mmol) in DMF (20 mL) was added iodoethane (1.08 g, 6.96 mmol) and CsCO (3.39 g, 10.4 mmol). The resulting solution was stirred at 100 °C for 3 h. The resulting solution was cooled to room temperature, diluted with water, and extracted with EA. The organic phase was concentrated in vacuo and purified by chromatography using PE:EA (1:1). This gave 800 mg (80.2%) of the title compound as a yellow solid.

[0636] Analysis data: LC-MS: (ES, m / z)=286[M+1];1H-NMR (400 MHz, 6d-DMSO) δ ppm 9.23 (d, 1H, J = 0.8 Hz), 8.03 (d, 1H, J = 0.8 Hz), 7.91 (d, 1H, J = 8.3 Hz), 7.20 (d, 1H, J = 8.4 Hz), 4.25 (q, 2H, J = 7.0 Hz), 1.47 (t, 3H, J = 6.9 Hz). Example C10: Synthesis of 3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline

[0637] [ka]

[0638] Step 1: Synthesis of (1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanol: A mixture of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (Example C4, 300 mg, 1.05 mmol, Example C4), (azetidin-3-yl)methanol hydrochloride (129 mg, 1.05 mmol), XantPhos Pd G4 (175 mg, 210 μmol), and CsCO3 (684 mg, 2.10 mmol) in dioxane (25 mL) was stirred at 100° C. for 16 hours. The reaction was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (230 mg, 76%) as a yellow solid.

[0639] Analytical data: LC-MS: (ES, m / z) = 291 [M+1]. Step 2: Synthesis of 3-chloro-8-(3-(iodomethyl)azetidin-1-yl)-5-isopropylisoquinoline: A mixture of {1-[3-chloro-5-(propan-2-yl)isoquinolin-8-yl]azetidin-3-yl}methanol (220 mg, 756 μmol), triphenylphosphine (296 mg, 1.13 mmol), imidazole (102 mg, 1.51 mmol), and iodine (230 mg, 907 μmol) in DCM (25 mL) was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by preparative TLC (PE:EA=20:1) to give the title compound (190 mg, 62%) as a yellow solid.

[0640] Analytical data: LC-MS: (ES, m / z) = 401 [M+1]. Step 3: Synthesis of 3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline: A mixture of 3-chloro-8-[3-(iodomethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (100 mg, 249 μmol) and sodium cyclopropanesulfinate (127 mg, 996 μmol) in DMF (15 mL) was stirred for 2 hours at 80° C. The solvent was removed, and the residue was purified by preparative TLC (PE:EA=2:1) ​​to give the title compound (100 mg, 94.5%) as a yellow solid.

[0641] Analytical data: LC-MS: (ES, m / z) = 379 [M+1]. Example C11: Synthesis of 8-bromo-3-chloro-5-cyclopropylisoquinoline

[0642] [ka]

[0643] To a solution of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (240 mg, 614 μmol) in dioxane / HO (10 mL / 2 mL), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (123 mg, 736 μmol), KCO (168 mg, 1.22 mmol), and Pd(dppf)Cl (50.1 mg, 61.4 μmol) were added. The mixture was stirred at 80 °C under a N atmosphere for 16 h. Water was added to the mixture, which was then extracted with EA. The organic phase was concentrated and purified by FLASH (50% EA in PE) to give 90 mg (52%) of the title compound as a yellow solid.

[0644] Analytical data: LC-MS: (ES, m / z) = 284 [M+1]. Example C12: Synthesis of 3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[0645] [ka]

[0646] Step 1: Synthesis of 7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: To a solution of 3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (150 mg, 425 μmol) in DMF (10 mL) was added NBS (60.1 mg, 340 μmol). The solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (170 mg, 81.7%) as a yellow solid.

[0647] Analytical data: LC-MS: (ES, m / z) = 431 [M+1]. Step 2: Synthesis of 3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: A mixture of 7-bromo-3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (75 mg, 173 μmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (8.68 mg, 69.2 μmol), KCO (23.8 mg, 173 μmol), and Pd(dppf)Cl (14.1 mg, 17.3 μmol) in dioxane / HO (7 mL / 2 mL) was stirred at 80 °C for 3 h. The mixture was extracted with EA. The organics were concentrated and purified by FLASH (5% MeOH in DCM) to give 55 mg (87%) of the title compound as a yellow solid.

[0648] Analytical data: LC-MS: (ES, m / z) = 367 [M+1]. Example C13: Synthesis of 3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[0649] [ka]

[0650] Step 1: Synthesis of 7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: NBS (163 mg, 918 μmol) was added batchwise to 3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (360 mg, 1.02 mmol) in DMF (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by preparative TLC using PE:EA=1:1 to give 350 mg of the title compound as a yellow solid.

[0651] Analytical data: LC-MS: (ES, m / z) = 431 [M+1]. Step 2: Synthesis of 3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: n-BuLi (2.5 M, 2.29 mmol, 916 μL) was added dropwise to 7-bromo-3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (330 mg, 764 μmol) and N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (479 mg, 1.52 mmol) in THF (20 mL) at −78 °C under a N atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with HO, diluted with EA, and washed with brine. The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by preparative TLC using DCM:MeOH=30:1 to give 80 mg of the title compound as a yellow solid.

[0652] Analytical data: LC-MS: (ES, m / z) = 371 [M+1]. Example C14: Synthesis of 3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline

[0653] [ka]

[0654] Step 1: Synthesis of 3-chloro-5-iodo-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: To a solution of 3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline (100 mg, 307 μmol) in AcOH (5 mL), iodo(sulfanyl)amine (58.6 mg, 337 μmol) was added and stirred at room temperature for 1 hour. Water was added, and the reaction mixture was extracted with EA. The organic phase was concentrated and purified by preparative TLC (DCM:MeOH=15:1) to give the product (100 mg) as a yellow solid.

[0655] Analytical data: LC-MS: (ES, m / z) = 451 [M+1]. Step 2: Synthesis of 3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline: A mixture of 3-chloro-5-iodo-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline (100 mg, 221 μmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (211 mg, 1.10 mmol), and CuI (4.18 mg, 22.0 μmol) in NMP (5 mL) was heated to 80° C. under a N atmosphere for 2 hours. The reaction mixture was diluted with water and extracted with EA. The organic layer was concentrated and purified by preparative TLC (EA:PE=2:1) ​​to give 40 mg of the product as a pale yellow solid.

[0656] Analytical data: LC-MS: (ES, m / z) = 393 [M+1]. Example C15: Synthesis of 2-(6-chloro-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-4-yl)propan-1-ol

[0657] [ka]

[0658] Step 1: Synthesis of 6-chloro-4-iodo-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridine: A mixture of 1,6-dichloro-4-iodo-2,7-naphthyridine (300 mg, 923 μmol), (2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (Example A4, 179 mg, 1.10 mmol), and TEA (186 mg, 1.84 mmol) in IPA (15 mL) was stirred at 100° C. for 3 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by TLC (PE:EA=1:1). This afforded 300 mg (72.1%) of the title compound as a pale yellow solid.

[0659] Analytical data: LC-MS: (ES, m / z) = 452 [M+1]. Step 2: Synthesis of 2-(6-chloro-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-4-yl)prop-2-en-1-ol: In a 50 mL sealed tube, 6-chloro-4-iodo-1-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-2,7-naphthyridine (200 mg, 663 μmol), 2-(4,4,5,5-tetrameth)-2,4-diol (122 mg, 663 μmol), KCO (122 mg, 884 μmol), and Pd(dppf)Cl (64.6 mg, 88.3 μmol) were placed in dioxane (20 mL) and HO (4 mL) under a N atmosphere. The resulting solution was stirred at 85 °C for 6 h. The mixture was diluted with EA and washed with brine. The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by flash column silica-CS (DCM:MeOH=10:1). This afforded 150 mg (89.2%) of the title compound as a white solid.

[0660] Analytical data: LC-MS: (ES, m / z) = 382 [M+1]. Step 3: Synthesis of 2-(6-chloro-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-4-yl)propan-1-ol: To a solution of 2-{6-chloro-1-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-2,7-naphthyridin-4-yl}prop-2-en-1-ol (100 mg, 261 μmol) in EA (30 mL) was added PtO (29.5 mg, 130 μmol). The mixture was then hydrogenated under a hydrogen balloon at room temperature for 1 hour. The mixture was filtered and concentrated. The residue was purified by TLC (DCM:MeOH=10:1). This afforded 110 mg of the title compound as a yellow solid.

[0661] Analytical data: LC-MS: (ES, m / z) = 384 [M+1]. Example C16: Synthesis of 3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline:

[0662] [ka]

[0663] Step 1: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-ol: To a solution of 3-chloro-5,7-difluoro-8-methoxy-isoquinoline (300 mg, 1.31 mmol, 1 equiv.) in DCM (5 mL) was added BBr3 (982 mg, 3.92 mmol, 3 equiv.) at −78° C., and the mixture was then stirred at 25° C. for 2 h. The mixture was quenched with 10 mL of water, and some solid precipitated. The solid was collected by filtration and washed with 10 mL of water. This gave 0.22 g (77%) of the title compound as a brown solid.

[0664] Analytical data: LC-MS: (ES, m / z): RT=0.645 min, LCMS: m / z=215.8 [M+1]. Step 2: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-yl trifluoromethanesulfonate: A mixture of 3-chloro-5,7-difluoro-isoquinolin-8-ol (200 mg, 923 μmol, 1 eq.), 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (994 mg, 2.78 mmol, 3 eq.) and TEA (282 mg, 2.78 mmol, 3 eq.) in DCM (5 mL) was stirred at 20° C. for 2 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (PE to PE / EA=50 / 1). This afforded 0.26 g (76%) of the title compound as a white solid.

[0665] Analytical data: LC-MS: (ES, m / z): RT=0.966 min, LCMS: m / z=348.0 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.33 (dd, J = 9.6, 10.4 Hz, 1H), 8.28 (s, 1H). Step 3: Synthesis of 3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline: To a mixture of (3-chloro-5,7-difluoro-8-isoquinolyl)trifluoromethanesulfonate (140 mg, 403 μmol, 1 equiv.), 3-(methylsulfonylmethyl)azetidine (159 mg, 604 μmol, 1.50 equiv., TFA salt), and CsCO (393 mg, 1.21 mmol, 3 equiv.) in toluene (1 mL) was added (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (23.2 mg, 40.3 μmol, 0.1 equiv.), BINAP (201 mg, 322 μmol, 0.8 equiv.), and Pd(OAc) (18.1 mg, 80.5 μmol, 0.2 equiv.), and the mixture was degassed and purged with N three times, then the mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=20:1 to 1:1) to obtain 10 mg (7%) of the title compound as a yellow solid.

[0666] Analytical data: LC-MS: (ES, m / z): RT=0.900 min, LCMS: m / z=347.1 [M+1]. 1 H NMR (400MHz, CDCl3) δ = 9.22 (s, 1H), 7.81 (s, 1H), 4.72-4.65 (m, 1H), 4.30-4.25 (m, 1H), 3.45-3.30 (m, 6H). Example 1, Synthesis of Compound 55: (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol

[0667] [ka]

[0668] Step 1: Synthesis of 3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: A mixture of CsCO (8.21 g, 25.2 mmol), 3-(methanesulfonylmethyl)azetidin-1-ium trifluoromethanesulfonate (6.91 g, 23.1 mmol), 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (from Example C4, 6.0 g, 21.0 mmol), and XantPhos Pd G (1.86 g, 2.10 mmol) in dioxane (100 mL) was stirred at 100 °C under a N atmosphere for 16 h. The mixture was diluted with EA (200 mL) and washed with brine. The organic layer was dried over NaSO and concentrated in vacuo. The redisue was purified by FLASH (DCM:MeOH = 30:1) to give 5.0 g (67%) of the title compound as a yellow solid.

[0669] Analytical data: LC-MS: (ES, m / z) = 353 [M+1]. Step 2: Synthesis of (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol: CsCO (3.81 g, 11.7 mmol) was added to C-Phos (627 mg, 1.07 mmol, 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl), Pd(dba) CHCl (1.42 g, 1.07 mmol), 3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (3.8 g, 10.7 mmol), and (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (2.64 g, 11.7 mmol, from Example B1) in dioxane (100 mL). The mixture was stirred at 100 °C under a N atmosphere for 16 h. The mixture was diluted with EA (500 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC column: XBridge Preparative OBD C18 column 30 x 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 41% B to 90% B in 10 min; 254 nm; 220 nm: to give 2.80 g (70%) of the title compound as a yellow solid.

[0670] Example 2, Compound 52: Synthesis of (3S,4R)-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3R,4S)-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

[0671] [ka]

[0672] To a solution of 3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (70 mg, 0.1983 mmol, from Step 1 of Example 1) in 1,4-dioxane was added cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (44.4 mg, 0.1983 mmol, Peak 1 from Example B10), CsCO (193 mg, 0.59 mmol), and allyl BrettPhos PdOTf (16.5 mg, 19.7 mmol). The mixture was stirred at 100 °C under a N atmosphere for 2 hours. The reaction mixture was cooled to room temperature and diluted with 20 mL of water. The resulting solution was extracted with EA (2 × 20 mL), and the organic layers were combined. The resulting mixture was washed with 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column 30 x 150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 45% B in 8 min; 254; 220 nm; Rt: 7.17 min. This gave 35 mg (32.7%) of the title compound as a yellow solid.

[0673] Example 3, Synthesis of Compound 111: (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol

[0674] [ka]

[0675] Step 1: Synthesis of 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline: To a solution of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (9 g, 31.6 mmol, from Example C4) in 1,4-dioxane (130 mL) was added (2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (5.15 g, 31.6 mmol, from Example A4), CsCO (20.6 g, 63.2 mmol), and Xantphos Pd G (1.51 g, 1.58 mmol) under nitrogen. The mixture was stirred at 100 °C under nitrogen for 3 h. The reaction mixture was cooled to room temperature and diluted with 300 mL of water. The resulting solution was extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-60% EA in PE) to give 7.2 g (62.6%) of 3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline as a yellow solid.

[0676] Analytical data: LC-MS: (ES, m / z) = 367 [M+1]. Step 2: Synthesis of (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol: A mixture of 3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline (5 g, 13.6 mmol), (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (3.07 g, 13.6 mmol, from Example B1), CsCO (8.86 g, 27.2 mmol), and Brettphos Pd G (616 mg, 0.68 mmol) in dioxane (60 mL) was stirred at 100 °C under nitrogen for 3 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting solution was extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0–5% MeOH in DCM). This gave 4.6 g (60.7%) of the title compound as a yellow solid.

[0677] Example 4, Synthesis of Compound 64: N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine

[0678] [ka]

[0679] In an 8 mL pressure tank reactor purged and maintained with an inert atmosphere of nitrogen, 3-chloro-5-isopropyl-8-[3-(methanesulfonylmethyl)azetidin-1-yl]isoquinoline (30 mg, 0.085 mmol, 1 equiv., from Step 1 of Example 1), 2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-amine (19.24 mg, 0.085 mmol, 1 equiv., from Example B33), BrettPhos Pd G3 (7.71 mg, 0.009 mmol, 0.1 equiv.), and Cs2CO3 (55.40 mg, 0.170 mmol, 2 equiv.) were placed in dioxane (2 mL). The resulting solution was stirred at 110 °C for 3 hours. The reaction was then quenched by the addition of 1 mL of water. The solid was filtered off. The resulting solution was extracted with EA (3 × 5 mL) and concentrated in vacuo. The residue was applied to a silica gel column using dichloromethane / methanol (15:1). The crude product was purified by preparative HPLC using the following cond...

Claims

1. Formula (I): 【Chemical 1】 [In the formula, Z is O or NH; Each A １ , A ２ , and A ３ is independently N or CR; each R is independently H, halogen, or CH ３ and Ring A is a 4-12 membered heterocyclyl; Each R １ are independently halogen, CN, OH, NR ａ R ｂ , C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C ３ ~C ６ Cycloalkyl or —O—C ３ ~C ６ is cycloalkyl, and R １ C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl or —O—C 3 -C 6 cycloalkyl represented by the formula: ａ R ｂ , C １ ~C ２ Alkyl, and C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkoxy; m is 0, 1, 2, 3, 4, 5, or 6; R ２ is H, halogen, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, or C ３ ~C ６ is cycloalkyl, and R ２ C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 3 -C 6 cycloalkyl represented by the formula: is optionally substituted with 1 to 3 groups selected from halogen and OH; R ３ is H or methyl; R ４ is H or methyl; R ５ is C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl or 4-6 membered monocyclic heterocyclyl, R ５ The C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered monocyclic heterocyclyl represented by the formula: ａ R ｂ , C １ ~C ２ Alkyl, and C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkoxy; R ６ is H or C 1 -C 4 alkyl, and the C 1 -C 4 alkyl is selected from halogen, CN, OH, NR ａ R ｂ , and C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkoxy; Each R ａ and R ｂ are independently H or C １ ~C ４ or a pharmaceutically acceptable salt thereof.

2. Structural Formula (II-A), (II-B), (II-C), (II-D), or (II-E): 【Chemistry 2】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

3. Structural formula (II-A): 【Chemistry 3】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

4. 4. The compound of claim 1, wherein Z is O, or a pharmaceutically acceptable salt thereof.

5. R ２ But H, fluorine, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, or C ３ ~C ６ is cycloalkyl, and R ２ C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl represented by the formula: is optionally substituted with 1 to 3 groups selected from halogen and OH; R ５ halogens, CN, and NR ａ R ｂ C optionally substituted with 1 to 3 groups selected from １ ~C ４ Alkyl; C ３ ~C ６ cycloalkyl; or 4-6 membered monocyclic heterocyclyl optionally substituted with C 1 -C 2 alkyl; R ａ and R ｂ are each independently selected from H, methyl and ethyl; R ６ H, methyl, ethyl, C １ ~C ２ haloalkyl, or C １ ~C ２ 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is aminoalkyl.

6. The A ring is a ring having 1 to 6 R １ 6. The compound of any one of claims 1 to 5, wherein R is a 4- to 7-membered monocyclic heterocyclyl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

7. The A ring is a ring having 1 to 6 R １ 6. The compound of any one of claims 1 to 5, wherein R is a 7- to 12-membered bicyclic heterocyclyl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

8. m is 1, 2, 3, 4, or 5; Each R １ are independently halogen, CN, OH, NR ａ R ｂ , C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, —O—C ３ ~C ６ is cycloalkyl, and R １ The C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —O—C 3 -C 6 cycloalkyl represented by the formula: ａ R ｂ , C １ ~C ２ Alkyl, and C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkoxy; R ２ is H, F, methyl, ethyl, isopropyl, CH(CH ３ ) CH ２ F, CH (CH ３ ) CH ２ OH, CF ３ , OCH ３ , OCH ２ CH ３ or cyclopropyl, R ６ But H, CH ３ , or C.H. ２ NH ２ 8. The compound of any one of claims 1 to 7, wherein:

9. The A ring is a ring having 1 to 6 R １ and the A ring is optionally substituted with pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, bicyclo[3.2.1]octanyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl or 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl, where at least one R １ But, OH, C １ ~C ４ Alkoxy, or —O—C ３ ~C ６ cycloalkyl, where R １ The C 1 -C 4 alkoxy or —O—C 3 -C 6 cycloalkyl represented by the formula: ａ R ｂ , C １ ~C ２ Alkyl, and C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkoxy; Each R １ are independently F, CN, OH, NH ２ , C.H. ３ , C.H. ２ CH ３ , CHF ２ , CH(OH)CH ３ , C.H. ２ OH, CH ２ NH ２ , C.H. ２ CH ２ NH ２ , OCH ３ , OCD ３ , OCH ２ CH ２ OH, OCH ２ CH(OH)CH ３ , OCH ２ C(OH)(CH ３ ) ２ , OCH ２ CH ２ OCH ３ , OCH ２ CH ２ NH ２ , OCH ２ CH ２ NHCH ３ , OCH ２ CH ２ N (CH ３ ) ２ , —O-cyclopropyl, NHCH ３ , or N(CH ３ ) ２ That is, 9. A compound according to any one of claims 1 to 5 and 8, or a pharmaceutically acceptable salt thereof.

10. 【Chemical 4】 but, 【Chemistry 5】 and R ２ is H or isopropyl, The A ring is a ring having 1 to 6 R １ piperidinyl optionally substituted with 10. A compound according to any one of claims 1 to 6, 8, and 9, or a pharmaceutically acceptable salt thereof.

11. The compound 【Chemistry 6】 2. The compound of claim 1, wherein:

12. 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. 13. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for use in a method for treating cancer, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt thereof, or said pharmaceutical composition to a subject in need thereof.

14. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 13, wherein the cancer is non-small cell lung cancer.

15. 15. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition according to claim 13 or 14, wherein the cancer is characterized by: i) epidermal growth factor receptor EGFR L858R mutation and / or exon 19 deletion; and ii) T790M mutation.

16. 16. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition of claim 15, wherein the cancer is further characterized by an epidermal growth factor receptor (EGFR) C797S mutation.

17. 17. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition according to any one of claims 13 to 16, wherein the method further comprises the step of administering to a subject in need thereof an effective amount of afatinib, osimertinib, erlotinib, or gefitinib.

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