Inhibitors of EGFR mutant forms

Abstract

The present disclosure provides a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, which can be used to treat cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 953,030, filed on December 23, 2019. The entire contents of the aforementioned application are incorporated herein by reference. Background Art

[0003] EGFR (epidermal growth factor receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. By binding to its ligand, such as epidermal growth factor (EGF), EGFR can form homodimers on the cell membrane or form heterodimers with other receptors of this family (e.g., erbB2, erbB3, or erbB4). The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating many downstream signaling pathways in the cell. These intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis. Disturbances in the EGFR signal transduction pathway (including increased expression of ligands and receptors), EGFR gene amplification and changes (e.g., mutations, deletions, etc.) can promote the malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. For example, changes in the EGFR gene, such as mutations and deletions, have been found in non-small cell lung cancer (NSCLC) tumors. The two most frequent EGFR alterations found in NSCLC tumors are a short in-frame deletion (del19) in exon 19 and L858R, a single missense mutation in exon 21 (Cancer Discovery 2016 6(6)601). Both alterations cause ligand-independent EGFR activation and are known as primary or activating mutations in EGFR-mutant NSCLC (EGFR M+). Clinical experience has shown objective response rates (ORRs) of approximately 60% to 85% in patients with EGFR M+ NSCLC treated with the EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib as first-line (1L) therapy (Lancet Oncol. 2010, Vol. 11, 121; Lancet Oncol. 2016, Vol. 17, 577; N. Engl. J. Med. 2017, Nov 18, Doi: 10.1056 / NEJMoa1713137; Lancet Oncol. 2016, Vol. 17, 577; N. Engl. J. Med. 2017, Nov 18, Doi: 10.1056 / NEJMoa1713137; Lancet Oncol. 2016, Vol. 17, 577; N. Engl. J. Med. 2016 ... Oncol. 2011, Vol. 12, 735), which confirmed that EGFR-mutant NSCLC tumors depend on oncogenic EGFR activity for survival and proliferation and established del19 and L858R mutant EGFR as oncogenic drivers of the disease, thereby validating drug targets and biomarkers for the treatment of NSCLC.

[0004] However, after an average of 10 to 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 Feb;11(2):121-8; Lancet Oncol. 2016 May;17(5):577-89; Lancet Oncol. 2011 Aug;12(8):735-42). The most prominent mechanism of resistance to first- and second-generation EGFR TKIs is due to the secondary mutation T790M in EGFR, which progresses in 50% to 70% of patients who receive first- and second-generation EGFR inhibitors (Blakely, 2012; Kobayashi, 2005). This secondary mutation reduces the affinity of the drug for its target, thereby conferring resistance and leading to tumor recurrence or disease progression.

[0005] Given the prevalence of this mutation in resistance to therapies targeting EGFR in lung cancer, many companies have attempted to develop new small molecule EGFR inhibitors that inhibit the resistance mutant EGFR-T790M to treat these patients with resistant lung cancer. For example, the third generation EGFR TKI (osimertinib) has been developed. ) to treat NSCLC patients if the cancer cells are positive for the primary EGFR mutation del19 or L858R, with or without the T790M mutation in the gene encoding EGFR.

[0006] Although the third-generation EGFR TKI osimertinib has shown efficacy in NSCLC patients, 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 resistance events (Cancer Letters 2016, Vol. 385: 51-54). The EGFR del19 / L858R T790M C797S cis-mutant kinase variant, commonly referred to as "triple mutant" EGFR, often appears in second-line (2L) patients after treatment with osimertinib and is no longer inhibited by first-, second-, or third-generation EGFR inhibitors.

[0007] There are no approved EGFR TKIs that can inhibit triple mutant variants. Therefore, there is a need to develop new EGFR inhibitors that can highly selectively inhibit EGFR mutants with the triple mutant del19 / L858R T790M C797S while having no or low activity against wild-type EGFR. In addition to treating mutant forms of EGFR (for which there are currently no therapies), these selective EGFR inhibitors may be more suitable as therapeutic agents, particularly for the treatment of cancer, due to the reduction of toxicology (diarrhea, rash) associated with wild-type EGFR inhibition. Summary of the Invention

[0008] The applicant has discovered novel compounds that are effective inhibitors of certain mutant forms of EGFR (see Synthesis Examples 1 to 43). In particular, it has been shown that the compounds of the present disclosure effectively inhibit certain mutant forms of EGFR. The compounds of the present disclosure (also referred to herein as "disclosed compounds") or pharmaceutically acceptable salts thereof effectively inhibit EGFR with one or more changes (including L858R and / or exon 19 deletion mutations, T790M mutations and / or C797S mutations). The compounds of the present disclosure or pharmaceutically acceptable salts thereof effectively inhibit EGFR with L858R and / or exon 19 deletion mutations, T790M mutations and C797S mutations (hereinafter "EGFR with LRTMCS mutations" or "triple mutant EGFR") (see Biological Example 1) and can be used to treat various cancers, for example, lung cancer (see Biological Example 2). Importantly, the compounds of the present disclosure are selective EGFR inhibitors, that is, the compounds of the present disclosure are inactive or have low activity against wild-type EGFR and kinase groups. Advantages associated with such selectivity may include promoting effective administration and reducing EGFR-mediated on-target toxicity. Some of the compounds disclosed herein exhibit good penetration of the brain and blood-brain barrier (e.g., a PGP efflux ratio of less than 5). Thus, it is expected that the compounds disclosed herein or pharmaceutically acceptable salts thereof may be effectively used to treat metastatic cancers, including brain metastases (including leptomeningeal disease and other systemic metastases). Some of the compounds disclosed herein also have the advantage of having high microsomal stability. The compounds disclosed herein may also have favorable toxicity properties associated with other non-kinase targets.

[0009] In one aspect, the present invention provides a compound represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] The definitions of the variables are provided below.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof ("pharmaceutical compositions of the present disclosure").

[0013] The present disclosure provides a method for treating a subject suffering from 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 metastases from non-small cell lung cancer.

[0014] 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 additionally have an epidermal growth factor receptor (EGFR) L858R mutation and / or an exon 19 deletion mutation and 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.

[0015] The treatment methods disclosed herein further comprise administering to the subject an effective amount of afatinib, osimertinib, erlotinib, or gefitinib.

[0016] 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.

[0017] The present disclosure also provides use of an effective amount of a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating cancer.

[0018] 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

[0019] definition

[0020] As used herein, the term "halo" means halogen and includes chlorine, fluorine, bromine, and iodine.

[0021] The term "alkyl," as used alone or as part of a larger moiety, such as "alkoxy" or "haloalkyl," refers to a saturated aliphatic straight or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has from 1 to 4 carbon atoms, i.e., (C1-C4)alkyl. As used herein, a "(C1-C4)alkyl" group means a group having from 1 to 4 carbon atoms arranged in a straight or branched chain. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0022] The term "alkenyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced by a double bond.

[0023] The term "alkoxy" means an alkyl group attached through an oxygen linking atom, which is represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy and butoxy.

[0024] The term "aminoalkyl" refers to an alkyl group substituted with -NH2.

[0025] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group, optionally substituted with one or more halogen atoms.

[0026] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, a cycloalkyl group has 3 to 6 carbon atoms. For example, C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a "cycloalkyl group" has 3 to 6 carbon atoms.

[0027] The term "heterocyclyl" or "heterocycle" refers to a radical of a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, tetravalent nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones ("4- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl is a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4- to 10-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. A heterocyclyl may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl"); polycyclic ring systems include fused, bridged, or spirocyclic systems). Exemplary monocyclic heterocyclyls include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxetanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems may include heteroatoms in one or more rings of the polycyclic ring system. Substituents (e.g., R 1 ) may be present on one or more rings in a polycyclic ring system.

[0028] A bridged bicyclic ring system has two non-aromatic rings (heterocyclyl or cycloalkyl) containing 7 to 12 ring atoms and which share three or more atoms, wherein the two bridgehead atoms are 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]heptyl, 3-azabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, and 8-oxa-3-azabicyclo[3.2.1]octyl.

[0029] A fused bicyclic ring system has two non-aromatic rings (heterocyclyl or cycloalkyl) containing 7 to 12 ring atoms and which share 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.

[0030] Spirobicyclic ring systems have two non-aromatic rings (heterocyclyl or cycloalkyl) containing 7 to 12 ring atoms and which share one ring atom. Examples of spirobicyclic ring systems include 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl.

[0031] Compounds of the present invention

[0032] Disclosed herein are embodiments of compounds having the general structure of Formula (I). These compounds are selective inhibitors of LRTM and LRTMCS EGFR. In contrast to other EGFR inhibitors (e.g., osimertinib) that irreversibly bind to EGFR, the compounds disclosed herein are non-covalent inhibitors.

[0033] In a first embodiment, the present invention provides a compound represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0034]

[0035] in:

[0036] Z is O or NH;

[0037] Each A 1 、A 2 and A 3 is independently N or CR; wherein each R is independently H, halogen or CH3;

[0038] Ring A is a 4- to 12-membered heterocyclic group;

[0039] Each R 1are independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or -O-C3-C6 cycloalkyl, wherein R 1 Indicated by or represented by R 1 The alkyl, alkoxy or cycloalkyl group represented by is optionally selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy groups; and / or

[0040] m is 0, 1, 2, 3, 4, 5 or 6;

[0041] R 2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy or C3-C6 cycloalkyl, wherein R 2 The alkyl, alkoxy or cycloalkyl represented by is optionally substituted by 1 to 3 groups selected from halogen and OH;

[0042] R 3 is H or methyl;

[0043] R 4 is H or methyl;

[0044] R 5 is H, C1-C4 alkyl, C3-C6 cycloalkyl or 4 to 6 membered monocyclic heterocyclic group, wherein R 5 The alkyl, cycloalkyl or heterocyclic group represented by a R b , C1-C2 alkyl and C1-C2 alkoxy groups;

[0045] R 6 is H or is optionally selected from halogen, CN, OH, NR a R b and C1-C4 alkyl substituted with 1 to 3 groups of C1-C2 alkoxy; and

[0046] Each R a and R b are independently H or C1-C4 alkyl.

[0047] In an alternative first embodiment, the present invention provides a compound represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0048]

[0049] in:

[0050] Z is O or NH;

[0051] Each A 1 、A 2 and A 3 is independently N or CR; wherein each R is independently H, halogen or CH3;

[0052] Ring A is a 4- to 10-membered heterocyclic group;

[0053] Each R 1 is independently halogen, CN, OH, NRaRb C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or -O-C3-C6 cycloalkyl, wherein R 1 Indicated by or represented by R 1 The alkyl, alkoxy or cycloalkyl group represented by is optionally selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy groups;

[0054] m is 0, 1, 2, 3, 4, 5 or 6;

[0055] R 2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy or C3-C6 cycloalkyl, wherein R 2 The alkyl, alkoxy or cycloalkyl represented by a and NR a R b substituted with 1 to 3 groups;

[0056] R 3 is H or methyl;

[0057] R 4 is H or methyl;

[0058] R 5 is H, C1-C4 alkyl, C3-C6 cycloalkyl or 4 to 6 membered monocyclic heterocyclic group, wherein R 5 The alkyl, cycloalkyl or heterocyclic group represented by a R b , C1-C2 alkyl and C1-C2 alkoxy groups;

[0059] R 6 is H or is optionally selected from halogen, CN, OH, NR a R b and C1-C4 alkyl substituted with 1 to 3 groups of C1-C2 alkoxy; and

[0060] Each R a and Rb are independently H or C1-C4 alkyl.

[0061] 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), or a pharmaceutically acceptable salt thereof:

[0062]

[0063]

[0064] wherein the variables are as defined in the first embodiment.

[0065] In a third embodiment, the present disclosure provides a compound represented by structural formula (II-A) or a pharmaceutically acceptable salt thereof:

[0066]

[0067] wherein the variables are as defined in the first embodiment.

[0068] 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 wherein the rest of these variables are as defined in the first embodiment.

[0069] 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, wherein R 2 The alkyl, alkoxy or cycloalkyl represented by is optionally substituted with 1 to 3 groups selected from halogen and OH, wherein the remaining 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, wherein R 2 The alkyl, alkoxy or cycloalkyl represented by is optionally substituted with 1 to 3 groups selected from halogen, OH and NH2, wherein the remainder of these variables are as defined in the first or fourth embodiment.

[0070] 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 6is H, methyl, ethyl, C1-C2 haloalkyl, or C1-C2 aminoalkyl, wherein the remainder of these variables are as defined in the first, fourth, or fifth embodiment.

[0071] 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; optionally selected from halogen, CN and NR a R b C1-C4 alkyl group substituted with 1 to 3 groups; C3-C6 cycloalkyl group; or a 4- to 6-membered monocyclic heterocyclic group optionally substituted with C1-C4 alkyl group; wherein R a and R b are each independently selected from H, methyl, and ethyl; and wherein the remainder of these variables are as defined in the first, fourth, fifth, or sixth embodiment.

[0072] In an eighth embodiment, the present invention provides a compound according to formula (I), (II-A), (II-B), (II-C), (II-D) or (II-E), or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted by 1 to 6 R 1 Substituted 4 to 7 membered monocyclic heterocyclyl, wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth or seventh embodiment.

[0073] In a ninth embodiment, the present invention provides a compound according to formula (I), (II-A), (II-B), (II-C), (II-D) or (II-E), or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted by 1 to 6 R 1 Substituted 7 to 12 membered bicyclic heterocyclyl wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth or seventh embodiment.

[0074] 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; each R 1 are independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, -O-C3-C6 cycloalkyl, wherein R 1 Indicated by or represented by R 1 The alkyl, alkoxy or cycloalkyl group represented by is optionally selected from deuterium, halogen, OH, NR a R b, C1-C2 alkyl, and C1-C2 alkoxy; and wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0075] 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, wherein the remaining 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, wherein the remainder of these variables are as defined in the first, fourth, fifth (or alternatively the fifth), sixth, seventh, eighth, ninth or tenth embodiment.

[0076] 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, wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment.

[0077] 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 Ring A is optionally replaced by 1 to 6 R 1substituted, and Ring A is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H -furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth, seventh, tenth, eleventh or twelfth embodiment.

[0078] 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, wherein R 1 Indicated by or represented by R 1 The alkoxy or cycloalkyl group in the group represented by is optionally selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl, and C1-C2 alkoxy, wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0079] In a fifteenth embodiment, the present invention provides a compound according to formula (I), (II-A), (II-B), (II-C), (II-D) or (II-E), or a pharmaceutically acceptable salt thereof, wherein each R 1and wherein the remaining variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiment. In a specific embodiment, each R 1 is independently F, OH, Me, Et, OMe, OCD3 or OCH2CH2OH. In another embodiment, each R 1 are independently F, OH, Me or OCD3.

[0080] In a sixteenth embodiment, the present invention 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 for wherein the remaining variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment. In a specific embodiment, for

[0081] In a seventeenth embodiment, the present invention provides a compound according to 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, wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0082] In an eighteenth embodiment, the present invention 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 Ring A is optionally substituted by 1 to 6 R 1 Substituted piperidinyl, wherein R 2is H or isopropyl, wherein the remainder of these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0083] 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.

[0084] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0085] Included in the teachings of the present invention are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group (e.g., carboxylic acid) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic 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).

[0086] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have the R or S configuration, or can be a mixture of the two. Stereoisomers refer to 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 chiral centers that are not identical and are not mirror images of each other.

[0087] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., where the configuration is indicated by a "wedge-shaped" 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 "racemic" or "racemate" is accompanied by the structure or name, as explained in the following two paragraphs). The "enrichment of the indicated configuration relative to the opposite configuration" is a molar percentage and is determined by dividing the number of compounds having a specified stereochemical configuration at the chiral center by the total number of all compounds in the mixture having the same or opposite stereochemical configuration.

[0088] When the stereochemical configuration at a chiral center in a compound is described by a chemical name (e.g., where the configuration is designated in the name by "R" or "S") or structure (e.g., where the configuration is designated by a "wedge-shaped" bond), and the nomenclature "racemic" or "racemate" accompanies the structure or chemical name, a racemic mixture is intended.

[0089] When two stereoisomers are described by their chemical names or structures and the chemical names or structures are linked by "and", it means a mixture of the two stereoisomers.

[0090] When two stereoisomers are described by their chemical names or structures and the names or structures are linked by "or", it means one or the other of the two stereoisomers, but not both.

[0091] When a disclosed compound having a chiral center is represented by a structure without indicating the configuration at the chiral center, the structure is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is described by its chemical name without indicating the configuration at the chiral center with "S" or "R," the name is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0092] 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 and diastereomeric mixtures of the compounds disclosed herein.

[0093] Enantiomeric and diastereomeric mixtures can be separated into their component enantiomers or stereoisomers by well-known methods (e.g., chiral gas chromatography, chiral 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 synthesis methods.

[0094] "Peak 1" in the experimental section refers to the expected reaction product compound obtained from chromatographic separation / purification that eluted earlier than the second expected reaction product compound from the same previous reaction. The second expected product compound is referred to as "peak 2."

[0095] When a compound of the present disclosure is named by a name or structure representing 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 enantiomers being named or described divided by the total weight of the mixture of the two enantiomers.

[0096] When the stereochemistry of a compound of the present disclosure is named or described by structure, and the named or described structure contains more than one stereoisomer (e.g., as a diastereomeric pair), it is understood that, unless otherwise indicated, it includes one of the included stereoisomers or any mixture of the included stereoisomers. It is further understood that the stereoisomeric purity of the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers contained in the name or structure by the total weight of the mixture of all stereoisomers.

[0097] 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 molar percentage and is determined by dividing the number of compounds with deuterium at the designated position by the total number of all compounds. When a position is designated as "H" or "hydrogen", that position has hydrogen at its natural abundance. When a position is silent as to the presence or absence of hydrogen or deuterium, that position has hydrogen at its natural abundance. A specific alternative embodiment relates to compounds of the present disclosure having 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".

[0098] 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, any moiety representing a moiety known to those skilled in the art to be substituted may be substituted, including one or more substituents. If more than one substituent is present, each substituent may be independently selected. These methods for substitution are well known in the art and / or taught by this disclosure. An optional substituent may be any substituent suitable for attachment to the moiety.

[0099] The compounds disclosed herein are selective EGFR inhibitors. As used herein, the term "selective EGFR inhibitor" refers to compounds that selectively inhibit certain mutant EGFR kinases relative to wild-type EGFR and a panel of kinases. In other words, the selective EGFR inhibitors have no activity or low activity against wild-type EGFR and a panel of kinases. When compared to the inhibitory activity of the selective EGFR inhibitors against wild-type EGFR and many other kinases, the IC 50 Value (i.e., IC 50 The selective EGFR inhibitors are more potent against certain mutant EGFR kinases (in terms of sub-nanomolar potency). Potency can be measured using known biochemical assays.

[0100] Some compounds of the present disclosure have the advantage of good brain penetration. The ability of a particular compound to penetrate the BBB and penetrate the brain can be assessed using various known methods or a combination of these methods. A frequently used in vitro method for predicting the brain penetration of a compound in vivo is the P-gp efflux ratio. P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) ​​and limits its substrate penetration into the central nervous system (CNS). Compounds found to be good P-gp substrates in vitro (i.e., having a high efflux ratio) are predicted to have poor brain penetration in vivo. In order 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 are measured for the compound. The P-gp efflux ratio is a measure of the ratio of Papp[BA] / Papp[AB]. In some embodiments, the 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.

[0101] Some compounds of the present disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Liver metabolism is the main elimination pathway for small molecule drugs. The clearance of compounds by liver metabolism can be assessed in vitro using human liver microsomes (HLM) or human hepatocytes. Compounds are incubated with HLM plus appropriate cofactors or human hepatocytes, and compound depletion is measured to determine the in vitro intrinsic clearance (Clint). Clint is scaled to total body clearance (CL), and the liver extraction ratio (ER) is determined by dividing CL by the standard human liver blood flow rate. Compounds with low liver extraction ratios are considered to have good metabolic stability. In some embodiments, compounds of the present disclosure have calculated ER values ​​of <0.3, <0.4, <0.5, <0.6.

[0102] Pharmaceutical composition

[0103] 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 (eg, a compound of Formula (I)) or a pharmaceutically acceptable salt thereof.

[0104] "Pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents" refer to substances that facilitate the formulation and / or administration of the active agent and / or absorption by a subject and that can be included in the pharmaceutical compositions of the present disclosure without causing significant adverse toxic effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline solution, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, sugars (e.g., lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and colorants. These formulations can be sterilized and, if desired, mixed with adjuvants (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring and / or aromatic substances), and similar substances that do not adversely react with or interfere with the activity of the compounds provided herein. Those skilled in the art will be aware of other pharmaceutical excipients suitable for use with the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0105] Pharmaceutical compositions of the present disclosure optionally include one or more pharmaceutically acceptable carriers and / or diluents, such as lactose, starch, cellulose and dextrose. Other excipients may also be included, such as flavorings, sweeteners and preservatives, such as methyl p-hydroxyphenylcarboxylate, ethyl p-hydroxyphenylcarboxylate, propyl p-hydroxyphenylcarboxylate and butyl p-hydroxyphenylcarboxylate. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th edition, Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare preparations applicable to various types of routes of administration. Conventional procedures and compositions for selecting and preparing suitable preparations are described in (such as Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia:The National Formulary (USP24NF19) published in 1999. Carriers, diluents and / or excipients are "acceptable" in terms of being compatible with other ingredients of the pharmaceutical composition and being harmless to its recipient.

[0106] Treatment

[0107] 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 as described herein. Mutant forms of EGFR include, for example, EGFR with LRTMCS mutations (exon 19 deletion (del19) or exon 21 (L858R) substitution mutations, T790M mutations, and C797S mutations). Subjects who "need to inhibit EGFR" are those who suffer from diseases for which beneficial therapeutic effects can be achieved by inhibiting at least one mutant EGFR, such as slowing disease progression, alleviating one or more symptoms associated with the disease, or prolonging the lifespan of the subject in view of the disease.

[0108] In some embodiments, the present disclosure provides a method of treating a disease / condition / or cancer associated with or modulated by mutant EGFR in a subject in need thereof, wherein inhibition of the mutant EGFR has therapeutic benefit, including but not limited to treating cancer. The method comprises administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0109] In another embodiment, the present disclosure provides a method for treating a subject with cancer, comprising administering an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein to the subject. Cancers to 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 cancers listed. Typically, cancer is characterized by one or more EGFR mutations as described herein. In a specific embodiment, cancer has progressed during or after EGFR tyrosine kinase inhibitor (TKI) therapy. In a specific embodiment, the disease has progressed during or after first-line osimertinib.

[0110] In a specific embodiment, the cancer to be treated is lung cancer. In a more specific embodiment, 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 specific embodiment, the lung cancer (or non-small cell lung cancer) has metastasized to the brain.

[0111] In another embodiment, the disease / condition / or cancer associated with or modulated by mutant EGFR is characterized by an EGFR genotype selected from genotypes 1 to 17 according to the following table (del18 = exon 18 deletion, specifically, for example, del E709_T710 insD; del19 = exon 19 deletion, specifically, for example, delE746_A750 (most common), delE746_S752insV, del747_A750insP, delL747_P753insS, and delS752_I759; ex20ins – exon 20 insertion, specifically, 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):

[0112] EGFR genotype

[0113]

[0114]

[0115]

[0116]

[0117] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del19.

[0118] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del 19 T790M.

[0119] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del 19 C797S.

[0120] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 C797X (C797G or C797N).

[0121] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del 19 T790MC797S.

[0122] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 T790M (C797G or C797N).

[0123] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein is characterized by an EGFR comprising EGFR del19 L792X (L792F, L792H, or L792Y).

[0124] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del19 T790ML792X (L792F, L792H, or L792Y).

[0125] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del 19 G796R (G796S).

[0126] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792R (L792V or L792P).

[0127] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L718Q (L718V).

[0128] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is characterized by an EGFR comprising EGFR del19 T790MG796R (G796S).

[0129] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is characterized by an EGFR comprising EGFR del19 T790ML792R (L792V or L792P).

[0130] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is characterized by an EGFR comprising EGFR del19 T790ML718Q(L718V).

[0131] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R.

[0132] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R T790M.

[0133] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R C797S.

[0134] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R C797X (797G or C797N).

[0135] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790MC797S.

[0136] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790MC797X (797G or C797N).

[0137] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R L792X (L792F, L792H, or L792Y).

[0138] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R L790ML792X (L792F, L792H, or L792Y).

[0139] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R G796R (G796S).

[0140] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R L792R (L792V or L792P).

[0141] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R L718Q (L718V).

[0142] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790MG796R (G796S).

[0143] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790ML792R (L792V or L792P).

[0144] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R T790ML718Q (L718V).

[0145] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del18.

[0146] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein is characterized by an EGFR comprising EGFR G719X (G719A, G719S, G719C, G719R, G719D, or G719V).

[0147] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR E709X (E709K, E709H, or E709A).

[0148] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein is characterized by an EGFR comprising EGFR E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).

[0149] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.

[0150] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins.

[0151] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins L718Q.

[0152] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins T790M.

[0153] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins C797S.

[0154] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR S7681I.

[0155] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR T790M.

[0156] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein is characterized by an EGFR comprising EGFR T790M C797S / GL792X (L792F, L792H, L792R, or L792Y).

[0157] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR genotype selected from genotypes 1 to 17.

[0158] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib.

[0159] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to afatinib.

[0160] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to dacomitinib.

[0161] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to gefitinib.

[0162] In another embodiment, the disease / condition / or cancer (eg, NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to erlotinib.

[0163] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and afatinib.

[0164] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and dacomitinib.

[0165] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and gefitinib.

[0166] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) being treated with a compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib and erlotinib.

[0167] Another embodiment is the treatment of a subject with metastatic NSCLC whose tumor has an activating exon 19 deletion or L858R EGFR mutation as detected by an approved molecular test and a resistance mutation disclosed herein. Another embodiment is a compound of the present disclosure used in combination with a first or third generation TKI indicated for the treatment of a subject with metastatic NSCLC whose tumor has T790M and C797S mutations as detected by an approved test and whose disease has progressed on or after at least two prior EGFR TKI therapies.

[0168] Another embodiment is a compound of the present disclosure for use in treating a subject with metastatic NSCLC whose disease has progressed on or after any EGFR TKI with on-target EGFR resistance. In a specific embodiment, a compound of the present disclosure is used in combination with a first or third generation TKI indicated for the treatment of a subject with metastatic NSCLC.

[0169] Another embodiment is a compound of the present disclosure for use in treating a subject with metastatic EGFR C797S mutation-positive NSCLC as detected by an approved molecular test, whose disease has progressed on or after first-line osimertinib. In a specific embodiment, a compound of the present disclosure is used in combination with a first-generation or third-generation TKI indicated for the treatment of a subject with metastatic NSCLC.

[0170] In specific embodiments, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.

[0171] Those skilled in the art can readily determine whether a subject has certain EGFR alterations in cells, cancers, genes or gene products, for example, whether a subject has one or more of the mutations or deletions described herein, using detection methods selected from those known in the art (e.g., hybridization-based methods, amplification-based methods, microarray analysis, flow cytometric analysis, DNA sequencing, next generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot and Southern blot).

[0172] In order 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 the subject. The sample is processed, nucleic acids are isolated using techniques known in the art, and then sequenced using methods known in the art. The sequence is then aligned with each exon, and the measure of transcriptional expression (e.g., RPKM, or reads / kilobases / million aligned reads) is quantified. Raw sequence and exon array data can be obtained from sources such as TCGA, ICGC, and NCBI gene expression databases (GEO). For a given sample, each exon coordinate is annotated with gene identifier information, and exons belonging to the kinase domain are marked. The exon level is then normalized across all tumor samples z-scores.

[0173] The compounds of the present disclosure, their pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein can be used to treat subjects who have become refractory to treatment with one or more other EGFR inhibitors. "Refractory" means that the subject's cancer previously responded to the drug but later responded poorly or not at all. In some embodiments, the subject has become refractory to treatment with one or more first-generation EGFR inhibitors (e.g., erlotinib, gefitinib, icotinib, or lapatinib). In some embodiments, the subject has become refractory to treatment with one or more second-generation EGFR inhibitors (e.g., afatinib, dacomitinib, poziotini, or neratinib). In some embodiments, the subject has become refractory to treatment with one or more first-generation inhibitors and one or more second-generation inhibitors. In some embodiments, the subject has become refractory to treatment with one or more third-generation inhibitors (e.g., osimertinib, nazartinib, or avitinib). In one embodiment, the subject has become refractory to treatment with one or more first generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more second generation EGFR inhibitors and one or more third generation EGFR inhibitors. In one embodiment, the subject has become refractory to treatment with one or more first generation inhibitors and one or more third generation EGFR inhibitors.

[0174] combination

[0175] The compounds of the present invention, 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 includes methods for treating a condition / disease / or cancer, comprising administering to a subject in need thereof a compound of the present invention, or its pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein, in combination with an EGFR (or EGFR mutation) inhibitor (e.g., afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, afatinib (AST 2818), amotinib (HS10296), BBT-176, BI-4020, CH7233163, gilteritinib, JND-3229, lazertinib, nazartinib (EGFR)). 816), PCC-0208027, regivitinib (BPI-7711), TQB3804, zoretinib (AZ-3759) or DZD9008); or EGFR antibodies (e.g., cetuximab, panitumumab, necitumumab, HLX07, JMT101); or a combination of bispecific EGFR and MET antibodies (e.g., amivantamab (JNJ-61186372, JNJ-372)). For the treatment of cancer (e.g., NSCLC), the use of 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, such as a first-generation, second-generation or third-generation EGFR inhibitor (i.e., as initial treatment before the cancer becomes refractory) can prevent or delay the cancer from becoming refractory. Typically, the cancer is characterized by one of the EGFR genotypes described herein.

[0176] Alternatively, the compounds of the present disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be administered in combination with other anticancer agents other than EGFR inhibitors, for example, in combination with: MEK, including mutant MEK inhibitors (trametinib, cobimetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib, glumetinib, tepotinib) and MET antibodies (emibetuzumab, telisotuzumab vedotin (ABBV)). 339)); mitotic kinase inhibitors (CDK4 / 6 inhibitors, such as palbociclib, ribociclib, abemaciclib, GIT38); anti-angiogenic agents, such as bevacizumab, nintedanib; apoptosis inducers, such as 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, ridoforolimus; 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 (MEDI 4736)); HER2 / neu receptor inhibitors (e.g., trastuzumab); anti-HER2 or anti-HER3 antibody-drug conjugates (e.g., patritumab deruxtecan (U3-1402), trastuzumab emtansine); or immunogene therapy (e.g., oncoprex).

[0177] A "subject" is a human in need of treatment.

[0178] Administration method and dosage form

[0179] The precise amount of compound administered to provide an "effective amount" to the subject will depend on the mode of administration, the type and severity of the cancer, and subject characteristics, such as general health, age, sex, weight, and tolerance to the drug. One skilled in the art will be able to determine an appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, for example, when administered in combination with an anticancer agent, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Suitable dosages of approved therapeutic agents are known and can be adjusted by one skilled in the art based on the subject's condition, the type of condition being treated, and by using the amount of the compound of formula (I) as reported in the literature and recommended in the Physician's Desk Reference (57th Edition, 2003).

[0180] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect can be therapeutic, including partially or substantially achieving one or more of the following: partially or substantially reducing the extent of the disease, condition, or cancer; alleviating 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.

[0181] The term "effective amount" means an amount that, when administered to a subject, results in a beneficial or desired result (including a clinical result, e.g., inhibition, suppression, or reduction of symptoms of the condition being treated in the subject as compared to a control). For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g / day, or 1 mg to about 5 g / day and in another alternative, 10 mg to 1 g / day).

[0182] As used herein, the terms "administer", "administering", "administration", and the like refer to methods that can be used to deliver a composition to the desired site of biological action. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used for the agents and methods described herein are found in, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0183] In addition, the compounds of the present disclosure, their pharmaceutically acceptable salts or pharmaceutical compositions of the present invention can be co-administered with other therapeutic agents. As used herein, the terms "co-administered," "administered in combination with ... " and their grammatical equivalents are intended to include administering two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same time or at different times. In some embodiments, one or more compounds of the present disclosure, their pharmaceutically acceptable salts or pharmaceutical compositions of the present disclosure will be co-administered with other agents. These terms include administering two or more agents to a subject so that the two agents and / or their metabolites are present in the subject at the same time. They include administering with separate compositions simultaneously, administering with separate compositions at different times, and / or administering with a composition in which two agents are present. Therefore, in some embodiments, the compounds as herein described and other agents are administered with a single composition. In some embodiments, the compounds as herein described and other agents are mixed in the composition.

[0184] The specific mode of administration and dosage regimen will be selected by the attending physician taking into account the details of the case (e.g., subject, disease, disease state involved, specific treatment). Treatment may involve daily or multi-day or less than daily (e.g., weekly or monthly, etc.) dosages for a period ranging from several days to several months or even several years. However, those skilled in the art will immediately know the appropriate and / or equivalent dosage of the disclosed EGFR inhibitors after looking up the dosage of the approved compositions for treating the disease as a guide.

[0185] The compounds of the present disclosure or their pharmaceutically acceptable salts can be administered to patients in various forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of this teaching can be administered, for example, orally, parenterally, buccal, sublingually, nasally, rectally, patch, pump or transdermally and pharmaceutical compositions can be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical administration modes. Parenteral administration can be performed by continuous infusion over a selected time period.

[0186] The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. In an embodiment, the composition is formulated according to conventional procedures to be suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0187] Typically, for oral therapeutic administration, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be combined with excipients and used in the form of edible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0188] Typically, for parenteral administration, solutions of the compounds of the present disclosure or solutions of pharmaceutically acceptable salts thereof are typically prepared in water suitably mixed with a surfactant (e.g., hydroxypropylcellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without ethanol) and oils. Under typical storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0189] Generally, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the disclosed compounds for the extemporaneous preparation of sterile injectable solutions or dispersions are suitable.

[0190] The following examples are intended to be illustrative and are not intended to limit the scope of the present disclosure in any way.

[0191] example

[0192] Example

[0193] Preparation of exemplary compounds

[0194] definition

[0195] TsOH 4-Methylbenzenesulfonic acid

[0196] TEA triethylamine

[0197] THF Tetrahydrofuran

[0198] MsCl methanesulfonyl chloride

[0199] DCM dichloromethane

[0200] NH4Cl ammonium chloride

[0201] MgSO4 magnesium sulfate

[0202] NaN3 sodium azide

[0203] DMF dimethylformamide

[0204] EA Ethyl acetate

[0205] Na2SO4 sodium sulfate

[0206] MeOH methanol

[0207] N2 nitrogen

[0208] H2 Hydrogen

[0209] LiAlH4 lithium aluminum hydride

[0210] NaHCO3 sodium bicarbonate

[0211] CbzCl benzyl chloroformate

[0212] PE petroleum ether

[0213] DAST N-ethyl-N-(trifluorothio)ethylamine

[0214] HCl hydrochloride

[0215] ACN acetonitrile

[0216] DIPEA Diisopropylethylamine

[0217] DMSO dimethyl sulfoxide

[0218] DMA dimethylacetamide

[0219] h hour

[0220] HPLC high-performance liquid chromatography

[0221] min

[0222] C degrees Celsius

[0223] IC 50 50% inhibitory concentration

[0224] IPA Isopropyl alcohol

[0225] MTBE methyl tert-butyl ether

[0226] rt room temperature

[0227] TFA trifluoroacetic acid

[0228] The method for preparing the compound of the present invention can be carried out in a suitable solvent, and the solvent can be easily selected by organic synthesis field technicians. Suitable solvent can be substantially unreactive with starting material (reactant), intermediate or product at the temperature (for example, the temperature in the range of the freezing temperature of the solvent to the boiling temperature of the solvent) of reacting. A given reaction can be carried out in a solvent or in a mixture more than a solvent. Depending on the specific reaction step, the suitable solvent for the specific reaction step can be selected by those skilled in the art.

[0229] 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 suitable protecting groups can be easily determined by those skilled in the art. The chemical reactions of protecting groups can be found in, for example, 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.

[0230] The reaction can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic methods, such as 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 chromatography (e.g., high performance liquid chromatography (HPLC) or thin layer chromatography (TLC)). Analytical instruments and methods used for compound characterization:

[0231] LC-MSLiquid chromatography-mass spectrometry (LC-MS) data (analyzing sample purity and identity) were acquired at 22.4 degrees Celsius using an Agilent model 1260 LC system equipped with an Agilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0 x 50 mm dimensions) reverse-phase column and an Agilent model 6120 mass spectrometer. The mobile phase consisted of a 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 mobile phase was used over a 4-minute period. The flow rate was a constant 1 mL / min.

[0232] Alternatively, liquid chromatography-mass spectrometry (LC-MS) data (analyzing sample purity and identity) were acquired at 22.4°C using a Shimadzu LCMS system equipped with an Agilent (Poroshel HPH-C18 2.7 μm particle size, 3.0 x 50 mm dimensions) reverse-phase column ESI ionization using a Shimadzu LCMS mass spectrometer. The mobile phase consisted of 5 mM NH4HCO3 (or 0.05% TFA) in water and acetonitrile. A constant gradient of 90% aqueous / 10% organic to 5% aqueous / 95% organic mobile phase was used over a 2-minute period. The flow rate was a constant 1.5 mL / min.

[0233] Preparative LC-MS :In a Shimadzu Discovery equipped with Luna 5u C18(2)100A, AXIA packaged 250x 21.2mm column reverse phase column Preparative HPLC was performed at 22.4 degrees Celsius on a Preparative system. The mobile phase consisted of a 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 mobile phase was used over a 25-minute period. The flow rate was a constant 20 mL / min. Reactions performed in a microwave were also performed in a Biotage Initiator microwave apparatus.

[0234] Alternatively, preparative HPLC was performed on a Waters Preparative system equipped with an XBridge Shield RP18 OBD column, 30*150 mm, 5 μm. The mobile phase consisted of a mixture of aqueous solvent (10 mmol / L NH4HCO3 + 0.05% NH3.H2O) and acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase was used over an 11-minute period. The flow rate was a constant 60 mL / min. Reactions performed in a microwave were also performed in a Biotage Initiator microwave apparatus.

[0235] Silica gel chromatography : At Teledyne Isco Rf device, IsoleraFour device or Silica gel chromatography was performed on an Isolera Prime apparatus.

[0236] Proton NMR : Acquired using a Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 sec with 1 sec delay; 16 to 64 scans) or an Avance 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.99 sec with 1 sec delay; 4 to 64 scans) or an Avance 300 MHz Unity Inova 300 MHz NMR instrument (acquisition time = 5.45 sec with 1 sec delay; 4 to 64 scans) 1 H NMR spectra. Unless otherwise noted, all protons are reported in parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent.

[0237] SFC : Waters preparative system.

[0238] Chiral HPLC was performed on an Agilent 1260 preparative system.

[0239] Those skilled in the art will appreciate that variations in gradients, column lengths, and flow rates are possible, and that some conditions may be more suitable for compound characterization than others, depending on the chemical being analyzed.

[0240] General synthesis reaction formula:

[0241] Reaction 1:

[0242]

[0243] In certain embodiments, optionally substituted bicyclic heteroaromatics A1 (wherein X = C or N, R = H, halo, optionally substituted alkyl, or -O-alkyl) are reacted with optionally substituted azetidines 1 (wherein R1 = H, alkyl, and R2 = optionally substituted methylsulfone or sulfonimide) using standard Buchwald coupling conditions to form optionally substituted condensation products B1. The resulting material is further homogenized by a second Buchwald coupling with optionally substituted pyrimidines or triazines (wherein Y = C, N, O; n = 0, 1, 2; and either or both of R3 and R4 are H, halo, optionally substituted alkyl, O-alkyl, or N-alkyl) to afford the final product C1.

[0244] Synthesis Example:

[0245] Example A1: Synthesis of 3-(ethylsulfonylmethyl)azetidine trifluoroacetate

[0246]

[0247] Step 1: Synthesis of tert-butyl 3-(ethylthiomethyl)azetidine-1-carboxylate:

[0248] 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 mixture solvent (CH3CN / H2O=3:1, 20 mL). The resulting solution was stirred at 60 ° C for 18 hours. The resulting solution was concentrated under vacuum. The residue was purified by chromatography using DCM / MeOH (30 / 1). 1.4 g (90%) of the title compound was obtained as an off-white solid.

[0249] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56].

[0250] Step 2: Synthesis of tert-butyl 3-(ethylsulfonylmethyl)azetidine-1-carboxylate:

[0251] Tert-butyl 3-[(ethylthio)methyl]azetidine-1-carboxylate (1.4 g, 6.05 mmol, 1 equivalent) was dissolved in a mixture solvent (THF:EtOH=1:1, 10 mL) and then pentapotassium diperoxymonosulfate (Oxone, 11.1 g, 18.1 mmol, 3 equivalents) was added to 0.5 mL of water. The resulting solution was stirred at 0 ° C for 10 minutes and then at room temperature for 2 hours. Concentrated under vacuum and purified by chromatography using DCM / MeOH (20:1) to give 1.3 g (81%) of the title compound as a white solid.

[0252] Analytical data: LC-MS: (ES, m / z) = 286 [M+23].

[0253] Step 3: Synthesis of 3-(ethylsulfonylmethyl)azetidine trifluoroacetate:

[0254] Trifluoroacetic acid (3.36 g, 29.5 mmol) was added to a solution of tert-butyl 3-[(ethylsulfonyl)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 under vacuum and the residue was washed with methyl tert-butyl ether to give 800 mg of the title compound as a white solid.

[0255] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0256] Example A2: Synthesis of 3-(isopropylsulfonylmethyl)azetidine

[0257]

[0258] Step I: Synthesis of tert-butyl 3-(isopropylthiomethyl)azetidine-1-carboxylate:

[0259] Tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (200 mg, 673 μmol, 1 eq) and (propan-2-ylthio) sodium (66.0 mg, 673 μmol, 1 eq) 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 combined, dried over anhydrous sodium sulfate and concentrated under vacuum. Produced 150 mg (90%) of the title compound.

[0260] Step 2: Synthesis of tert-butyl 3-(isopropylsulfonylmethyl)azetidine-1-carboxylate:

[0261] Tert-butyl 3-[(propyl-2-thio)methyl]azetidine-1-carboxylate (140 mg, 570 μmol, 1 equivalent) and pentapotassium diperoxymonosulfate (525 mg, 855 μmol, 1.50 equivalents) were dissolved in a mixed solution (THF: EtOH: H2O = 1: 1: 1; 1 mL). The resulting solution was stirred at room temperature for 2 hours. Sodium sulfite solution was added to the resulting solution to terminate the reaction, followed by extraction with EA. The organic layers were combined and concentrated under vacuum. 130 mg (82%) of the title compound was obtained as off-white.

[0262] Analytical data: LC-MS: (ES, m / z) = 300 [M+23].

[0263] Step 3: Synthesis of 3-(isopropylsulfonylmethyl)azetidine trifluoroacetate:

[0264] DCM (4 mL) / TFA (1 mL) containing tert-butyl 3-[(propane-2-sulfonyl)methyl]azetidine-1-carboxylate (120 mg, 432 μmol) was placed in an 8 mL tube. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under vacuum. 70 mg of the title compound was obtained as a white solid.

[0265] Analytical data: LC-MS: (ES, m / z) = 178 [M+1].

[0266] Example A3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidine

[0267]

[0268] Step 1: Synthesis of benzyl 3-((trifluoromethylsulfanyl)methyl)azetidine-1-carboxylate:

[0269] A mixture of benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (100 mg, 0.450 mmol, 1 eq), AgSCF3 (420 mg, 1.8 mmol, 4.00 eq) and nBu4NI (1725 mg, 5.4 mmol, 12 eq) in toluene (8 mL) was stirred at 80 ° C for 12 hours. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column with EA / PE (3:1). 50 mg (36.4%) of the title compound was obtained as a light yellow solid.

[0270] Analytical data: LC-MS: (ES, m / z=306[M+1].

[0271] Step 2: Synthesis of benzyl 3-((trifluoromethylsulfonyl)methyl)azetidine-1-carboxylate:

[0272] Potassium peroxymonosulfate (330.5 mg, 1.97 mmol, 3 equivalents) was added to a solution of benzyl 3-[[(trifluoromethyl)thio]methyl]azetidine-1-carboxylate (200 mg, 0.66 mmol, 1 equivalent) in THF (1 mL) / EtOH (1 mL) / H2O (1 mL). The resulting solution was stirred at 60 ° C for 2 hours. The reaction was then quenched by adding 1 mL of Na2S2O3 and extracted with 3x5 mL of EA. The residue was applied to a silica gel column with EA / PE (3: 1). 120 mg (54.5%) of the title compound were produced as a light yellow oil.

[0273] Analytical data: LC-MS: (ES, m / z) = 338 [M+1].

[0274] Step 3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidine hydrobromide:

[0275] Benzyl 3-(trifluoromethanesulfonylmethyl)azetidine-1-carboxylate (50 mg, 0.148 mmol, 1 equiv) was added to ethane peroxyacyl bromide (30% in AcOH, 1 mL). The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated to produce 20 mg (66.4%) of 3-(trifluoromethanesulfonylmethyl)azetidine hydrobromide as a light yellow solid. The crude product was used directly in the next step without further purification.

[0276] Analytical data: LC-MS: (ES, m / z): =204 [M+1].

[0277] Example A4: Synthesis of (2R, 3S)-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0278]

[0279] Step 1: Synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate:

[0280] (2R,3S)-1-benzhydryl-2-methylazetidin-3-ol (Pharmablock, 20 g, 78.9 mmol) was dissolved in 300 mL of DCM and TEA (9.55 g, 94.6 mmol) was added. The reaction mixture was cooled in an ice bath. Methanesulfonyl chloride (9.93 g, 86.7 mmol) was added dropwise and allowed to stir, slowly warming to room temperature and stirring overnight. The mixture was diluted with DCM and washed with water. 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.

[0281] Analytical data: LC-MS: (ES, m / z) = 332 [M+1].

[0282] Step 2: Synthesis of (S)-methyl 2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate

[0283] (2R, 3S) -1- benzhydryl -2- methylazetidine -3- base methanesulfonate (26g, 78.4mmol) and methyl 2- (methylsulfonyl) acetate (15.3g, 101mmol) are dissolved in 260mL DMF, then NaH (3.75g of 60% dispersion contained in mineral oil, 6.63mmol) is added and stirred for about 15 minutes, until hydrogen evolution stops. The reaction mixture is heated to 80 DEG C and spends overnight. The cooling reaction is then diluted with about 200mL water and extracted with EA, washed with water, brine and the combined organic matter, dried over sodium sulfate, filtered and evaporated to obtain a crude product. Residue is purified by chromatography (0 to 7% MeOH / DCM). The pure elution fraction is combined and evaporated to obtain 24g (80%) of the title compound in a light yellow foam.

[0284] Step 3: Synthesis of (2R,3S)-1-diphenylmethyl-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0285] (S)-methyl-2-((2R, 3S)-1-benzhydryl-2-methylazetidine-3-yl)-2-(methylsulfonyl)acetate (24 g, 61.9 mmol) was dissolved in 240 mL of DMA and lithium chloride (20.9 g, 495 mmol) was added and the flask was placed in a preheated block maintained at 150 ° C. LC / MS indicated that the starting material was consumed after 1.5 hours. It was cooled to room temperature and diluted with water, extracted with EA and the combined organics were washed with water, brine, and dried over sodium sulfate. It was filtered and evaporated to give the crude product, which was further purified by chromatography (0 to 5% MeOH / DCM). The pure extracts were combined and evaporated to give 19 g (93%) of the title compound as a light yellow foam.

[0286] Analytical data: LC-MS: (ES, m / z) = 330 [M+1].

[0287] Step 4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0288] To a solution of (2R,3S)-1-(diphenylmethyl)-3-(methylsulfonylmethyl)-2-methylazetidine (1.9 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 overnight. The reaction mixture was filtered and evaporated to give the crude title compound (17 g) as a light brown oil.

[0289] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0290] Example A5: Synthesis of 3-methyl-3-(methylsulfonylmethyl)azetidine

[0291]

[0292] Step I: Synthesis of tert-butyl 3-methyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate:

[0293] Methanesulfonyl chloride (255 mg, 2.23 mmol) was added dropwise to a solution of 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 under vacuum to give 350 mg (95%) of the title compound as a colorless oil.

[0294] Analytical data: LC-MS: (ES, m / z) = 224 [M+1-56].

[0295] Step 2: Synthesis of tert-butyl 3-methyl-3-(methylsulfonylmethyl)azetidine-1-carboxylate:

[0296] At room temperature, sodium methyl sulfide (175 mg, 2.50 mmol) was added to ACN (30 mL) containing tert-butyl 3-[(methylsulfonyloxy)methyl]-3-methylazetidine-1-carboxylate (350 mg, 1.25 mmol). 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 under vacuum. The residue was purified by silica gel column with PE:EA=1:1. This produced 250 mg (75%) of the title compound as a white solid.

[0297] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56].

[0298] Step 3: Synthesis of tert-butyl 3-methyl-3-(methylsulfonylmethyl)azetidine-1-carboxylate:

[0299] At room temperature, potassium peroxymonosulfate (362 mg, 2.16 mmol) was added to THF / H2O / EtOH (5 / 5 / 5 mL) containing tert-butyl 3-methyl-3-[(methylthio)methyl]azetidine-1-carboxylate (250 mg, 1.08 mmol). 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 under vacuum. The residue was purified by silica gel column with DCM:MeOH=20:1. This produced 200 mg (88%) of colorless title compound.

[0300] Analytical data: LC-MS: (ES, m / z) = 208 [M+1-56].

[0301] Step 4: Synthesis of 3-methyl-3-(methylsulfonylmethyl)azetidine:

[0302] At room temperature, TFA (5 mL) was added to tert-butyl 3-(methylsulfonylmethyl)-3-methylazetidine-1-carboxylate (150 mg, 569 μmol) in DCM (15 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to give 100 mg of the title compound as a colorless oil.

[0303] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0304] Example A6: Synthesis of N-((azetidin-3-ylmethyl)(methyl)(oxo)-16-thiomethyl)benzamide

[0305]

[0306] Step 1: Synthesis of tert-butyl 3-(methylthiomethyl)azetidine-1-carboxylate:

[0307] A mixture of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (5.05 g, 17 mmol, 1 eq) and NaSMe (3.56 g, 25.5 mmol, 1.50 eq) in MeCN (30 mL) and H O (10 mL) was heated to 60 ° C for 18 hours. 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 Na SO. The solution was concentrated to give the title compound (3.69 g, quantitative) as a light yellow oil.

[0308] Step 2: Synthesis of tert-butyl 3-(methylsulfinylmethyl)azetidine-1-carboxylate:

[0309] To a solution of tert-butyl 3-[(methylthio)methyl]azetidine-1-carboxylate (3.69 g, 17 mmol, 1 eq) in DCM (50 mL) was added mCPBA (2.92 g, 17 mmol, 1 eq) in portions at 0 ° C. The reaction was carried out at 0 ° C. for 2 hours 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 light yellow syrup.

[0310] Step 3: Synthesis of tert-butyl 3-(S-methylsulfonyliminomethyl)azetidine-1-carboxylate:

[0311] A mixture of tert-butyl 3-(methylsulfinylmethyl)azetidine-1-carboxylate (2.68 g, 11.5 mmol, 1 eq), ammonium acetate (4.41 g, 57.4 mmol, 5.00 eq) and PhI(OAc) (5.53 mg, 17.2 mmol, 1.50 eq) 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 light yellow syrup.

[0312] Analytical data: LC-MS: (ES, m / z) = 249 [M+1].

[0313] Step 4: Synthesis of tert-butyl 3-((N-benzoyl-S-methylsulfonylimino)methyl)azetidine-1-carboxylate:

[0314] At 0 °C, 3-{[imino(methyl)oxy- 6 To a mixture of tert-butyl azetidine-1-carboxylate (372 mg, 1.50 mmol, 1 eq) and DMAP (366 mg, 3 mmol, 2 eq) was added BzCl (281 mg, 2 mmol, 1.33 eq). The reaction was allowed to proceed at room temperature for 3 hours 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.

[0315] Analytical data: LC-MS: (ES, m / z) = 375 [M+23].

[0316] Step 5: Synthesis of N-((azetidin-3-ylmethyl)(methyl)(oxo)-16-thiomethyl)benzamide:

[0317] tert-Butyl 3-((N-benzoyl-S-methylsulfonylimino)methyl)azetidine-1-carboxylate (440 mg, 1.25 mmol, 1 eq) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 4 h. The mixture was concentrated to give the title compound (315 mg, quantitative) as a yellow syrup as trifluoroacetic acid salt.

[0318] Example A7: Synthesis of (2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidine

[0319]

[0320] Step 1: Synthesis of methyl 2-(ethylthio)acetate:

[0321] A solution of methyl 2-thioacetate (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 under vacuum to give the title compound (20 g) as a light yellow oil.

[0322] Analytical data: LC-MS: (ES, m / z) = 157 [M+23].

[0323] Step 2: Synthesis of methyl 2-(ethylsulfonyl)acetate:

[0324] To a solution of methyl 2-(ethylthio)acetate (20 g, 149 mmol) in DCM (500 mL) was added m-CPBA (76.7 g, 446 mmol) at 0°C, and the reaction was stirred at room temperature overnight. The reaction mixture was washed with water and concentrated under vacuum. The residue was applied to a silica gel column with EA / PE (1:3) to give the title compound (13.5 g) as a light yellow oil.

[0325] Step 3: Synthesis of methyl 2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(ethylsulfonyl)acetate:

[0326] (2R, 3S) -1- benzhydryl -2- methylazetidine -3- base methanesulfonate (step 1, Example A4 13g 39.2mmol) and 2- (ethylsulfonyl) methyl acetate were dissolved in 130mL DMF, followed by addition of NaH (1.12g of 60% dispersion in mineral oil, 47.0mmol) and stirring for approximately 15 minutes until hydrogen evolution stopped. The reaction mixture was heated to 80°C overnight. The reaction was cooled, then diluted with water and extracted with EA, the combined organic matter was washed with water and brine, and dried over sodium sulfate. Filtered and evaporated to obtain a crude product. The crude product was purified by chromatography (0 to 7% MeOH / DCM) to obtain 8g of the title compound as light yellow foam.

[0327] Analytical data: LC-MS: (ES, m / z) = 402 [M+1].

[0328] Step 4: Synthesis of (2R,3S)-1-diphenylmethyl-3-(ethylsulfonylmethyl)-2-methylazetidine:

[0329] To a solution of methyl 2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-(ethylsulfonyl)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 hours. Cooled to room temperature, diluted with 150 mL of water and extracted with EA (x 3), the combined organics were washed with water (x 3), brine and dried over sodium sulfate. Filtered and evaporated to give the crude product, which was purified by chromatography (0 to 5% MeOH / DCM) to give 6 g of the title compound as a light yellow foam.

[0330] Analytical data: LC-MS: (ES, m / z) = 344 [M+1].

[0331] Step 5: Synthesis of (2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidine:

[0332] A solution of methyl 2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-(ethylsulfonyl)acetate (6 g, 14.9 mmol) in MeOH (270 mL) / TFA (30 mL) was stirred at room temperature under an atmosphere of H overnight. The reaction was filtered and concentrated in vacuo to give the title compound as a light brown oil, 3.8 g (trifluoroacetic acid salt).

[0333] Analytical data: LC-MS: (ES, m / z) = 178 [M+1].

[0334] Example A8: Synthesis of racemic-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxo)-16-sulfanylidene)benzamide

[0335]

[0336] Step 1: Synthesis of racemic-(trans)-3-(hydroxymethyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester:

[0337] To a solution of rac-(trans)-1-[(tert-butoxy)carbonyl]-2-methylazetidine-3-carboxylic acid (1.50 g, 7 mmol, 1 equivalent) in THF (20 mL) was added BH 3 (21.0 mL, 21.0 mmol, 3 equivalents, 1 M in THF) at 0° C. The reaction was carried out at room temperature for 18 hours and then quenched with 1N HCl (10 mL). The mixture was neutralized with 10% Na 2 CO 3 . 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.

[0338] Analyze the data: 1 H-NMR(300MHz,CD3Cl)δppm 4.09-3.99(m,1H),3.91(t,1H,J=8.5Hz),3.76(dd,2H,J=6.5,5.2Hz),3.60(dd,1H,J=8 .6,6.0Hz),2.33-2.21(m,1H),1.54(t,1H,J=5.3Hz),1.46(s,9H),1.41(d,3H,J=6.3Hz)

[0339] Step 2: Synthesis of tert-butyl (trans)-2-methyl-3-(methylthiomethyl)azetidine-1-carboxylate:

[0340] At 0 ° C, to a solution of racemic -(trans)-3-(hydroxymethyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester (1.20 g, 6 mmol, 1 equivalent) in DCM (35 mL) was added TEA (1.21 g, 12.0 mmol, 2 equivalents), followed by MsCl (889 mg, 7.80 mmol, 1.3 equivalents). The reaction was carried out at 0 ° C for 1 hour 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 H2O (3 mL). NaSMe (840 mg, 12.0 mmol, 2 equivalents) was added. The reaction was carried out at 60 ° C for 18 hours. 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.

[0341] Analyze the data: 1H-NMR(300MHz,CD3Cl)δppm 3.96(dd,2H,J=9.8,7.0Hz), 3.51(dd,1H,J=8.7,6.1Hz), 2.69(d,2H,J=7. 8Hz), 2.34-2.23 (m, 1H), 2.12 (s, 3H), 1.46 (s, 9H), 1.42 (d, 3H, J = 6.2Hz).

[0342] Step 3: Synthesis of tert-butyl (trans)-2-methyl-3-(methylsulfinylmethyl)azetidine-1-carboxylate:

[0343] To a solution of tert-butyl 2-methyl-3-[(methylthio)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) in portions at 0 ° C. for 2 hours, 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 light yellow oil.

[0344] Analyze the data: 1 H-NMR(300MHz,CD3Cl)δppm 4.15-4.02(m,2H),3.66(td,1H,J=9.0,6.2Hz),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).

[0345] Step 4: Synthesis of racemic-(2R,3S)-2-methyl-3-(S-methylsulfonyliminomethyl)azetidine-1-carboxylic acid tert-butyl ester:

[0346] A mixture of rac-(trans)-tert-butyl 3-(methylsulfinylmethyl)-2-methylazetidine-1-carboxylate (1.23 g, 5 mmol, 1 eq), PhI(OAc)2 (2.41 g, 7.50 mmol, 1.5 eq) and ammonium acetate (2.31 g, 30.0 mmol, 6 eq) in ACN (30 mL) was stirred at 35 ° C. for 18 hours. After cooling down 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 light yellow syrup.

[0347] Analytical data: LC-MS: (ES, m / z) = 263 [M+1].

[0348] Step 5: Synthesis of racemic-(trans)-3-((N-benzoyl-S-methylsulfonylimino)methyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester:

[0349] At 0 °C, rac-(trans)-3-{[imino(methyl)oxy-λ 6 To a mixture of tert-butyl 2-methylazetidine-1-carboxylate (393 mg, 1.5 mmol, 1 equiv) and DMAP (292 mg, 2.40 mmol, 1.6 equiv) was added benzoyl chloride (274 mg, 1.95 mmol, 1.3 equiv). The reaction was carried out at 0 ° C for 2 hours, followed by quenching with saturated NaHCO 3 (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.

[0350] Analytical data: LC-MS: (ES, m / z) = 367 [M+1].

[0351] Step 5: Synthesis of racemic-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxo)-16-sulfanylide)benzamide:

[0352] A solution of rac-(trans)-tert-butyl 3-((N-benzoyl-S-methylsulfonylimino)methyl)-2-methylazetidine-1-carboxylate (732 mg, 2 mmol, 1 eq) in TFA (2 mL) and DCM (6 mL) was stirred at room temperature for 3 h. The mixture was concentrated to give the title compound (370 mg, 69.6%) as a colorless syrup.

[0353] Analytical data: LC-MS: (ES, m / z) = 267 [M+1].

[0354] 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

[0355]

[0356] Step 1: Synthesis of tert-butyl 3-methyl-4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate:

[0357] 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 hours. 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.

[0358] Analyze the data: 1 H-NMR (400MHz, 6d-DMSO) δppm 3.68-3.66 (m, 2H), 3.43 (t, 2H, J = 5.8Hz), 2.05 (tq, 2H, J = 6.0, 2.0Hz), 1.53-1.47 (m, 3H), 1.41 (s, 9H), 0.15 (s, 9H).

[0359] Step 2: Synthesis of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate:

[0360] A mixture of tert-butyl 5-methyl-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylate (10 g, 35.0 mmol, 1 eq) and SelectFluor (13.6 g, 38.5 mmol, 1.10 eq) in acetonitrile (100 mL) was stirred at 0° C. for 1 hour. 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 yielded 8 g (98.8%) of the title compound as a light yellow oil.

[0361] Step 3: Synthesis of tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate:

[0362] A mixture of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (7 g, 30.2 mmol, 1 eq) and NaBH4 (1.37 g, 36.2 mmol, 1.12 eq) 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 crude title compound as a light yellow oil.

[0363] Step 4: Synthesis of 3-fluoro-3-methylpiperidin-4-ol hydrochloride:

[0364] To the 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.

[0365] Step 5: Synthesis of 1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol:

[0366] A mixture of 2-chloropyrimidin-4-amine (2.7 g, 20.8 mmol, 1 eq), 3-fluoro-3-methylpiperidin-4-ol hydrochloride (3.86 g, 22.8 mmol, 1.10 eq) and TEA (6.30 g, 62.4 mmol, 3 eq) in isopropanol (45 mL) was stirred at 130 ° C. for 5 hours in a sealed vial. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated under vacuum to give the crude title compound (6 g) as a yellow oil.

[0367] 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 Prep OBD C18 column 30×150 mm 5 μm; mobile phase A: water (3 MMOL / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 10% B to 30% B in 35 minutes; 254 / 220 nm; Rt: 21.12 minutes). The fraction containing the desired compound was evaporated to dryness to give the cis racemate (1.3 g, 26.1%) and the trans racemate (500 mg, 10.0%) as a white solid.

[0368] The cis racemate (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*25 cm, 5 μm; mobile phase A: CO2: 50, mobile phase B: MEOH (0.1% DEA): 50; flow rate: 170 mL / min; 220 nm). The fractions containing the desired compound were evaporated to dryness to give (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol as a white solid (stereochemistry determined by x-ray crystallography of compound 55; 500 mg, peak 1) and (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol as a white solid (500 mg, peak 2).

[0369] Analytical data: LC-MS: (ES, m / z) = 227 [M+1]; 1 H-NMR(400MHz,6d-DMSO)δppm 7.71(d,1H,J=5.6Hz),6.37(s,2H),5.69(d,1H,J=5.6Hz), 4.93(d,1H,J=6.5Hz), 4.66(ddd,1H,J=14.1,9.1,2.2Hz), 4.60-4.50(m,1H),3.44(ddt,1H,J=24.8,11.0,5.6Hz),3.02-2.78(m,2H),1.69-1.53(m,2H),1.31(d,3H,J=21.2Hz).

[0370] The trans racemate was separated by preparative chiral SFC using the following conditions (column: CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 μm; mobile phase A: CO2: 70, mobile phase B: MeOH-preparative: 30; flow rate: 40 mL / min; 220 nm). The 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) (peak 1) as a white solid 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) (peak 2) as a white solid.

[0371] Analytical data: LC-MS: (ES, m / z) = 227 [M+1]; 1 H-NMR(300MHz,6d-DMSO)δppm 7.72(d,1H J=5.7Hz),6.40(s,2H),5.70(d,1H,J=5.6Hz),5.24(d,1H,J=4.5Hz),3.83-3.56(m, 5H), 1.78 (ddt, 1H, J = 12.9, 10.0, 4.7Hz), 1.48-1.36 (m, 1H), 1.24 (d, 3H, J = 22.5Hz).

[0372] Example B2: Synthesis of (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine and (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine

[0373]

[0374] Step 1: Synthesis of tert-butyl 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate:

[0375] Tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (2 g, 8.50 mmol, 1 eq), trimethylsulfonium iodide (5.61 g, 25.5 mmol, 3 eq), and t-BuOK (2.85 g, 25.5 mmol, 3 eq) were dissolved / suspended in t-BuOH. The mixture was stirred at 50°C for 2 days. Water was added to the reaction mixture and extracted with EA. The organic layer was concentrated under vacuum. This yielded 2 g (89%) of the title compound.

[0376] Step 2: Synthesis of 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane:

[0377] 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 under vacuum to give the title compound 2.1 g as a trifluoroacetate salt. The crude product was used directly in the next step.

[0378] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0379] Step 3: Synthesis of (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine and (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine:

[0380] TEA (12.3 g, 122 mmol, 2 equivalents) was added to DMSO (100 mL) containing 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane (10 g, 61.2 mmol, 1 equivalent) and 2-chloropyrimidine-4-amine (8.41 g, 61.2 mmol, equivalent). The reaction was stirred at 100 ° C for 2 hours. Water was added to the mixture and extracted with EA. The organic layers were combined and washed with brine, dried and concentrated. The residue was purified by FLASH (5% MeOH / DCM) to give the title compound (2.1 g).

[0381] The results were analyzed by preparative SFC-HPLC using the following conditions (column: CHIRALART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: EtOH; flow rate: 40 mL / min; gradient: 35% B; 254nm) separated 2.1g of product and the fraction containing the desired compound was evaporated to dryness to give 800mg of Peak 1: (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine or (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine and Peak 2: 805mg of (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine or (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine.

[0382] Peak 1: (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine or (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine:

[0383] Analytical data: LC-MS: (ES, m / z) = 257 [M+1]; 1H-NMR(300MHz,6d-DMSO)δppm 7.74(d,1H,J=5.6Hz),6.52(s,2H),5.77(d,1H,J=5.7Hz),4.46(t,2H,J=7.8Hz),4.23(td,1H,J=14.1,7.2Hz),3.93-3.74(m,2H),3.53 (ddd,1H,J=13.2,8.9,3.5Hz),2.74(dt,1H,J=11.4,7.5Hz),2.50-2.39(m,1H),2.10-1.97(m,1H),1.90(ddt,1H,J=13.4,8.9,4.3Hz).

[0384] Peak 2: (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine or (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine:

[0385] Analytical data: LC-MS: (ES, m / z) = 257 [M+1]; 1 H-NMR(300MHz,6d-DMSO)δppm 7.75(d,1H,J=5.7Hz),6.52(s,2H),5.77(d,1H,J=5.6Hz),4.46(t,2H,J=7.8Hz),4.23(td,1H,J=14.2,7.2Hz),3.93-3.74(m,2H),3.53 (ddd,1H,J=13.1,8.8,3.5Hz),2.74(dt,1H,J=11.4,7.5Hz),2.50-2.41(m,1H),2.10-1.97(m,1H),1.91(ddt,1H,J=13.4,8.8,4.3Hz).

[0386] Example B3: Synthesis of 2-(4-methylpiperazin-1-yl)pyrimidin-4-amine

[0387]

[0388] A mixture of 2-chloropyrimidin-4-amine (300 mg, 2.31 mmol, 1 equivalent), 1-methylpiperazine (231 mg, 2.31 mmol, 1 equivalent) and TEA (466 mg, 4.62 mmol, 2 equivalents) in IPA (3 mL) was heated to 100 ° C for 1.5 hours. LCMS showed that 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 produced 270 mg (60%) of the title compound as a yellow solid.

[0389] Analytical data: LC-MS: (ES, m / z) = 194 [M+1].

[0390] Example B4: Synthesis of 2-(4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0391]

[0392] 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 / DCM) to give the title compound as a light yellow solid, 1.12 g (53%).

[0393] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0394] Example B5: Synthesis of 2-morpholinopyrimidin-4-amine

[0395]

[0396] A mixture of 2-chloropyrimidin-4-amine (296 mg, 2.3 mmol, 1 eq), morpholine (200 mg, 2.3 mmol, 1 eq) and TEA (460 mg, 4.6 mmol, 2.0 eq) in IPA (5 mL) was stirred at 100 ° C for 5 hours. 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.

[0397] Analytical data: LC-MS: (ES, m / z) = 181 [M+1].

[0398] Example B6: Synthesis of rac-2-(1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine

[0399]

[0400] A mixture of 1-oxa-7-azaspiro[3.5]nonane (1.27 g, 10 mmol, 1 eq.), DIPEA (2.6 g, 20 mmol, 2 eq.) and 2-chloropyrimidine-4-amine (1.29 g, 10 mmol, 10.00 eq.) in DMSO (12 mL) was stirred overnight at 120 ° C. 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 light yellow solid.

[0401] Analytical data: LC-MS: (ES, m / z) = 221 [M+1].

[0402] Example B7: Synthesis of 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrimidin-4-amine

[0403]

[0404] To a solution of commercially available (3aR, 6aS)-hexahydro-1H-furo[3,4-c]pyrrole (841 mg, 6.49 mmol, 1 equiv) in IPA was added 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), heated to 100 ° C and stirred overnight. LCMS showed that the reaction was complete. Water was added to the mixture and extracted with EA. The organic phase was concentrated and purified by FLASH (5% MeOH / DCM). This obtained 500 mg (37%) of the title compound as a light yellow solid.

[0405] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0406] Example B8: Synthesis of 2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrimidin-4-amine

[0407]

[0408] In a 20 mL sealed tube, 2-chloropyrimidin-4-amine (600 mg, 4.63 mmol, 1 eq), (3R,4S)-3,4-difluoropyrrolidine (495 mg, 4.63 mmol, 1 eq), and TEA (1.39 g, 13.8 mmol, 3 eq) in IPA (10 mL) were added under nitrogen and the mixture was heated to 100° C. for 12 hours. The reaction mixture was filtered and evaporated to give 800 mg (86%) of the title compound as a yellow solid.

[0409] Analytical data: LC-MS: (ES, m / z) = 201 [M+1].

[0410] Example B9: Synthesis of 1-(4-aminopyrimidin-2-yl)-4-methylpiperidin-4-ol

[0411]

[0412] 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 / DCM) to give 210 mg (50%) of the title compound.

[0413] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0414] 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

[0415]

[0416] Step 1: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol:

[0417] A mixture of cis-4-methoxypiperidin-3-ol (1.7 g, 13 mmol, 1 eq), 2-chloropyrimidin-4-amine (1.7 g, 13 mmol, 1 eq) and TEA (2.6 g, 26 mmol, 2.0 eq) in IPA (15 mL) was stirred overnight at 100° C. The mixture was concentrated, and the residue was purified by FLASH (5% MeOH / DCM) to give 2.4 g (82.7%) of the title compound as a yellow solid.

[0418] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0419] 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:

[0420] 2.4 g of cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol was separated by chiral SFC under the following conditions: column name, CHIRALPAK IA (4.6*150 mm, 5 μm); solvent, CO2 / 10% MEOH (0.1% DEA); flow rate, 4 mL / min; the fraction containing the desired compound was evaporated to dryness to obtain 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).

[0421] 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

[0422]

[0423] Step 1: Synthesis of cis-5-fluoro-3,3-dimethylpiperidin-4-ol:

[0424] 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 white solid as the hydrochloride salt (3.6 g).

[0425] Step 2: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol:

[0426] 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 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC: column: 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: 5% B to 32% B in 8 minutes; 254 / 220 nm; Rt: 6.92 minutes; the fraction containing the desired compound was evaporated to dryness to give the title compound (1.8 g, 39.4%) as a white solid.

[0427] Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[0428] 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:

[0429] 1.8 g of the cis racemate were separated by preparative chiral HPLC on column: EnantioPak-A1-5(02), 5*25 cm, 5 μm; mobile phase A: CO2:60, mobile phase B: EtOH 0.1% DEA; flow rate: 2 mL / min; 220 nm. The 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 as a white solid (776 mg, 43.3%), 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 as a white solid (700 mg, 39.1%).

[0430] (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:

[0431] Analytical data: LC-MS: (ES, m / z) = 241 [M+1]; 1 H-NMR(300MHz,6d-DMSO)δppm 7.69(d,1H,J=5.7Hz),6.36(s,2H),5.67(d,1H,J=5.6Hz),5.00(d,1H,J=5.4Hz),4.75-4.47(m,1H),4.09-3.93(m,1H) ,3.86-3.67(m,1H),3.62(d,1H,J=12.9Hz),3.37(ddd,1H,J=22.0,5.5,2.9Hz),3.31-3.18(m,1H),0.95-0.78(m,6H).

[0432] 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

[0433]

[0434] Step 1: Synthesis of racemic cis-tert-butyl 3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate:

[0435] 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 (aqueous solution), 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.

[0436] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56].

[0437] Step 2: Synthesis of racemic-cis-3-fluoro-4-methylpiperidin-4-ol:

[0438] Tert-butyl 3-fluoro-4-hydroxy-4-methylpiperidin-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 g (crude) of 3-fluoro-4-methylpiperidin-4-ol as a yellow solid. The crude product was used directly in the next step.

[0439] Analytical data: LC-MS: (ES, m / z) = 134 [M+1].

[0440] Step 3: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol:

[0441] 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 light yellow solid.

[0442] Analytical data: LC-MS: (ES, m / z) = 227 [M+1].

[0443] 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:

[0444] Racemic-cis 1-(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: CO2 / 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 determined 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.

[0445] Peak 1: (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol:

[0446] Analyze the data: 1H-NMR(300MHz,6d-DMSO)δppm 7.73(d,1H J=5.6Hz),6.40(s,2H),5.72(d,1H,J=5.6Hz),4.71(s,1H),4.39-3.92(m,3H),3.38(dddd,2H,J=4 0.5, 13.6, 10.3, 4.6Hz), 1.62 (q, 1H, J = 6.2Hz), 1.42 (td, 1H, J = 13.6, 12.0, 4.3Hz,), 1.20 (s, 3H).

[0447] Peak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

[0448] Analyze the data: 1 H-NMR(300MHz,6d-DMSO)δppm 7.73(d,1H,J=5.6Hz),6.40(s,2H),5.72(d,1H,J=5.6Hz),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, 4.8Hz), 3.31 (ddd, 1H, J = 13.4, 8.3, 3.2Hz), 1.61 (ddt, 1H, J = 14.1, 7.2, 3.9Hz), 1.41 (ddd, 1H, J = 13.9, 10.3, 4.4Hz), 1.20 (s, 3H).

[0449] 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

[0450]

[0451] Step 1: Synthesis of 1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol:

[0452] 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 / DCM) to give 320 mg (65%) of the title compound as a white solid.

[0453] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0454] 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:

[0455] 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 name: CHIRALPAK AD-3 3*100 mm, 3 μm; co-solvent: MeOH (0.1% DEA); Gradient (B%): 10% to 50% in 4.0 minutes, hold at 50% for 2.0 minutes; Back pressure (psi): 1500.000; Flow rate: 2 mL / min, to give 145 mg of Peak 1: (S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol or (R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol and Peak 2: 150 mg of (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. Both were light yellow solids.

[0456] Analyze the data: 1 H-NMR(300MHz,6d-DMSO)δppm 7.74(d,1H,J=5.6Hz),6.45(s,2H),5.74(d,1H,J=5.7Hz),5.41(s,1H),4.58(dt,1H,J=13.4,9.4Hz),4.29(d,1H,J =13.3Hz),3.59-3.38(m,1H),3.23(ddd,1H,J=13.8,9.6,4.7Hz),1.62(q,2H,J=5.8,4.8Hz),1.22(d,3H,J=1.6Hz)

[0457] Example B14: Synthesis of racemic-(trans)-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

[0458]

[0459] To a solution of 2-chloropyrimidine-4-amine (216 mg, 1.67 mmol) in IPA was added racemic-(3R, 4R)-4-fluoropiperidin-3-ol hydrochloride (200 mg, 1.67 mmol) and TEA (337 mg, 3.34 mmol), heated to 100 ° C and stirred overnight. LCMS showed that the reaction was complete. Water was added to the mixture and extracted with EA. The organic phase was concentrated and purified by FLASH. This obtained 180 mg (65%) of the title compound as a yellow solid.

[0460] Analytical data: LC-MS: (ES, m / z) = 213 [M+1].

[0461] Example B15: Synthesis of racemic-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol

[0462]

[0463] Step 1: Synthesis of (1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-ol:

[0464] 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.

[0465] Analytical data: LC-MS: (ES, m / z) = 128 [M+1].

[0466] Step 2: Synthesis of racemic-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol:

[0467] 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 at 100° C. for 16 hours. The reaction mixture was concentrated and purified by preparative TLC (10% MeOH / DCM) to give 110 mg (64%) of the crude product as a yellow solid.

[0468] Analytical data: LC-MS: (ES, m / z) = 221 [M+1].

[0469] Example B16: Synthesis of racemic-1-(1-(4-aminopyrimidin-2-yl)-3-fluoropyrrolidin-3-yl)ethanol

[0470]

[0471] Step 1: Synthesis of racemic tert-butyl 3-fluoro-3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate:

[0472] 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 h. The reaction mixture was extracted with EA, and the combined organic layers were dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with EA / PE (1:6) to give 900 mg (76%) of the title compound as a light yellow oil.

[0473] Analytical data: LC-MS: (ES, m / z) = 221 [M+1-56].

[0474] Step 2: Synthesis of racemic tert-butyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate:

[0475] At -60 ° C, under N2, to a solution of racemic 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). 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 under vacuum to give 780 mg of the title compound as a light yellow oil (crude).

[0476] Step 3: Synthesis of racemic tert-butyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate:

[0477] To a solution of tert-butyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate (780 mg, 3.37 mmol) in MeOH (10 mL) was added NaBH4 (191 mg, 5.05 mmol) at 0° C. and stirred at room temperature for 1.5 hours. The reaction was concentrated under vacuum and extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 700 mg of the product as a light yellow oil.

[0478] Step 4: Synthesis of racemic-1-(3-fluoropyrrolidin-3-yl)ethanol:

[0479] To a solution of 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 under vacuum to give 500 mg of the product as a light yellow solid.

[0480] Step 5: Synthesis of racemic-1-(1-(4-aminopyrimidin-2-yl)-3-fluoropyrrolidin-3-yl)ethanol:

[0481] 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 under vacuum and purified by TLC (DCM:MeOH=15:1) to give 800 mg of the product as a light yellow solid.

[0482] Analytical data: LC-MS: (ES, m / z) = 227 [M+1].

[0483] Example B17: Synthesis of rac-2-(4-aminopyrimidin-2-yl)-2-aza-bicyclo[2.2.1]heptan-5-ol

[0484]

[0485] Step 1: Synthesis of racemic-2-aza-bicyclo[2.2.1]heptan-5-ol:

[0486] To a solution of 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 that the reaction was complete and the solution was concentrated to give 450 mg of product, which was used directly in the next step.

[0487] Analytical data: LC-MS: (ES, m / z) = 114 [M+1].

[0488] Step 2: Synthesis of rac-2-(4-aminopyrimidin-2-yl)-2-aza-bicyclo[2.2.1]heptan-5-ol:

[0489] A mixture of 2-chloropyrimidine-4-amine (200 mg, 1.54 mmol), racemic 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 that 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 the title compound 180 mg as a yellow solid.

[0490] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0491] Example B18: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

[0492]

[0493] Step 1: Synthesis of cis-4-fluoropiperidin-3-ol:

[0494] Dissolve tert-butyl (cis)-4-fluoro-3-hydroxypiperidine-1-carboxylate (300 mg) in dioxane (1 mL). Add HCl in dioxane (4 M, 2 mL) and stir for 1 hour. Concentrate the reaction mixture to give the title compound as a white solid (140 mg).

[0495] Analytical data: LC-MS: (ES, m / z) = 120 [M+1].

[0496] Step 2: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol:

[0497] 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 h at 120° C. Water was added, and the mixture was extracted with EA and purified by preparative TLC (5% MeOH / DCM) to give the title compound (95 mg) as a yellow solid.

[0498] Analytical data: LC-MS: (ES, m / z) = 213 [M+1].

[0499] Example B19: Synthesis of 2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyrimidin-4-amine

[0500]

[0501] To a solution of 2-chloropyrimidine-4-amine (1 g, 7.71 mmol) in IPA (12 mL) was added 1,4-dioxa-8-azaspiro [4.5] decane (1.10 g, 7.71 mmol) and TEA (1.55 g, 15.4 mmol), heated to 100 ° C and stirred overnight. Water was added to the mixture, and the mixture was extracted with EA. The organic layer was concentrated and purified by FLASH (5% MeOH / DCM). The title compound 1.5g (82.8%) was thus obtained as a yellow solid.

[0502] Analytical data: LC-MS: (ES, m / z) = 237 [M+1].

[0503] Example B20: Synthesis of racemic tert-butyl 4-(4-aminopyrimidin-2-yl)-2-(difluoromethyl)piperazine-1-carboxylate

[0504]

[0505] A mixture of 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.

[0506] Analytical data: LC-MS: (ES, m / z) = 330 [M+1].

[0507] 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

[0508]

[0509] To a solution of racemic-trans-3-methylpiperidin-4-ol (800 mg, 6.94 mmol) in IPA (10 mL) was added 2-chloropyrimidine-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 under vacuum. The crude product was flash purified using the following conditions: DCM: MEOH = 10: 1. This produced 1.2 g (83.3%) of the title compound as a white solid.

[0510] Racemic-trans-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol (1.2 g, 5.76 mmol) was further separated by chiral preparative HPLC using the following conditions: column: CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MEOH (2 mM NH3-MEOH); flow rate: 40 mL / min; gradient: 25% B; 220 nm, to obtain Peak 1: 500 mg of (3R, 4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S, 4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol and Peak 2: 460 mg of (3S, 4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R, 4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a white solid.

[0511] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0512] 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

[0513]

[0514] Step 1: Synthesis of tert-butyl 3-fluoro-4-hydroxy-3,4-dimethylpiperidine-1-carboxylate:

[0515] 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 was added LiMe (27 mL, 43.2 mmol) at 0°C. The reaction was stirred at 0°C for 1 hour. The reaction was quenched with H2O 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.

[0516] Step 2: Synthesis of 3-fluoro-3,4-dimethylpiperidin-4-ol:

[0517] Racemic tert-butyl 3-fluoro-4-hydroxy-3,4-dimethylpiperidine-1-carboxylate (6 g, 24.2 mmol) was placed in 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.

[0518] 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:

[0519] 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 light yellow solid.

[0520] 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 μm; mobile phase A; mobile phase B: MeOH (0.1% DEA); flow rate: 2 mL / min; gradient: 10% B; 220 nm; to obtain peak 1: racemic-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: racemic-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.

[0521] Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[0522] 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

[0523]

[0524] Step 1: Synthesis of racemic tert-butyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate:

[0525] At room temperature, to a solution of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate (7.95 g, 35 mmol, 1 equivalent) in DMF (35 mL), TEA (7.07 g, 70.0 mmol, 2 equivalents) was added, followed by TMSCl (5.67 g, 52.5 mmol, 1.50 equivalents). The reaction was carried out at 120 ° C for 18 hours and then quenched with saturated NaHCO 3 . 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 equivalent) was added at 0 ° C. The mixture was stirred at room temperature for 2 hours and then quenched with saline. 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).

[0526] Step 2: Synthesis of racemic 3-ethyl-3-fluoro-4-oxopiperidine-1-(9H-fluoren-9-yl)methyl carboxylate:

[0527] 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), TEA (13.3 g, 132 mmol, 5.00 equiv) was added, followed by (9H-fluoren-9-yl)methyl chloroformate (10.2 g, 39.5 mmol, 1.50 equiv). The reaction was carried out at room temperature for 2 hours. Saturated NaHCO 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% for 2 steps) as a colorless syrup.

[0528] Analytical data: LC-MS: (ES, m / z) = 390 [M+23].

[0529] Step 3: Synthesis of racemic-cis-3-ethyl-3-fluoro-4-hydroxypiperidin-1-(9H-fluoren-9-yl)carboxylic acid methyl ester and racemic-trans-3-ethyl-3-fluoro-4-hydroxypiperidin-1-(9H-fluoren-9-yl)carboxylic acid methyl ester:

[0530] Into a 25 mL round-bottom flask was placed methyl 3-ethyl-3-fluoro-4-oxopiperidine-1-9H-fluoren-9-ylcarboxylate (500 mg, 1.361 mmol, 1 equivalent), methanol (10 mL), and NaBH4 (102.97 mg, 2.722 mmol, 2 equivalents). 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 with EA / PE (1:1). This produced 200 mg of Peak 1: rac-cis-3-ethyl-3-fluoro-4-hydroxypiperidin-1-(9H-fluoren-9-yl)carboxylic acid methyl ester (identified as cis by 2D NMR) and 100 mg of Peak 2: rac-trans-3-ethyl-3-fluoro-4-hydroxypiperidin-1-(9H-fluoren-9-yl)carboxylic acid methyl ester (identified as trans by 2D NMR).

[0531] Analytical data: LC-MS: (ES, m / z) = 370 [M+1].

[0532] Step 4: Synthesis of racemic-cis-3-ethyl-3-fluoropiperidin-4-ol and racemic-trans-3-ethyl-3-fluoropiperidin-4-ol:

[0533] Diethylamine (3 mL) was added to a solution of rac-cis-methyl 3-ethyl-3-fluoro-4-hydroxypiperidin-1-(9H-fluoren-9-yl)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 yielded 60 mg (75%) of the title compound as a light yellow oil.

[0534] Analytical data: LC-MS: (ES, m / z) = 148 [M+1].

[0535] Step 5: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol and racemic-trans-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol:

[0536] A mixture of rac-cis-3-ethyl-3-fluoropiperidin-4-ol (1 g, 6.794 mmol, 1 eq), 2-chloropyrimidin-4-amine (0.88 g, 6.794 mmol, 1 eq) and TEA (2.06 g, 20.38 mmol, 3 eq) 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 with DCM / MeOH (5: 1). This produced 1 g (61.3%) of rac-cis-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol as a light yellow solid.

[0537] Analytical 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)

[0538] A mixture of rac-trans-3-ethyl-3-fluoropiperidin-4-ol (900 mg, 6.114 mmol, 1 eq), 2-chloropyrimidin-4-amine (792.12 mg, 6.114 mmol, 1 eq) and TEA (1856.15 mg, 18.343 mmol, 3 eq) 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 with DCM / MeOH (5: 1). This produced 500 mg (34.03%) of rac-trans-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol as a light yellow solid.

[0539] Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[0540] 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

[0541]

[0542] A mixture of 2-chloropyrimidin-4-amine (700 mg, 5.42 mmol), racemic-(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 with DCM / MeOH (20: 1). This produced 700 mg (56%) of racemic-(3R, 4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a yellow solid. The rac-(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol was purified by preparative HPLC using the following conditions: column: CHIRALPAKID-3, 4.6*100 mm, 3 μm; mobile phase A; mobile phase B: IPA (0.1% DEA); flow rate: 4 mL / min; gradient: 10% B; 220 nm; The fractions containing the desired compound were evaporated to dryness to give 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%).

[0543] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0544] Example B25: Synthesis of 2-(1,4-dioxa-9-azaspiro[5.5]undec-9-yl)pyrimidin-4-amine

[0545]

[0546] 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.

[0547] Analytical data: LC-MS: (ES, m / z) = 251 [M+1].

[0548] 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

[0549]

[0550] Step 1: Synthesis of racemic tert-butyl 5-fluoro-5-methyl-4-(triethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate:

[0551] To a solution of 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 hour. TESCl (6.11 g, 40.6 mmol) was then added and 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 with 10% EtOAc / PE to give the title compound (6.2 g, 88%) as a colorless oil.

[0552] Step 2: Synthesis of racemic tert-butyl 3,5-difluoro-3-methyl-4-oxopiperidine-1-carboxylate:

[0553] To a solution of 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 with 30% EtOAc / PE to give the title compound (3 g, 67%) as a light yellow oil.

[0554] Step 3: Synthesis of racemic tert-butyl 3,5-difluoro-4-hydroxy-3-methylpiperidine-1-carboxylate:

[0555] To a solution of racemic 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) under 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 under vacuum. This produced 2.9 g (82.6%) of the title compound as a colorless oil.

[0556] Analytical data: LC-MS: (ES, m / z) = 196 [M+1-56].

[0557] Step 4: Synthesis of racemic-3,5-difluoro-3-methylpiperidin-4-ol:

[0558] Racemic 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 under vacuum to give the title compound (1.6 g) as a salt.

[0559] Analytical data: LC-MS: (ES, m / z) = 152 [M+1].

[0560] 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:

[0561] Into three 40 mL sealed tubes were placed 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 hours. The reaction mixture was cooled to room temperature and diluted with water, extracted with EA, and concentrated under vacuum. The residue was purified by preparative HPLC using the following conditions: Column: 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 over 7 minutes; 254; 220 nm. This resulted in 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 and 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 150 mg of 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 and 150 mg of 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. 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.

[0562] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0563] Example B27: Synthesis of rac-2-(6-fluoro-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyrimidin-4-amine

[0564]

[0565] Step 1: Synthesis of benzyl 1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate:

[0566] 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 chloroformate (386 mg, 3.83 mmol) at 0 ° C. and stirred at room temperature for 3 hours. 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 title compound (800 mg) as a yellow oil.

[0567] Analytical data: LC-MS: (ES, m / z) = 278 [M+1].

[0568] Step 2: Synthesis of racemic 6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylic acid benzyl ester:

[0569] At room temperature, H2SO4 (14.1 mg, 144 μmol) was added to a mixture of 1,4-dioxa-8-azaspiro [4.5] decane-8-carboxylic acid benzyl ester (800 mg, 2.88 mmol) and SelectFluor (2.04 g, 5.76 mmol) in ACN (10 mL), and stirred at 50 ° C for 1 hour, ethylene glycol (886 mg, 14.3 mmol) was added and stirred for 2 hours. 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.

[0570] Analytical data: LC-MS: (ES, m / z) = 296 [M+1].

[0571] Step 3: Synthesis of racemic-6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane:

[0572] A mixture of rac-6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylic acid benzyl ester (600 mg, 2.03 mmol) and Pd / C (239 mg, 2.03 mmol) in MeOH (20 mL) was stirred at room temperature under a hydrogen atmosphere for 2 h. The reaction mixture was filtered and evaporated to give the title compound (340 mg) as a brown oil.

[0573] Analytical data: LC-MS: (ES, m / z) = 162 [M+1].

[0574] Step 4: Synthesis of racemic-2-(6-fluoro-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyrimidin-4-amine:

[0575] A mixture of 2-chloropyrimidin-4-amine (180 mg, 1.38 mmol), racemic-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 Na2SO4, filtered, evaporated and purified by column chromatography (DCM:MeOH=30:1) to give the title compound (200 mg) as a yellow solid.

[0576] Analytical data: LC-MS: (ES, m / z) = 255 [M+1].

[0577] 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

[0578]

[0579] At room temperature, 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). The mixture was stirred at 100 ° C for 16 hours. The mixture was concentrated under vacuum and the residue was purified by silica gel column with DCM: MeOH = 20: 1. This produced 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: CO2, mobile phase B: EtOH (8 mmol / LNH3.MeOH)-HPLC; flow rate: 40 mL / min; gradient: 25% B; 254 nm. This produced 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.

[0580] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0581] Example B29: Synthesis of 2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethylamine

[0582]

[0583] Step 1: Synthesis of tert-butyl 3-((2-hydroxyethylthio)methyl)azetidine-1-carboxylate:

[0584] To a 50mL flask is added tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (3g, 10.0mmol) dissolved in THF (10mL). To this is added 2-sulfhydryl ethane-1-ol (781mg, 10.0mmol), K2CO3 (4.20g, 30.0mmol). The mixture is stirred at room temperature overnight. The reaction is quenched with water and extracted with EA. The organic layer is dried and concentrated to give the title compound (2.8g) (crude) as a brown oil.

[0585] Analytical data: LC-MS: (ES, m / z) = 248 [M+1].

[0586] Step 2: Synthesis of tert-butyl 3-((2-hydroxyethylsulfonyl)methyl)azetidine-1-carboxylate:

[0587] To a 50 mL flask was added tert-butyl 3-{[(2-hydroxyethyl)thio]methyl}azetidine-1-carboxylate (2.7 g, 1.2 mmol) dissolved in THF / EtOH / HO (10 mL). To this was added potassium peroxymonosulfonate (744 mg, 1.2 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was extracted with EA. The organic layer was dried and concentrated to give the title compound (2.4 g crude) as a yellow solid.

[0588] Step 3: Synthesis of tert-butyl 3-(vinylsulfonylmethyl)azetidine-1-carboxylate:

[0589] 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 extracted with EA. The organic layer was dried and concentrated to give the title compound (1.8 g) as a brown solid.

[0590] Analytical data: LC-MS: (ES, m / z) = 206 [M+1-56].

[0591] Step 4: Synthesis of tert-butyl 3-((2-(dimethylamino)ethylsulfonyl)methyl)azetidine-1-carboxylate:

[0592] To a 50 mL flask was added tert-butyl 3-[(ethylenesulfonyl)methyl]azetidine-1-carboxylate (1.8 g) dissolved in DCM (10 mL). 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 extracted with DCM. The organic layers were combined and purified using DCM / MeOH (20 / 1) to give the title compound (1.5 g) as a brown solid.

[0593] Analytical data: LC-MS: (ES, m / z) = 307 [M+1].

[0594] Step 5: Synthesis of 2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethylamine:

[0595] 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 a trifluoroacetate salt as a yellow solid, 1.2 g (crude).

[0596] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0597] Example B30: Synthesis of 3-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1,2,4-triazine-5-amine

[0598]

[0599] Step 1: Synthesis of 3,5-dichloro-1,2,4-triazine:

[0600] 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 hours. 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 NaSO, and concentrated to dryness to give the crude product, which was used in the next step without further purification (200 mg, crude).

[0601] Step 2: Synthesis of 3-chloro-1,2,4-triazine-5-amine:

[0602] 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 minutes; LC-MS showed the reaction was complete. Evaporation to dryness and purification by preparative HPLC gave the title compound (50 mg, 20% yield over 2 steps).

[0603] Analytical data: LC-MS: (ES, m / z) = 131 [M+1].

[0604] Step 3: Synthesis of 3-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1,2,4-triazine-5-amine:

[0605] To a solution of 3-chloro-1,2,4-triazine-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 with DCM / MeOH (20: 1). This produced 30 mg (59%) of the title compound as a light yellow solid.

[0606] Analytical data: LC-MS: (ES, m / z) = 222 [M+1].

[0607] Example B31: Synthesis of 3-(4-methoxypiperidin-1-yl)-1,2,4-triazine-5-amine

[0608]

[0609] To a solution of 3-chloro-1,2,4-triazine-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 layer was concentrated and the residue was purified by preparative TLC with PE / EA (5: 1). This produced 30 mg (62%) of the title compound as a light yellow solid.

[0610] Analytical data: LC-MS: (ES, m / z) = 210 [M+1].

[0611] Example B32: Synthesis of 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0612]

[0613] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylate:

[0614] 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. Mel (497 mg, 3.5 mmol) was added, 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 Na2SO4, filtered and evaporated to give the title compound (750 mg, crude) as a yellow oil.

[0615] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56].

[0616] Step 2: Synthesis of (3R,4S)-3-fluoro-4-methoxypiperidine:

[0617] To a solution of tert-butyl (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylate (750 mg, 3.21 mmol) in DCM (10 mL) was added TFA (2 mL) and stirred at room temperature for 3 hours. The reaction mixture was evaporated to give the title compound as a brown oil (700 mg crude).

[0618] Step 3: Synthesis of 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine:

[0619] 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 / PE) to give the title compound (550 mg) as a yellow solid.

[0620] Example B33: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0621]

[0622] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate:

[0623] At 0 ° C, sodium hydride (218.90 mg, 9.122 mmol, 4 equivalents) was added to tert-butyl (3S, 4R) -3- fluoro-4-hydroxypiperidine -1- carboxylate (500 mg, 2.280 mmol, 1 equivalent) contained in THF (10 mL). After stirring for 20 minutes, iodomethane (1294.73 mg, 9.122 mmol, 4 equivalents) was added. The resulting solution was stirred for another 1 hour at 0 ° C. The reaction was then quenched by adding 10 mL of water. The solid was filtered out. The resulting solution was extracted with EA and concentrated under vacuum. This produced 500 mg (94.1%) of the title compound as a light yellow oil.

[0624] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56].

[0625] Step 2: Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine:

[0626] A solution of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate (500 mg, 2.143 mmol, 1 eq) in TFA / DCM (3 / 10 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give 500 mg (crude) of the title compound as a solid.

[0627] Step 3: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine:

[0628] A mixture of (3S,4R)-3-fluoro-4-methoxypiperidine (3 g, 22.528 mmol, 1 eq), 2-chloropyrimidin-4-amine (2.33 g, 0.018 mmol, 0.8 eq) and TEA (6.84 g, 0.068 mmol, 3 eq) in IPA (3 mL) was stirred at 100° C. for 12 h. The solvent was removed under vacuum and the residue was purified by FLASH (5% MeOH / DCM) to give 3.3 g (66%) of the title compound as a light yellow solid.

[0629] Analytical data: LC-MS: (ES, m / z) = 227 [M+1]. 1H-NMR(400MHz,6d-DMSO)δppm 7.72(d,1H,J=5.6Hz),6.39(s,2H),5.71(d,1H,J=5.6Hz),4.83(d,1H,J=49.3Hz),4.60-4.49(m,1H),4 .29(d,1H,J=13.3Hz),3.55-3.42(m,1H),3.28(d,1H,J=13.3Hz),3.20-3.04(m,1H),1.76-1.48(m,2H)

[0630] Example B34: Synthesis of 2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)pyrimidin-4-amine

[0631]

[0632] 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 / DCM) to give the title compound (300 mg, 73.8%) as a yellow solid.

[0633] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0634] Example B35: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol

[0635]

[0636] Step 1: Synthesis of racemic tert-butyl 4-hydroxy-2,4-dimethylpiperidine-1-carboxylate:

[0637] Methyllithium (822 mg, 37.4 mmol) was added dropwise to 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 hour. The reaction was quenched with water / ice and extracted with EA. The organic layers were combined and concentrated under vacuum. This produced 4.2 g (98.1%) of the title compound as a yellow solid.

[0638] Analytical data: LC-MS: (ES, m / z) = 230 [M+1].

[0639] Step 2: Synthesis of racemic 2,4-dimethylpiperidin-4-ol:

[0640] To a stirred solution of 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 under vacuum. The crude product was used directly in the next step.

[0641] Analytical data: LC-MS: (ES, m / z) = 130 [M+1].

[0642] Step 3: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol:

[0643] To a stirred solution of racemic 2,4-dimethylpiperidin-4-ol (2 g, 15.4 mmol) and 2-chloropyrimidine-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 was extracted with DCM / MeOH (10: 1). The residue was purified by preparative TLC with DCM / MeOH (10: 1). This produced 0.2 g of the title compound as a white solid.

[0644] Analytical data: LC-MS: (ES, m / z) = 223 [M+1].

[0645] Example B36: Synthesis of rac-2-(6-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)pyrimidin-4-amine

[0646]

[0647] 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 at 100° C. for 3 hours. The solution was concentrated and the residue was purified on preparative TLC (DCM:MeOH=10:1) to give the title compound (100 mg) as a white solid.

[0648] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0649] Example B37: Synthesis of tert-butyl 3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate

[0650]

[0651] Step 1: Synthesis of benzyl 3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate:

[0652] Into a 100mL round-bottom flask was placed benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.2g, 5.42mmol), TEA (822mg, 8.13mmol) and methanesulfonyl chloride (620mg, 5.42mmol) in DCM (20mL). The resulting solution was stirred at room temperature for 6 hours. The solution was washed with water and purified by preparative TLC (20% EA / PE). This produced 1.0g of the title compound as a white solid.

[0653] Analytical data: LC-MS: (ES, m / z) = 300 [M+1].

[0654] Step 2: Synthesis of tert-butyl 3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylthio)azetidine-1-carboxylate:

[0655] A mixture of benzyl 3-[(methylsulfonyloxy)methyl]azetidine-1-carboxylate (530 mg, 1.77 mmol), tert-butyl 3-thioazetidine-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 h. 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.

[0656] Analytical data: LC-MS: (ES, m / z) = 293 [M+1-100].

[0657] Step 3: Synthesis of tert-butyl 3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylsulfonyl)azetidine-1-carboxylate:

[0658] Potassium peroxymonosulfate (4.21 g, 6.86 mmol) was added to a solution of benzyl 3-[({1-[(tert-butoxy)carbonyl]azetidin-3-yl}thio)methyl]azetidine-1-carboxylate (900 mg, 2.29 mmol) in EtOH / THF / H O (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 with DCM / MeOH (100: 1) to give 680 mg of the title compound as a white solid.

[0659] Analytical data: LC-MS: (ES, m / z) = 325 [M+1-100].

[0660] Step 4: Synthesis of tert-butyl 3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate:

[0661] Under a hydrogen atmosphere, 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 for 4 h. The solid was filtered off and the mother solvent was concentrated under reduced pressure to give the title compound (480 mg) as a white solid.

[0662] Analytical data: LC-MS: (ES, m / z) = 291 [M+1].

[0663] Example B38: Synthesis of rac-1-(4-aminopyrimidin-2-yl)azepan-4-ol

[0664]

[0665] 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 at 100° C. for 3 h. 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.

[0666] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0667] 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

[0668]

[0669] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-methoxypiperidine-1-carboxylate:

[0670] At 0 DEG C, NaH (20.23mg, 0.843mmol, 2 equivalents) is added to DMF (5mL) containing tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-formate (100mg, 0.422mmol, 1 equivalent). After stirring for 30 minutes, MeI (89.74mg, 0.632mmol, 1.5 equivalents) is added and the mixture is stirred at room temperature for 2 hours. The reaction is then quenched by adding 10mL water. The resulting solution is extracted with EA and concentrated. This produces 150mg (crude) of the title compound as a light yellow solid.

[0671] Analytical data: LC-MS: (ES, m / z) = 252 [M+1].

[0672] Step 2: Synthesis of 3,3-difluoro-4-methoxypiperidine:

[0673] A solution of tert-butyl 3,3-difluoro-4-methoxypiperidine-1-carboxylate (300 mg, 1.194 mmol) and DCM (15 mL) in 4M HCl / dioxane (5 mL) was stirred at room temperature for 12 hours. The resulting mixture was concentrated. This produced 280 mg (crude) of the title compound as a light yellow solid as the HCl salt.

[0674] Analytical data: LC-MS: (ES, m / z) = 152 [M+1].

[0675] 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:

[0676] A mixture of 3,3-difluoro-4-methoxypiperidine (1.5 g, 9.923 mmol, 1 eq), 2-chloropyrimidin-4-amine (1.29 g, 9.923 mmol, 1 eq) and TEA (3.01 g, 29.77 mmol, 3 eq) in IPA (10 mL) was stirred at 100 ° C for 3 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with EA / PE (1:1). This yielded 1.1 g (45.4%) of the title compound as a yellow solid.

[0677] 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*50 mm, 3 μm; co-solvent: MeOH (0.1% DEA) gradient (B%): 10% to 50% in 4.0 minutes, hold at 50% for 2 minutes; back pressure (psi): 1500.000; flow rate (mL / min) to afford 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) as a light 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) as a light yellow solid.

[0678] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0679] Example B40: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-5,5-dimethylpiperidin-4-ol

[0680]

[0681] Step 1: Synthesis of racemic tert-butyl 5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylate:

[0682] At 0 ° C, under N2 atmosphere, 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). The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA and water. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was used directly in the next step.

[0683] 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 layer was concentrated and the residue was purified by flash chromatography with PE / EA (5: 1). This produced 500 mg (51%) of the title compound as a light yellow solid.

[0684] Analytical data: LC-MS: (ES, m / z) = 246 [M+1].

[0685] Step 2: Synthesis of tert-butyl 3,3-difluoro-5,5-dimethyl-4-oxopiperidine-1-carboxylate:

[0686] At -78 ° C, under N2 atmosphere, to a solution of racemic -5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (100 mg, 407 μmol) in THF was added LiHMDS (46.4 mg, 814 μmol). 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 with PE / EA (5: 1). This produced 60 mg (56%) of the title compound as a light yellow solid.

[0687] Analytical data: LC-MS: (ES, m / z) = 208 [M+1-56].

[0688] Step 3: Synthesis of racemic tert-butyl 3,3-difluoro-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate:

[0689] 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 under vacuum. The crude product (75 mg) was used directly in the next step.

[0690] Analytical data: LC-MS: (ES, m / z) = 210 [M+1-56].

[0691] Step 4: Synthesis of racemic-3,3-difluoro-5,5-dimethylpiperidin-4-ol:

[0692] At room temperature, racemic 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). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum to give 40 mg (86%) of the title compound as a brown liquid.

[0693] Analytical data: LC-MS: (ES, m / z) = 166 [M+1].

[0694] Step 5: Synthesis of racemic tert-butyl 2-(3,3-difluoro-4-hydroxy-5,5-dimethylpiperidin-1-yl)pyrimidin-4-ylcarbamate:

[0695] A mixture of rac-3,3-difluoro-5,5-dimethylpiperidin-4-ol (100 mg, 605 μmol), tert-butyl N-(2-bromopyrimidin-4-yl)-N-[(tert-butoxy)carbonyl]carbamate (226 mg, 605 μmol), CuI (57.3 mg, 302 μmol), L-proline (6.95 mg, 60.5 μmol), and K PO (383 mg, 1.81 mmol) in DMSO was stirred at 100 ° C. under N 2 atmosphere for 2 hours. Water was added and the mixture was extracted with EA. The organic phase was concentrated and the residue was purified by preparative TLC with DCM / MeOH (20:1). This gave 100 mg (36%) of the product as a yellow solid.

[0696] Analytical data: LC-MS: (ES, m / z) = 359 [M+1].

[0697] Step 6: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-5,5-dimethylpiperidin-4-ol:

[0698] Racemic 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) was stirred in DCM / TFA (10 / 3 mL) at room temperature for 2 h. The solvent was concentrated in vacuo to give 100 mg (90%) of the title compound as a brown solid.

[0699] Analytical data: LC-MS: (ES, m / z) = 259 [M+1].

[0700] Example B41: Synthesis of racemic-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol

[0701]

[0702] To a solution of 3-chloro-1,2,4-triazine-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 with PE / EA (5: 1). This produced 260 mg (53%) of 1-(5-amino-1,2,4-triazine-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% NH₃H₂O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5B to 10B over 7 minutes; 254 / 220 nm. This yielded 90 mg of racemic-cis-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol and 30 mg of racemic-trans-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol. Both were yellow solids.

[0703] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[0704] 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

[0705]

[0706] Step 1: Synthesis of racemic-(cis)-3,4-dihydroxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0707] To a mixture of tert-butyl 5-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate (200 mg, 1012 μmol) and NMO (142.2 mg, 1214 μmol) in acetone (6 mL) and water (2 mL) was added K OsO 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 Na SO . Filtered and concentrated to dryness to give the title compound (180 mg) as a dark yellow oil.

[0708] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56].

[0709] Step 2: Synthesis of racemic-(cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0710] At room temperature, MeI (367 mg, 2.59 mmol) is added to a mixture of Ag contained in DMF (20 mL) O (399 mg, 1.72 mmol) and (cis)-3,4-dihydroxy-3-methylpiperidine-1-tert-butyl formate (200 mg, 864 μmol). The mixture is stirred at room temperature for 2 days. The solid is filtered out and the filtrate is diluted with EA and washed with H O. The organic layer is dried over Na SO and concentrated under vacuum to obtain 160 mg of racemic-(cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-tert-butyl formate mixed with racemic-(cis)-4-hydroxy-3-methoxy-3-methylpiperidine-1-tert-butyl formate, which is used in the next step without further purification.

[0711] Analytical data: LC-MS: (ES, m / z) = 190 [M+1-56].

[0712] Step 3: Synthesis of racemic-(cis)-4-methoxy-3-methylpiperidin-3-ol:

[0713] At room temperature, TFA (5 mL) was added dropwise to a mixture of racemic-(cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester (160 mg, 652 μmol) in DCM (15 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum to give 100 mg of racemic-(cis)-4-methoxy-3-methylpiperidin-3-ol mixed with racemic-(cis)-3-methoxy-3-methylpiperidin-4-ol as a colorless oil.

[0714] Analytical data: LC-MS: (ES, m / z) = 146 [M+1].

[0715] Step 4: Synthesis of racemic-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-ol and racemic-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol:

[0716] At room temperature, 2-chloropyrimidin-4-amine (100 mg, 771 μmol) is added to TEA (388 mg, 385 mmol) and racemic-(cis)-4-methoxy-3-methylpiperidin-3-ol (111 mg, 771 μmol) / racemic-(cis)-3-methoxy-3-methylpiperidin-4-ol contained in IPA. The mixture is heated to 100 ° C for 16 hours. The mixture is concentrated under vacuum. The residue is purified by preparative TLC with DCM: MeOH = 25: 1. This produces 120 mg of racemic-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol mixed with racemic-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-3-ol as a brown oil.

[0717] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0718] Example B43: Synthesis of 3-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazine-5-amine

[0719]

[0720] 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-triazine-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 with PE / EA (5:1). This gave 40 mg (39%) of the title compound as a yellow solid.

[0721] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[0722] Example B44: Synthesis of 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethanol

[0723]

[0724] 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 Na2SO4, filtered, evaporated and purified by column chromatography (DCM:MeOH=20:1) to give the title compound (270 mg) as a yellow solid.

[0725] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0726] Example B45: Synthesis of racemic-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol

[0727]

[0728] Step 1: Synthesis of racemic 1-tert-butyl 3-methyl 4-methoxypiperidine-1,3-dicarboxylate:

[0729] At 0 ° C, NaH (1.3g, 34.5mmol) is added to a solution of racemic-4-hydroxypiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester (6.0g, 23.0mmol) in DMF (50mL). After stirring for 10 minutes, iodomethane (4.8g, 34.5mmol) is added. The mixture is stirred at room temperature overnight. Water is added and the mixture is extracted with EA. The organic phase is washed with water, dried and concentrated. The residue is purified by FLASH (20% EA / PE) to obtain 3.0g (47%) of the title compound as a colorless oil.

[0730] Analytical data: LC-MS: (ES, m / z) = 274 [M+1].

[0731] Step 2: Synthesis of racemic tert-butyl 3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate:

[0732] LiBH4 (2 M in THF, 15 mmol) was added to a solution of rac-4-methoxypiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester (2 g, 7.3 mmol) in THF (40 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. 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.

[0733] Analytical data: LC-MS: (ES, m / z) = 246 [M+1].

[0734] Step 3: Synthesis of racemic-(4-methoxypiperidin-3-yl)methanol:

[0735] 1.2 g of racemic 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.

[0736] Analytical data: LC-MS: (ES, m / z) = 146 [M+1].

[0737] Step 4: Synthesis of racemic-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol:

[0738] 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 / DCM) to give 400 mg of rac-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol as a light yellow solid.

[0739] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0740] Example B46: Synthesis of (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol

[0741]

[0742] Step 1: Synthesis of (4-methoxypiperidin-4-yl)methanol:

[0743] To a solution of 4-methoxypiperidine-4-carboxylic acid hydrochloride (200 mg, 1.02 mmol) in THF (25 mL) was added LiAlH4 (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.

[0744] Analytical data: LC-MS: (ES, m / z) = 146 [M+1].

[0745] Step 2: Synthesis of (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol:

[0746] A mixture of (4-methoxypiperidin-4-yl)methanol (400 mg, crude), 4-chloropyrimidin-2-amine (130 mg, 1.01 mmol), and TEA (306 mg, 3.03 mmol) in IPA (25 mL) was stirred at 100° C. for 2 h. 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 light yellow solid.

[0747] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0748] Example B47: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-2-methylpiperidin-4-ol

[0749]

[0750] 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 / DCM) to give 200 mg of the title compound as a yellow solid.

[0751] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0752] Example B48: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate

[0753]

[0754] Step 1: Synthesis of tert-butyl 2-(piperidin-4-yloxy)ethylcarbamate:

[0755] 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 at 50° C. under 5 atm H₂ atmosphere overnight. 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 title compound as a colorless oil.

[0756] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0757] Step 2: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate:

[0758] A mixture of 250 mg of crude tert-butyl 2-(piperidin-4-yloxy)ethylcarbamate, 2-chloropyrimidin-4-amine (129 mg, 1.0 mmol) and TEA (200 mg, 2.0 mmol) in DMSO (1 mL) was stirred overnight at 120 ° C. Water was added and the mixture was extracted with EA. The organic phase was washed, concentrated and purified by preparative TLC (5% MeOH / DCM) to give 70 mg of the title compound as a yellow oil.

[0759] Analytical data: LC-MS: (ES, m / z) = 338 [M+1].

[0760] Example B49: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile and racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile

[0761]

[0762] Step 1: Synthesis of racemic tert-butyl 3-carbamoyl-4-methoxypiperidine-1-carboxylate:

[0763] 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 hour. The mixture was extracted with DCM, dried and concentrated to give the title compound (500 mg) as a colorless oil.

[0764] Analytical data: LC-MS: (ES, m / z) = 259 [M+1].

[0765] Step 2: Synthesis of racemic tert-butyl 3-cyano-4-methoxypiperidine-1-carboxylate:

[0766] TFAA (810 mg, 3.86 mmol) was added to a solution of 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 produced the title compound (400 mg) as a colorless oil.

[0767] Analytical data: LC-MS: (ES, m / z) = 185 [M+1-56].

[0768] Step 3: Synthesis of racemic 4-methoxypiperidine-3-carbonitrile:

[0769] To a solution of 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. This gave the title compound (500 mg) as a light yellow oil.

[0770] Analytical data: LC-MS: (ES, m / z) = 141 [M+1].

[0771] Step 4: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile and racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile:

[0772] A mixture of 2-chloropyrimidin-4-amine (461 mg, 3.56 mmol), racemic 4-methoxypiperidine-3-carbonitrile (500 mg, 3.56 mmol), and DIPEA (1.37 g, 10.6 mmol) in DMSO (20 mL) was stirred at 120° C. for 3 hours. The reaction mixture was purified on preparative HPLC using an XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water (0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13B to 23B over 7 minutes; 254 / 220 nm. This resulted in 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.

[0773] Racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile:

[0774] Analytical data: LC-MS: (ES, m / z) = 234 [M+1]; 1H-NMR(300MHz,3d-CD3Cl)δppm 7.94(d,1H,J=5.6Hz),5.81(d,1H,J=5.7Hz),4.68(s,2H),4.37(dd,1H,J=13.4,7.0Hz),4.14-4.00(m,1H),3.8 5(dd,1H,J=13.1,3.6Hz),3.68-3.57(m,2H),3.49(s,3H),3.04(dtd,1H,J=6.7,3.8,2.0Hz),1.99-1.71(m,2H)

[0775] Racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile:

[0776] Analytical data: LC-MS: (ES, m / z) = 234 [M+1]; 1 H-NMR(300MHz,3d-CD3Cl)δppm 7.93(d,1H,J=5.6Hz),5.82(d,1H,J=5.6Hz),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=13.4,9.5Hz),3.19(ddd,1H,J=13.6,10.4,3.1Hz),2.64(td,1H,J=9.1,4.0Hz),2.21-2.07(m,1H),1.53-1.34(m,1H)

[0777] Example B50: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-3-methoxypiperidin-4-ol

[0778]

[0779] Step 1: Synthesis of racemic tert-butyl 4-hydroxy-3-methoxypiperidine-1-carboxylate:

[0780] To a solution of racemic tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate (2 g, 8.72 mmol) in THF (50 mL) was added NaBH (395 mg, 10.4 mmol) at 0°C and stirred at room temperature 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, and evaporated to give the title compound (2 g, crude) as a yellow semisolid.

[0781] Analytical data: LC-MS: (ES, m / z) = 232 [M+1].

[0782] Step 2: Synthesis of racemic 3-methoxypiperidin-4-ol:

[0783] A solution of 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 h. The reaction mixture was evaporated to give the title compound (700 mg, crude) as a yellow semisolid.

[0784] Analytical data: LC-MS: (ES, m / z) = 132 [M+1].

[0785] Step 3: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-3-methoxypiperidin-4-ol:

[0786] A mixture of racemic 2-chloropyrimidine-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 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (150 mL × 3) and washed with brine (50 mL). The organic layer was dried over Na SO , filtered, evaporated and purified by column chromatography (EA) to give the title compound (220 mg) as a yellow solid.

[0787] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0788] Example B51: Synthesis of 2-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

[0789]

[0790] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(2-hydroxyethoxy)piperidine-1-carboxylate:

[0791] At 0 ° C, NaH (455 mg, 11.4 mmol) was added to 10 mL of DMF containing tert-butyl (3R, 4S) -3-fluoro-4-hydroxypiperidine-1-carboxylate (1.0 g, 4.56 mmol). 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 under vacuum. The residue was purified by FLASH with PE: EA = 10: 1 to give 1.1 g of the title compound as a colorless oil.

[0792] Step 2: Synthesis of 2-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol:

[0793] At room temperature, TFA (5mL) is added to DCM (20mL) containing (3R, 4S) -4- {2- [(tert-butyldimethylsilyl) oxy] ethoxy} -3-fluoropiperidine -1- carboxylic acid tert-butyl ester (1.1g, 2.91mmol). The resulting mixture is stirred at room temperature for 1 hour. The mixture is concentrated under vacuum and the residue is mixed with DMSO (10mL) containing 2-chloropyrimidine -4- amine (317mg, 2.45mmol) and DIEA (1.26mg, 9.80mmol). The mixture is heated to 100 ° C and stirred for 16 hours. The mixture is diluted with EA and washed with brine. The organic layer is dried over Na2SO4 and concentrated under vacuum. The residue is purified by FLASH with MeOH: EA = 1: 15 to obtain 450mg of the title compound as a yellow solid.

[0794] Analytical data: LC-MS: (ES, m / z) = 257 [M+1]; 1 H-NMR(400MHz,6d-DMSO)δppm 7.72(d,1H,J=5.6Hz),6.41(s,2H),5.71(d,1H,J=5.6Hz),4.91-4.73(m,1H),4.67-4.50(m,2H),4.3 4(d,1H,J=13.0Hz),3.69-3.46(m,5H),3.30-3.17(m,1H),3.06(d,1H,J=11.3Hz),1.80-1.54(m,2H).

[0795] Example B52: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

[0796]

[0797] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxyethoxy)piperidine-1-carboxylate:

[0798] At 0 ° C, NaH (1.35 g, 33.9 mmol) was added in batches to DMF (10 mL) containing tert-butyl (3S, 4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (3.0 g, 13.6 mmol). The mixture was stirred at 0 ° C for 20 minutes, (2-bromoethoxy) (tert-butyl) dimethylsilane (9.76 g, 40.8 mmol) was added and 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 under vacuum. The residue was purified by FLASH with PE: EA = 10: 1 to obtain 3.0 g of the title compound as a colorless oil.

[0799] Step 2: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol:

[0800] At room temperature, TFA (15mL) is added to DCM (20mL) containing (3S, 4R) -4- {2- [(tert-butyldimethylsilyl) oxy] ethoxy} -3-fluoropiperidine -1- carboxylic acid tert-butyl ester (3.0g, 7.94mmol). The resulting mixture is stirred at room temperature for 1 hour. The mixture is concentrated under vacuum and the residue is mixed with DMSO (10mL) containing 2-chloropyrimidine -4- amine (873mg, 6.74mmol) and DIEA (629mg, 4.88mmol). The mixture is stirred at 100 ° C overnight. The mixture is diluted with EA 50mL and washed with brine, the organic layer is dried over Na2SO4 and concentrated under vacuum. The residue is purified by FLASH with MeOH:EA=1:15 to obtain 1.1g of the title compound as a yellow solid.

[0801] Analytical data: LC-MS: (ES, m / z) = 257 [M+1]; 1 H-NMR (400MHz, 6d-DMSO) δppm7.72 (d, 1H, J = 5.6Hz), 6.41 (s, 2H), 5.71 (d, 1H, J = 5.6Hz), 4.94-4.69 (m, 1H), 4.67-4. 52(m,2H),4.34(d,1H,J=13.3Hz),3.72-3.45(m,5H),3.31-3.19(m,1H),3.07(t,1H,J=11.4Hz),1.77-1.44(m,2H).

[0802] Example B53: Synthesis of racemic-cis-tert-butyl 1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate and racemic-trans-tert-butyl 1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate

[0803]

[0804] Step 1: Synthesis of racemic-1-(tert-butyloxycarbonyl)-4-methoxypiperidine-3-carboxylic acid:

[0805] A mixture of rac-1-tert-butyl 3-methyl 4-methoxypiperidine-1,3-dicarboxylate (3 g, 10.9 mmol) and NaOH (871 mg, 21.8 mmol) in MeOH (25 mL) and water (10 mL) was stirred at 80° C. for 1 hour. 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 light yellow oil.

[0806] Analytical data: LC-MS: (ES, m / z) = 282 [M+23].

[0807] Step 2: Synthesis of racemic 4-methoxypiperidine-3-carboxylic acid:

[0808] 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 light yellow oil.

[0809] Analytical data: LC-MS: (ES, m / z) = 160 [M+1].

[0810] Step 3: Synthesis of racemic-1-(benzyloxycarbonyl)-4-methoxypiperidine-3-carboxylic acid:

[0811] 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 hour, the resulting mixture was washed with EA. The aqueous layer was acidified with 1N HCl and extracted with EA. The organic layer was dried over NaSO and concentrated to dryness to give the title compound (1.2 g, 70% for two steps) as a colorless oil.

[0812] Analytical data: LC-MS: (ES, m / z) = 294 [M+1].

[0813] Step 4: Synthesis of racemic 3-(tert-butoxycarbonylamino)-4-methoxypiperidine-1-carboxylic acid benzyl ester:

[0814] 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 / PE to give the title compound (300 mg) as a colorless oil.

[0815] Analytical data: LC-MS: (ES, m / z) = 387 [M+23].

[0816] Step 5: Synthesis of racemic tert-butyl 4-methoxypiperidin-3-ylcarbamate:

[0817] 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 h. The solid was filtered off and the filtrate was concentrated to dryness to give the title compound (100 mg) as a colorless oil.

[0818] Analytical data: LC-MS: (ES, m / z) = 231 [M+1].

[0819] Step 6: Synthesis of racemic-cis-tert-butyl 1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate and racemic-trans-tert-butyl 1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate:

[0820] 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 at 100° C. for 3 hours. The resulting mixture was purified on 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-tert-butyl 1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate (55 mg) as an off-white solid.

[0821] Analytical data: LC-MS: (ES, m / z) = 324 [M+1].

[0822] 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

[0823]

[0824] Step 1: Synthesis of tert-butyl 5,5-difluoro-5,6-dihydropyridine-1(2H)-carboxylate:

[0825] At 0 ° C, to a solution of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (355 mg, 1.5 mmol, 1 equiv) in DCM (6 mL), DMAP (274 mg, 2.25 mmol, 1.5 equiv) was added, followed by trifluoromethanesulfonyl trifluoromethanesulfonate (550 mg, 1.95 mmol, 1.3 equiv). The reaction was carried out at 0 ° C for 1 hour, after which it was quenched with saturated NaHCO (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.

[0826] Analyze the data: 1 H-NMR (400MHz, CD3Cl) δppm 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).

[0827] Step 2: Synthesis of cis-tert-butyl 3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylate:

[0828] To a mixture of tert-butyl 3,3-difluoro-1,2,3,6-tetrahydropyridine-1-carboxylate (153 mg, 700 μmol, 1 eq) in acetone (4 mL) and H2O (1 mL) was added K2OsO4.2H2O (12.8 mg, 35 μmol, 0.05 eq) and NMO (244 mg, 2.1 mmol, 3 eq) at room temperature. The reaction was carried out at 40°C for 18 hours. After cooling down to room temperature, the mixture was diluted with EA (50 mL) and washed with 10% Na2S2O3 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.

[0829] Analyze the data: 1 H-NMR(400MHz,6d-DMSO)δppm 5.88(d,1H,J=5.1Hz),5.18(d,1H,J=5.9Hz),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).

[0830] Step 3: Synthesis of cis-tert-butyl 3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate:

[0831] At 0 ° C, to a solution of cis-3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylic acid tert-butyl ester (69.6 mg, 275 μmol, 1 equivalent) in THF (2 mL) was added NaH (10.9 mg, 275 μmol, 1 equivalent, 60%). After 30 minutes, MeI (39.0 mg, 275 μmol, 1 equivalent) was added. The reaction was carried out at 0 ° C for 1 hour and at room temperature for 18 hours. 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.

[0832] Step 4: Synthesis of cis-5,5-difluoro-4-methoxypiperidin-3-ol:

[0833] A solution of tert-butyl cis-3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate (240 mg, 900 μιηοΐ, 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.

[0834] Analytical data: LC-MS: (ES, m / z) = 168 [M+1].

[0835] 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:

[0836] 220mg of cis-5,5-difluoro-4-methoxypiperidin-3-ol was dissolved in IPA (2mL). 2-Chloropyrimidine-4-amine (116mg, 900μmol, 1 equivalent) was added, followed by TEA (454mg, 4.50mmol, 5 equivalents). The reaction was carried out at 100 ° C for 18 hours. After cooling down 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 (50mg, 21.36%) as a white solid. The compound was separated by preparative chiral HPLC using the following conditions: CHIRAL Cellulose-SB4.6*100mm 3μm; mobile phase: Hex (0.1% DEA): IPA = 70:30; flow rate: 1.0 mL / min, to obtain 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) 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 light yellow solid.

[0837] Analytical data: LC-MS: (ES, m / z) = 261 [M+1]; 1 H-NMR(300MHz,3d-CD3Cl)δppm 7.95(d,1H,J=5.6Hz),5.82(d,1H,J=5.6Hz),4.87-4.70(m,1H),4.67-4.48(m,3H),3.91(s,1H),3.67(d,3H,J =1.0Hz), 3.67-3.60 (m, 1H), 3.51 (ddd, 1H, J = 29.0, 14.0, 1.8Hz), 3.12 (dd, 1H, J = 12.9, 10.1Hz), 2.41 (s, 1H).

[0838] Example B55: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

[0839]

[0840] Step 1: Synthesis of racemic cis-tert-butyl 3,4-dihydroxy-4-methylpiperidine-1-carboxylate:

[0841] 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 H O (1 mL) was added K OsO 2H O (50.4 mg, 152 μmol) and NMO (533 mg, 4.56 mmol) at room temperature and stirred for 12 hours. The reaction mixture was diluted with saturated aqueous Na S SO and extracted with EA and brine. The organic layer was dried over Na SO , filtered, and evaporated to give the title compound (350 mg, crude) as a yellow solid.

[0842] Analytical data: LC-MS: (ES, m / z) = 254 [M+23].

[0843] Step 2: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol:

[0844] To a solution of racemic-cis-3,4-dihydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (350 mg, crude) in DCM (6 mL) was added TFA (2 mL) and stirred at room temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in IPA (3 mL), 2-chloropyrimidine-4-amine (160 mg, 1.23 mmol) and TEA (621 mg, 6.15 mmol) were added, 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 Na2SO4, 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.

[0845] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0846] Example B56: Synthesis of racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

[0847]

[0848] Step 1: Synthesis of tert-butyl 6-methyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate:

[0849] 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 / PE) to give 460 mg of the title compound as a colorless oil.

[0850] Analytical data: LC-MS: (ES, m / z) = 214 [M+1].

[0851] Step 2: Synthesis of racemic-trans-3,4-dihydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0852] To a solution of tert-butyl 6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (100 mg, 468 μmol) in H O (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 the title compound as a yellow oil, 180 mg.

[0853] Analytical data: LC-MS: (ES, m / z) = 232 [M+1].

[0854] Step 2: Synthesis of racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol:

[0855] To a solution of racemic -trans-3,4-dihydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (300mg, 1.29mmol) contained in DCM (10mL) TFA (3mL) was added 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 (2mL), 2-chloropyrimidine-4-amine (88.8mg, 686μmol) and DIEA (441mg, 3.42mmol) were added, and the solution was heated to 120°C for 10 hours. The mixture was extracted with EA and water. The organic matter was concentrated and purified by FLASH (50% MeOH / DCM) to give 80mg of the title compound as a light yellow solid.

[0856] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0857] Example B57: Synthesis of tert-butyl 1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-ylcarbamate

[0858]

[0859] A mixture of rac-tert-butyl N-(3,3-difluoropiperidin-4-yl)carbamate (200 mg, 0.85 mmol, 1 eq), 2-chloropyrimidin-4-amine (109.67 mg, 0.847 mmol, 1 eq), and TEA (256.98 mg, 2.540 mmol, 3 eq) 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 with DCM / MeOH (20: 1). This gave 100 mg (35.9%) of the title compound as a light yellow solid.

[0860] Analytical data: LC-MS: (ES, m / z) = 330 [M+1].

[0861] Example B58: Synthesis of racemic-cis-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-4-methylpiperidin-4-ol

[0862]

[0863] A mixture of 3-chloro-1,2,4-triazine-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 hours. Water was added and the reaction was extracted with EA. The organic layer was purified by preparative TLC (DCM:MeOH=10:1). This produced 300 mg (34.4%) of the title compound as a gray solid.

[0864] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[0865] 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

[0866]

[0867] Step 1: Synthesis of racemic tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate:

[0868]

[00155] tert-Butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (4 g, 17 mmol, Example Bl) 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 hour. Iodomethane (4.82 g, 34.2 mmol) was added and the reaction was stirred at room temperature for another 2 hours. The reaction was quenched with water / ice, extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 5.1 g of tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate as a colorless oil.

[0869] Step 2: Synthesis of racemic 2-(3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine:

[0870] Racemic -3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester (5.1g) is dissolved in HCl / dioxane (4M, 50mL). The reaction is stirred at room temperature for 2 hours. The mixture is concentrated under vacuum. The residue is mixed with IPA (30mL) containing 2-chloropyrimidine-4- (4.21g, 32.5mmol) and TEA (5.47g, 54.2mmol). The mixture is stirred and stirred at 100°C for 16 hours. The reaction is concentrated under vacuum and the residue is purified by FLASH (DCM:MeOH=10:1). This produces 1.6g of the title compound as a white solid, which is further separated into four isomers using the following conditions:

[0871] Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[0872] Column name: CHIRAL ND (2) 4.6*100 mm, 3 μm; co-solvent: MeOH (0.1% DEA); gradient (B%): 10% to 50% in 4.0 minutes, maintained at 50% for 2.0 minutes; flow rate (mL / min) to obtain 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 light yellow solids.

[0873] Column name: CHIRAL ND (2) 4.6*100 mm, 3 μm; co-solvent: MeOH (0.1% DEA); gradient (B%): 10% to 50% in 4.0 minutes, maintained at 50% for 2.0 minutes; flow rate (mL / min) to obtain 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 light yellow solids.

[0874] Example B60: Synthesis of tert-butyl 2-(azetidin-3-yl)-2-(methylsulfonyl)ethylcarbamate

[0875]

[0876] Step 1: Synthesis of rac-3-(1-(methylsulfonyl)prop-2-ynyl)azetidine-1-carboxylic acid benzyl ester:

[0877] At room temperature, CsCO (544 mg, 1.67 mmol) was added to DMF (5 mL) containing 2-methylsulfonylacetonitrile (1 g, 8.39 mmol) and benzyl 3-iodoazetidine-1-carboxylate (3.96 g, 12.5 mmol). 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 NaSO and concentrated under vacuum. 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.

[0878] Analytical data: LC-MS: (ES, m / z) = 308 [M+1].

[0879] Step 2: Synthesis of racemic 3-(2-amino-1-(methylsulfonyl)ethyl)azetidine-1-carboxylic acid benzyl ester:

[0880] Benzyl 3-[cyano(methylsulfonyl)methyl]azetidine-1-carboxylate (1.2 g, 3.89 mmol) and Raney nickel (10 mg) in EtOH (4 mL) were stirred at room temperature under an atmosphere of H2 for 8 h. 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.

[0881] Analytical data: LC-MS: (ES, m / z) = 313 [M+1].

[0882] Step 3: Synthesis of racemic 3-(2-(tert-butoxycarbonylamino)-1-(methylsulfonyl)ethyl)azetidine-1-carboxylic acid benzyl ester:

[0883] (Boc) O (829 mg, 3.84 mmol) was added to dioxane / H O (10 mL / 3 mL) containing Na CO (407 mg, 3.84 mmol) and racemic benzyl 3-(2-amino-1-methylsulfonylethyl)azetidine-1-carboxylate (600 mg, 1.92 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA and washed with brine, and the organic layer was dried over Na SO and concentrated under vacuum. 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.

[0884] Analytical data: LC-MS: (ES, m / z) = 413 [M+1].

[0885] Step 4: Synthesis of tert-butyl 2-(azetidin-3-yl)-2-(methylsulfonyl)ethylcarbamate:

[0886] A mixture of rac-benzyl 3-(2-amino-1-methanesulfonylethyl)azetidine-1-carboxylate (600 mg, 1.92 mmol) and Pd(OH)2 / C (300 mg, 2.14 mmol) in MeOH (50 mL) was stirred at room temperature under a hydrogen atmosphere 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.

[0887] Analytical data: LC-MS: (ES, m / z) = 279 [M+1].

[0888] Example B61: Synthesis of racemic-cis-2-(hexahydrofuro[3,4-b]pyrrol-1-yl)pyrimidin-4-amine

[0889]

[0890] A mixture of 2-chloropyrimidin-4-amine (370 mg, 2.85 mmol), racemic-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 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=20:1) to give the title compound (410 mg, 69.8%) as a yellow solid.

[0891] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0892] Example B62: Synthesis of tert-butyl (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methylcarbamate

[0893]

[0894] Step 1: Synthesis of 1-tert-butyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate:

[0895] 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 minutes, MeI (1.23 g, 8.67 mmol) was added and stirred for 2 hours. 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 / PE to obtain 1-tert-butyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate (1.3 g) as a light yellow oil.

[0896] Analytical data: LC-MS: (ES, m / z) = 296 [M+23].

[0897] Step 2: Synthesis of 1-benzyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate:

[0898] 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 KCO (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 NaSO and concentrated to dryness to give the title compound (1.2 g) as a colorless oil.

[0899] Analytical data: LC-MS: (ES, m / z) = 309 [M+1].

[0900] Step 3: Synthesis of 1-(benzyloxycarbonyl)-4-methoxypiperidine-4-carboxylic acid:

[0901] 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 Na SO, filtered and concentrated to dryness to give the title compound (1 g) as a colorless oil.

[0902] Analytical data: LC-MS: (ES, m / z) = 294 [M+1].

[0903] Step 4: Synthesis of benzyl 4-carbamoyl-4-methoxypiperidine-1-carboxylate:

[0904] 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 and washed with water, dried over NaSO, filtered, and concentrated to dryness. The residue was purified on a silica gel column with 60% EtOAc / PE to give the title compound (900 mg) as a colorless oil.

[0905] Analytical data: LC-MS: (ES, m / z) = 293 [M+1].

[0906] Step 5: Synthesis of benzyl 4-(aminomethyl)-4-methoxypiperidine-1-carboxylate:

[0907] 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). 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.

[0908] Analytical data: LC-MS: (ES, m / z) = 279 [M+1].

[0909] Step 6: Synthesis of benzyl 4-((tert-butoxycarbonylamino)methyl)-4-methoxypiperidine-1-carboxylate:

[0910] A solution of benzyl 4-(aminomethyl)-4-methoxypiperidine-1-carboxylate (1.4 g, crude) and Boc O (1.21 g, 5.58 mmol) in DCM (20 mL) was stirred at room temperature for 1 hour. Water was added and the organic layer was separated and purified on a silica gel column using 60% EA / PE to give the title compound (250 mg) as a colorless oil.

[0911] Analytical data: LC-MS: (ES, m / z) = 401 [M+23].

[0912] Step 7: Synthesis of tert-butyl (4-methoxypiperidin-4-yl)methylcarbamate:

[0913] 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 H₂ atmosphere 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.

[0914] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0915] Step 8: Synthesis of tert-butyl (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methylcarbamate:

[0916] 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 at 80° C. for 2 h. The mixture was concentrated and the residue was purified on preparative TLC (EtOAc:PE=1:1) to give the title compound (95 mg) as an off-white solid.

[0917] Analytical data: LC-MS: (ES, m / z) = 338 [M+1].

[0918] Example B63: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yloxy)ethanol

[0919]

[0920] 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-disilatridec-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 under vacuum to give 200 mg of the title compound as a colorless oil.

[0921] Analytical data: LC-MS: (ES, m / z) = 271 [M+1].

[0922] Example B64: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate

[0923]

[0924] Step 1: Synthesis of benzyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate:

[0925] At -78 ° C, to a solution of ACN (1.73 g, 42.1 mmol) contained in THF (80 mL) was added n-Buli (23.5 mL, 58.9 mmol, 2.5 M). The mixture was stirred at -78 ° C for 30 minutes. Then a solution of 4-oxopiperidine-1-carboxylic acid benzyl ester (10.3 g, 44.2 mmol) contained 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 under vacuum. The residue was purified by Flash Column Silica-CS (PE: EA = 10: 1 to 3: 2). This produced 1 g (90.9%) of the title compound as a light yellow solid.

[0926] Analytical data: LC-MS: (ES, m / z) = 275 [M+1].

[0927] Step 2: Synthesis of benzyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate:

[0928] At 0 ° C, NaH (216 mg, 5.45 mmol) was added to a solution of 4- (cyanomethyl) -4-hydroxypiperidine -1- carboxylic acid benzyl ester (250 mg, 911 μmol) and iodomethane (283 mg, 2 mmol) in DMF (30 mL). The mixture was then stirred at room temperature for 13 hours. The mixture was quenched with H2O (4 mL), extracted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by Flash Column Silica-CS (PE: EA = 1: 1). This produced 940 mg of 4- (cyanomethyl) -4-methoxypiperidine -1- carboxylic acid benzyl ester as a light yellow gum.

[0929] Analytical data: LC-MS: (ES, m / z) = 311 [M+23].

[0930] Step 3: Synthesis of benzyl 4-(2-aminoethyl)-4-methoxypiperidine-1-carboxylate:

[0931] 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).

[0932] Analytical data: LC-MS: (ES, m / z) = 293 [M+1].

[0933] Step 4: Synthesis of benzyl 4-(2-(tert-butoxycarbonylamino)ethyl)-4-methoxypiperidine-1-carboxylate:

[0934] 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 under vacuum. The residue was purified by Flash Column Silica-CS (PE: EA = 10: 1 to 3: 2). This produced 900 mg (79.6%) of the title compound as a light yellow gum.

[0935] Analytical data: LC-MS: (ES, m / z) = 415 [M+23].

[0936] Step 5: Synthesis of tert-butyl 2-(4-methoxypiperidin-4-yl)ethylcarbamate:

[0937] 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 bed of celite, washed with MeOH (100 mL), and the filtrate was concentrated to give the crude product (250 mg) of the title compound, which was used directly in the next step.

[0938] Analytical data: LC-MS: (ES, m / z) = 259 [M+1].

[0939] Step 6: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate:

[0940] To a solution of tert-butyl N-[2-(4-methoxypiperidin-4-yl)ethyl]carbamate (260 mg, 1 mmol) in IPA (16 mL) was 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 under vacuum. The residue was purified by preparative TLC (DCM: MeOH = 10: 1). This produced 280 mg (79.7%) of the title compound as a light yellow solid.

[0941] Analytical data: LC-MS: (ES, m / z) = 352 [M+1].

[0942] Example B65: Synthesis of 1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0943]

[0944] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate:

[0945] At 0 ° C, NaH (175.12 mg, 7.297 mmol, 8 equivalents) was added to a mixture of (3R, 4S)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.912 mmol, 1 equivalent) and 2,2-dimethyloxirane (526.19 mg, 7.297 mmol, 8 equivalents) in DMF (5 mL). The resulting solution was stirred at room temperature overnight. The reaction was quenched by adding 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 light yellow oil.

[0946] Analytical data: LC-MS: (ES, m / z) = 292 [M+1].

[0947] Step 2: Synthesis of 1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol:

[0948] (3R, 4S) -3- fluoro- 4- (2- hydroxy -2- methylpropoxy) piperidine -1- tert-butyl carboxylate (100.00 mg, 0.343 mmol) is added to a solution of TFA (1 mL) contained in DCM (3 mL). The resulting solution is stirred at room temperature for 2 hours. The resulting mixture is concentrated under vacuum, and the residue is mixed with IPA (2 mL) containing 2- chloropyrimidine -4- amine (50 mg, 0.386 mmol, 1 equivalent) and TEA (117.16 mg, 1.158 mmol, 3 equivalents). The resulting solution is stirred at 100 ° C for 12 hours. The mixture is concentrated under vacuum and the residue is applied to a silica gel column with DCM / MeOH (15: 1). This produces 20 mg (18.22%) of the title compound as a light yellow oil.

[0949] Analytical data: LC-MS: (ES, m / z) = 285 [M+1].

[0950] Example B66: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0951]

[0952] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate:

[0953] NaH (262.68 mg, 10.946 mmol, 6 equivalents) was added to a solution of tert-butyl (3S, 4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (400.00 mg, 1.824 mmol, 1 equivalent) and 2,2-dimethyloxirane (1315.49 mg, 18.244 mmol, 10 equivalents) in DMF (20.00 mL). The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding 3 mL of water. The resulting solution was extracted with EA and concentrated under vacuum. This produced 200 mg (37.63%) of the title compound as a yellow oil.

[0954] Analytical data: LC-MS: (ES, m / z) = 292 [M+1].

[0955] Step 2: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol:

[0956] (3S, 4R) -3- fluoro- 4- (2- hydroxy -2- methylpropoxy) piperidine -1- tert-butyl formate (200.00 mg, 0.686 mmol, 1 equivalent) is added to DCM / TFA (8.00 mL / 4.00 mL). The resulting solution is stirred at room temperature for 2 hours. The resulting mixture is concentrated under vacuum. At 100 ° C, the residue is mixed with IPA (3 mL) containing 2- chloropyrimidine -4- amine (67.74 mg, 0.523 mmol, 1 equivalent) and TEA (158.73 mg, 1.569 mmol, 3.0 equivalents) and stirred for 3 hours. The solvent is removed and the residue is applied to a silica gel column with DCM / MeOH (15: 1). This produces 55 mg (37%) of the title compound as a light yellow oil.

[0957] Analytical data: LC-MS: (ES, m / z) = 285 [M+1].

[0958] Example B67: Synthesis of 2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine

[0959]

[0960] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate:

[0961] At 0 DEG C, NaH (218mg, 9.08mmol) is added to DMF (20mL, 22.6mmol) containing (3R, 4S) -3- fluoro- 4- hydroxypiperidine -1- carboxylic acid tert-butyl ester (1000mg, 4.56mmol). After stirring for 20 minutes, CD3I (3.30g, 22.8mmol) is added, and the solution is stirred at room temperature for 16 hours. The reaction is quenched by adding 5mL water. The solid is filtered out. The resulting solution is extracted with EA, washed with brine and concentrated. This produces 1140mg of the title compound as a light yellow oil.

[0962] Step 2: Synthesis of 2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine:

[0963] TFA (2mL) is added to DCM (6mL) containing (3R, 4S) -3- fluoro- 4- (methoxy -d3) piperidine -1- tert-butyl formate (1140mg, 4.82mmol) and the solution is stirred at room temperature for 2 hours. The mixture is concentrated under vacuum and the residue is dissolved in IPA (20mL), then dissolved in 2- chloropyrimidine -4- amine (496mg, 3.83mmol) and TEA (0.6mL). The mixture is stirred at 100 ° C overnight. The mixture is concentrated and the residue is purified by FLASH (5% MeOH / EA) to obtain 425mg of the title compound as a light yellow solid.

[0964] Analytical data: LC-MS: (ES, m / z) = 230 [M+1].

[0965] Example B68: Synthesis of 2-((3R,4S)-4-cyclopropyloxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

[0966]

[0967] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(vinyloxy)piperidine-1-carboxylate:

[0968] A mixture of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1 eq), vinyl acetate (515 mg, 5.99 mmol, 5 eq), Ir(COD)Cl (80.3 mg, 120 μmol, 0.1 eq) and NaCO (127 mg, 1.20 mmol, 1 eq) in toluene (1.5 mL) was heated to 100 ° C for 3 hours. After cooling down 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.

[0969] Step 2: Synthesis of 2-((3R,4S)-4-cyclopropyloxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine:

[0970] 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-(vinyloxy)-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. TEA (404 mg, 4.00 mmol, 5 equiv), 2-chloropyrimidine-4-amine (72.5 mg, 560 μmol, 0.7 equiv) and IPA (2 mL) were added to the residue. The mixture was heated to 100 ° C for 18 hours. After cooling down to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (DCM / MeOH = 25: 1) to give 2- [(3R, 4S) -4- cyclopropyloxy-3-fluoropiperidin-1-yl] pyrimidin-4-amine (80 mg, 40%) as a white solid.

[0971] Analyze the data: 1H-NMR (400 MHz, 3d-CD3Cl) δ ppm 7.94(d,1H,J=5.6Hz),5.78(d,1H,J=5.6Hz),4.83(ddt,1H,J=48.3,5.7,2.7H z),4.68-4.59(m,1H),4.58(s,2H),4.32(dddd,1H,J=13.4,5.7,4.0,1.5Hz), 3.84-3.71(m,1H),3.61-3.42(m,2H),3.35(dddd,1H,J=13.2,9.3,3.6,1.7Hz ),2.05-1.91(m,1H),1.89-1.74(m,1H),0.72-0.63(m,2H),0.58-0.49(m,2H).

[0972] Example B69: Synthesis of racemic 2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol

[0973]

[0974] Step 1: Synthesis of racemic tert-butyl 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,3-difluoropiperidine-1-carboxylate:

[0975] At 0 ° C, to a solution of racemic -3,3-difluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3g, 2.6mmol) in DMF (20mL) was added NaH (1.25g, 31.5mmol, 60%). The mixture was stirred at 0 ° C for 0.5 hours. Then (2-bromoethoxy) (tert-butyl) dimethylsilane (9.04g, 37.8mmol) was added. The mixture was stirred at room temperature for 13 hours. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated under vacuum. The residue was purified by Flash Column Silica-CS (PE: EA = 1: 0 to 10: 1). This produced 3.8g (76.3%) of the title compound as a yellow oil.

[0976] Step 2: Synthesis of racemic 2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol:

[0977] At 0 ° C, HCl / dioxane (20 mL) was added to a solution of racemic -4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (3.7 g, 9.35 mmol) in DCM (10 mL). The mixture was then stirred at room temperature for 2 hours. The reaction was concentrated and the residue was dissolved in IPA (4 mL), followed by dissolution in TEA (278 mg, 2.75 mmol) and 2-chloropyrimidine-4-amine (84.7 mg, 654 μmol). 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 under vacuum. The residue was purified by Flash Column Silica-CS (DCM:MeOH=10: 1). This produced 2 g (79.6%) of the title compound as a light yellow solid.

[0978] Analytical data: LC-MS: (ES, m / z) = 275 [M+1].

[0979] Example B70: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine

[0980]

[0981] Step 1: Synthesis of 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine:

[0982] Tert-butyl(chloro)dimethylsilane (5.98 g, 39.7 mmol) was added portionwise to a DMF solution containing 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) at 0 ° C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA (500 mL) and washed with brine, the organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography with PE:EA=2:1 to give 7.5 g of the title compound as a colorless oil.

[0983] Analytical data: LC-MS: (ES, m / z) = 341 [M+1].

[0984] 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:

[0985] 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 under vacuum. The residue was purified by flash chromatography with PE:EA=5:1 to give 10.0 g of the title compound as a colorless oil.

[0986] Analytical data: LC-MS: (ES, m / z) = 601 [M+1].

[0987] Step 3: Synthesis of (3S,4R)-1-(4-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol:

[0988] 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-disilatridec-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 with PE:EA=4:1 to give 6.5 g of the title compound as a colorless oil.

[0989] Analytical data: LC-MS: (ES, m / z) = 487 [M+1].

[0990] 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:

[0991] At 0 ° C, NaH (310 mg, 7.75 mmol) was added to DMF containing 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-disilatridecane-7-yl) pyrimidine (2 g, 3.10 mmol). 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 under vacuum. 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.

[0992] Analytical data: LC-MS: (ES, m / z) = 645 [M+1].

[0993] 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:

[0994] At room temperature, TBAF (10 mL, 10 mmol) was added to a THF (10 mL) solution of 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-disilatridecane-7-yl)pyrimidine (600 mg, 930 μmol). The mixture was stirred at reflux for 1 hour. The mixture was concentrated under vacuum. The residue was purified by silica gel column with PE:EA=2:1. This produced 200 mg of the title compound as a colorless oil.

[0995] Analytical data: LC-MS: (ES, m / z) = 531 [M+1].

[0996] 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:

[0997] (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (456 mg, 2.26 mmol) was added dropwise to a mixture of PPh (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-disilatridec-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 under vacuum. The residue was purified by preparative TLC with PE:EA=5:1 to give 280 mg of the title compound as a yellow solid.

[0998] Analytical data: LC-MS: (ES, m / z) = 556 [M+1].

[0999] Step 7: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine:

[1000] At room temperature, 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-disilatridec-7-yl)pyrimidine (260 mg, 467 μmol) in EtOH. The mixture was stirred at reflux for 1 hour. The mixture was concentrated under vacuum to give 120 mg of 2-[(3S, 4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl]pyrimidin-4-amine as a colorless oil.

[1001] Analytical data: LC-MS: (ES, m / z) = 296 [M+1].

[1002] Example B71: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol

[1003]

[1004] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(oxirane-2-ylmethoxy)piperidine-1-carboxylate:

[1005] At 0 ° C, NaH (109 mg, 4.56 mmol) was added to a solution of tert-butyl (3S, 4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.28 mmol) in DMF, 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 layer was concentrated and the crude product 600 mg (95%) of the title compound was used as a brown solid.

[1006] Analytical data: LC-MS: (ES, m / z) = 220 [M+1-56].

[1007] Step 2: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylate:

[1008] To a solution of tert-butyl (3S,4R)-3-fluoro-4-[(oxirane-2-yl)methoxy]piperidine-1-carboxylate (750 mg, 2.72 mmol) in THF was added LiBHEt (1 M in THF) at 0°C under an 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.

[1009] Analytical data: LC-MS: (ES, m / z) = 222 [M+1-56].

[1010] Step 3: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol:

[1011] At room temperature, HCl (4M in dioxane solution) is added to a solution of (3S, 4R)-3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylic acid tert-butyl ester (600 mg, 2.16 mmol) contained in DCM. The mixture is stirred at room temperature for 2 hours. The resulting mixture is concentrated under vacuum. The residue is dissolved in DMSO (3 mL), then dissolved in 2-chloropyrimidine-4-amine (380 mg, 2.93 mmol) and DIEA (1.13 g, 8.79 mmol). The mixture is stirred at 120 ° C for 2 hours. The mixture is extracted with EA and water. The organic layers are combined and dried over Na2SO4. The organic layer is concentrated and the residue is purified by preparative TLC with DCM / MeOH (15: 1). This produces 210 mg of the title compound as a yellow solid.

[1012] Analytical data: LC-MS: (ES, m / z) = 271 [M+1].

[1013] Example B72: Synthesis of 2-((3S,4R)-4-cyclopropyloxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

[1014]

[1015] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(vinyloxy)piperidine-1-carboxylate:

[1016] A mixture of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1 eq), ethyl acetate (515 mg, 5.99 mmol, 5 eq), Ir(COD)Cl (80.3 mg, 120 μmol, 0.1 eq) and NaCO (127 mg, 1.20 mmol, 1 eq) in toluene (1.5 mL) was heated to 100 ° C for 3 hours. After cooling down 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.

[1017] Step 2: Synthesis of 2-((3S,4R)-4-cyclopropyloxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine:

[1018] To a solution of diiodomethane (1.17 g, 4.39 mmol, 5.5 equiv) in DCM (2 mL) at 0°C was added diethylzinc (3.59 mL, 3.59 mmol, 4.5 equiv, 1 M in heptane). The mixture was stirred at 0°C for 1 hour. A solution of tert-butyl (3S,4R)-4-(vinyloxy)-3-fluoropiperidine-1-carboxylate (196 mg, 800 μmol, 1 equiv) in DCM (2 mL) was added. The reaction was allowed to proceed 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 were added triethylamine (404 mg, 4.00 mmol, 5 equiv), 2-chloropyrimidin-4-amine (72.5 mg, 560 μmol, 0.7 equiv), and IPA (2 mL). The mixture was heated to 100° C. for 18 hours. After cooling down 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.

[1019] Analyze the data: 1H-NMR(400MHz,3d-CD3Cl)δppm 7.94(d,1H,J=5.6Hz), 5.78(d,1H,J=5.6Hz), 4.84(ddd,1H,J=48.1,5.8,2.8Hz), 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=13.3,9.4,3.6,1.7Hz),1.98(dddd,1H,J=13.4,6.8,5.4 ,3.2Hz),1.83(ddd,1H,J=9.6,7.8,4.6Hz),0.72-0.64(m,2H),0.57-0.47(m,2H).

[1020] Example B73: Synthesis of 3-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazine-5-amine

[1021]

[1022] 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, concentrated, and the residue was purified by preparative TLC with PE / EA (5:1). This yielded 40 mg (39%) of the title compound as a yellow solid.

[1023] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[1024] Example B74: Synthesis of rac-(all cis)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxypiperidin-3-ol

[1025]

[1026] Step 1: Synthesis of racemic-trans-6-(hydroxymethyl)-cis-2,2-dimethyldihydrofuran[3,4-d][1,3]dioxolane-4(3aH)-one:

[1027] Into a 100 mL round-bottom flask was placed racemic-cis-3,4-dihydroxy-trans-5-(hydroxymethyl)tetrahydrofuran-2-one (3 g, 20.2 mmol, 1 eq), TsOH HO (385 mg, 2.03 mmol, 0.100 eq) and anhydrous acetone (60 mL), and then 2,2-dimethoxypropane (2.53 g, 24.3 mmol, 1.20 eq) was added at 0 ° C for 5 minutes. The resulting solution was stirred at 25 ° C for 2 hours. Sodium bicarbonate solid (255 mg, 3.04 mmol, 0.150 eq) was then added to the mixture and stirred for 5 minutes. The reaction mixture was filtered and concentrated under vacuum. This produced 3.8 g (100%) of the title compound as a white solid.

[1028] Step 2: Synthesis of racemic-((cis)-2,2-dimethyl-6-oxotetrahydrofuran[3,4-d][1,3]dioxolane-trans-4-yl)methanesulfonic acid methyl ester:

[1029] Into a 100mL round-bottom flask was placed racemic-trans-6-(hydroxymethyl)-cis-2,2-dimethyldihydrofuran [3,4-d] [1,3] dioxolane-4 (3aH) -one (3.81g, 20.3mmol, 1 equivalent) and TEA (4.10g, 40.5mmol, 2 equivalents) and THF (70mL), and then MsCl (2.78g, 24.3mmol, 1.20 equivalents) was added dropwise at 0°C. The resulting solution was stirred at 25°C for 1 hour. The mixture was diluted with DCM (20mL) and washed with saturated NH4Cl aqueous solution (20mL×3). The organic layer was dried over MgSO4, filtered and concentrated under vacuum. This produced 5.0g (93%) of the title compound as an orange oil, which was used directly in the next step without further purification.

[1030] Analytical data: LC-MS: (ES, m / z): RT = 0.274 min, LCMS: m / z = 267 [M+1], 1 H NMR (400MHz, CDCl3) δ4.89-4.73(m,3H),4.54-4.41(m,2H),3.06(s,3H),1.49(s,3H),1.41(s,3H).

[1031] Step 3: Synthesis of racemic-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuran[3,4-d][1,3]dioxolane-4(3aH)-one:

[1032] Into a 100 mL round-bottom flask was placed rac-((cis)-2,2-dimethyl-6-oxotetrahydrofuran[3,4-d][1,3]dioxolane-trans-4-yl)methanesulfonic acid methyl ester (5.00 g, 18.8 mmol, 1 equivalent), NaN3 (3.66 g, 56.3 mmol, 3 equivalents) and DMF (60 mL). The resulting solution was stirred in an oil bath at 75 ° C for 3 hours. The reaction mixture was diluted with EA (150 mL) and washed with brine (50 mL × 3). The collected organic phase was dried over Na2SO4, filtered and concentrated under vacuum. This produced 3.2 g (80%) of the title compound as a red oil.

[1033] Analyze the data: 1 H NMR (400MHz, CDCl3) δ4.85 (d, J = 5.6Hz, 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).

[1034] Step 4: Synthesis of racemic-(all cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolano[4,5-c]pyridin-4(3aH)-one:

[1035] Under N2 atmosphere, into a 100mL round-bottom flask was placed racemic-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuran [3,4-d] [1,3] dioxolane-4 (3aH) -one (3.20g, 15.0mmol, 1 equivalent), Pd / C (300mg, 10% purity) and MeOH (30mL). The resulting solution was stirred at 25 ° C under H2 (50psi) atmosphere for 3 hours. The mixture was filtered and concentrated under vacuum. This produced 2.7g (93%) of the title compound as a colorless oil.

[1036] Analyze the data: 1 H NMR (400MHz, CDCl3) δ7.03-6.83(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).

[1037] Step 5: Synthesis of racemic-(all cis)-2,2-dimethylhexahydro-[1,3]dioxolano[4,5-c]pyridin-7-ol:

[1038] Into a 100mL round-bottom flask was placed THF (50mL) containing racemic -(all cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolane and [4,5-c]pyridine-4 (3aH) -one (2.55g, 13.6mmol, 1 equivalent), LiAlH4 (2.58g, 68.1mmol, 5.00 equivalents) and stirred at 70°C under N2 atmosphere for 6 hours. The reaction mixture was quenched with H2O (3mL). The reaction mixture was diluted with EA / MeOH (100mL, v / v=20 / 1), dried over Na2SO4, filtered and concentrated under vacuum. This produced 2.4g (crude) of the title compound as a white solid.

[1039] Analytical data: LC-MS: (ES, m / z): RT = 0.086 min, LCMS: m / z = 174 [M+1].

[1040] Step 6: Synthesis of rac-(all cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolano[4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester

[1041] Into a 100 mL round-bottom flask was placed rac-(all cis)-2,2-dimethylhexahydro-[1,3]dioxolano[4,5-c]pyridin-7-ol (2.36 g, 13.6 mmol, 1 eq), NaHCO 3 (3.43 g, 40.9 mmol, 3 eq), CbzCl (2.56 g, 15.0 mmol, 1.10 eq) and THF (50 mL). The resulting solution was stirred at 50 ° C in an oil bath for 2 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO 2, PE / EA = 3 / 1 and DCM / MeOH = 20 / 1). This produced 2.3 g (53%) of the title compound as a white solid.

[1042] Analytical data: LC-MS: (ES, m / z): RT = 0.665 min, LCMS: m / z = 308 [M+1], 1 H NMR (400MHz, CDCl3) δ7.41-7.30(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).

[1043] Step 7: Synthesis of racemic-(all cis)-7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolano[4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester:

[1044] Into a 50mL round-bottom flask was placed racemic-(all cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolane and [4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester (500mg, 1.63mmol, 1 equivalent) and anhydrous DCM (8mL), and DAST (786mg, 4.88mmol, 3 equivalents) was added at 0 to 10°C. The resulting solution was stirred at 0 to 10°C for 1 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution until pH was about 8 and extracted with DCM (20mL×3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum, and the residue was purified by column chromatography (SiO2, PE / EA=3 / 1 and EA / MeOH=20 / 1). This produced 0.38g (75%) of the title compound as a colorless oil.

[1045] Analytical data: LC-MS: (ES, m / z): RT = 0.741 min, LCMS: m / z = 310 [M+1]. 1 H NMR (400MHz, CDCl3) δ7.38-7.32(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).

[1046] Step 8: Synthesis of racemic-(all cis)-3-fluoro-4,5-dihydroxypiperidine-1-carboxylic acid benzyl ester:

[1047] Into a 50 mL round-bottom flask was placed racemic-(all cis)-7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolano[4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester (383 mg, 1.24 mmol, 1 equivalent) and HCl / MeOH (10.1 mL, 32.6 equivalents, 4 mol / L). The resulting solution was stirred at 25 ° C for 2 hours. The mixture was concentrated under vacuum. This produced 0.28 g (84%) of the title compound as a white solid.

[1048] Analyze the data: 1 H NMR (400MHz, CDCl3) δ7.42-7.31(m,5H),5.16(s,2H),4.73-4.52(m,1H),4.02-3.51(m,6H).

[1049] Step 9: Synthesis of racemic (all cis)-3-fluoro-5-hydroxy-4-methoxypiperidine-1-carboxylic acid benzyl ester and (3R,4S,5S)-3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylic acid benzyl ester:

[1050] Into a 25 mL round-bottom flask was placed rac-(all cis)-3-fluoro-4,5-dihydroxypiperidine-1-carboxylic acid benzyl ester (110 mg, 409 μmol, 1 eq), Ag2O (94.7 mg, 409 μmol, 1 eq), MeI (145 mg, 1.02 mmol, 2.50 eq) and DMF (3 mL). The resulting solution was stirred at 25 ° C for 24 hours. The mixture was filtered, diluted with EA (30 mL) and washed with brine (30 mL × 3). The collected organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC; mobile phase: water (10 mmol / L NH4HCO3) and ACN (18.0% ACN increased to 38.0% in 10 minutes); detector, UV 254 / 220 nm. This produced 20 mg (17%) of the title compound as a colorless oil.

[1051] Analytical data: LC-MS: (ES, m / z): RT = 0.689 min, LCMS: m / z = 284 [M+1], 1 H NMR (400 MHz, CDCl3) 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). And 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]. 1 H NMR (400MHz, 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).

[1052] Step 10: Synthesis of racemic-(all cis)-5-fluoro-4-methoxypiperidin-3-ol:

[1053] Into a 25mL round-bottom flask was placed racemic-(all cis)-3-fluoro-5-hydroxy-4-methoxypiperidine-1-benzyl carboxylate and racemic-(all cis)-3-fluoro-4-hydroxy-5-methoxypiperidine-1-benzyl carboxylate (5.00 mg, 17.7 μmol, 1 equivalent), Pd / C (5 mg, 10% purity) and THF (1 mL). The resulting solution was stirred at 25 ° C under H (15 psi) for 2 hours. The mixture was filtered and concentrated under vacuum. This produced 2.6 mg (100%) of the title compound as a yellow solid.

[1054] Step 11: Synthesis of racemic-(all cis)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxypiperidin-3-ol:

[1055] Into a 250 mL round-bottom flask was placed 2-chloropyrimidin-4-amine (2.28 mg, 17.6 μmol, 1 equivalent), racemic-(all cis)-5-fluoro-4-methoxy-piperidin-3-ol (2.63 mg, 17.6 μmol, 1 equivalent), DIEA (4.56 mg, 35.3 μmol, 2 equivalents) and DMSO (1 mL). The resulting solution was stirred at 100 ° C for 12 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by silica gel preparative TLC (PE: EA = 1: 2). This produced 3.5 mg (81%) of the title compound.

[1056] Analytical data: LC-MS: (ES, m / z): RT = 0.077 min, LCMS: m / z = 243 [M+1].

[1057] Example B75: Synthesis of racemic-(all cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol:

[1058]

[1059] Step 1: Synthesis of racemic-(all cis)-3-fluoro-5-methoxypiperidin-4-ol:

[1060] Into a 25 mL round-bottom flask was placed racemic-(all cis)-3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylic acid benzyl ester (50.0 mg, 176 μmol, 1 equivalent), Pd / C (15.0 mg, 10% purity) and THF (3 mL). The resulting solution was stirred at 25 ° C under H (15 psi) for 2 hours. The reaction was filtered and concentrated under vacuum to give the title compound. This produced 28 mg (100%) of the title compound as a colorless oil.

[1061] Analyze the data: 1H NMR (400MHz, CDCl3) δ7.03-6.83(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).

[1062] Step 2: Synthesis of racemic-(all cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol:

[1063] Into a 25 mL round-bottom flask was placed rac-(all cis)-3-fluoro-5-methoxypiperidin-4-ol (28.0 mg, 188 μmol, 1 eq), 2-chloropyrimidin-4-amine (36.5 mg, 282 μmol, 1.50 eq), DIEA (60.6 mg, 469 μmol, 2.50 eq), CsF (28.5 mg, 188 μmol, 1 eq), and DMSO (1 mL). The resulting solution was stirred at 100° C. for 36 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC; mobile phase: water (10 mmol / L NH4HCO3) and ACN (0% ACN increased to 20.0% over 10 minutes); detector: UV 254 / 220 nm. This yielded 15 mg (33%) of the title compound as a yellow solid.

[1064] Analyze the data: 1 H NMR(400MHz, CDCl3)7.93(d,J=5.6Hz,1H),5.79(d,J=5.6Hz,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).

[1065] Example B76: Synthesis of rac-2-((all cis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine

[1066]

[1067] Step I: Synthesis of racemic-(3S,4R,5R)-3-fluoro-4,5-dimethoxypiperidine:

[1068] Into a 25 mL round-bottom flask was placed rac-(all cis)-3-fluoro-4,5-dimethoxy-piperidine-1-carboxylic acid benzyl ester (generated from overalkylation of 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 at 25° C. under an atmosphere of H (15 psi) for 2 hours. The mixture was filtered and concentrated under vacuum. This yielded 16 mg (100%) of the title compound as a colorless oil.

[1069] Step 2: Synthesis of racemic-2-((all cis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine:

[1070] A 25 mL round-bottom flask was charged with rac-(all cis)-3-fluoro-4,5-dimethoxy-piperidine (16 mg, 98.1 μmol, 1 eq), 2-chloropyrimidin-4-amine (25.4 mg, 196 μmol, 2 eq), DIEA (38.0 mg, 294 μmol, 51.2 μL, 3 eq), CsF (29.8 mg, 196 μmol, 2 eq), 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 H O (5 mL x 3). The collected aqueous phase was concentrated under vacuum. The residue was purified by preparative HPLC using water (10 mmol / L NH HCO ) and ACN (0% ACN increased to 30.0% over 10 min); detector: UV 254 / 220 nm. This resulted in 8.0 mg (32%) of the title compound as a colorless oil.

[1071] Analytical data: LC-MS: (ES, m / z): RT = 1.141 min, LCMS: m / z = 257 [M+1].

[1072] Example B77: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol:

[1073]

[1074] Step 1: Synthesis of racemic 3,3-difluoro-5-hydroxy-4-methoxy-piperidine-1-carboxylic acid benzyl ester:

[1075] To a solution of rac-3,3-difluoro-4,5-dihydroxy-piperidine-1-carboxylic acid benzyl ester (prepared as from Example 54, Step 2 (Boc protected), 170 mg, 591 μmol, 1 eq) and Ag O (137 mg, 591 μmol, 1 eq) in DMF (5 mL) was added MeI (210 mg, 1.48 mmol, 92.1 μL, 2.50 eq) dropwise and the mixture was stirred at 25° C. for 16 h while protecting from light. The mixture was diluted with water (60 mL) and extracted with EA (40 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na SO , filtered and concentrated under vacuum. The crude material was purified by preparative HPLC [column: Xtimate C18 150*40mm*10μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 31% to 51%, 10 minutes]. This resulted in 110 mg (61%) of the title compound as a colorless oil.

[1076] Analyze the data: 1 H NMR (400MHz, CDCl3) δ7.44-7.30(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 = 3.6Hz, 1H), 3.53-3.27 (m, 1H), 3.07-2.88 (m, 1H), 2.37 (s, 1H).

[1077] Step 2: Synthesis of racemic-5,5-difluoro-4-methoxy-piperidin-3-ol:

[1078] To a solution of racemic-3,3-difluoro-5-hydroxy-4-methoxy-piperidine-1-carboxylic acid benzyl ester (100 mg, 331 μmol, 1 equivalent) in THF (5 mL) was added Pd / C (10 mg, 10% purity) under N2. The mixture was stirred at 25 ° C under H2 (15 psi) for 1 hour. The mixture was filtered and the filtrate was concentrated. The reaction mixture was filtered and the filtrate was concentrated. This produced 50 mg (90%) of the title compound as a colorless oil, which was used directly in the next step.

[1079] Step 3: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol:

[1080] To a solution of rac-5,5-difluoro-4-methoxy-piperidin-3-ol (50.0 mg, 299 μmol, 1 eq) and DIEA (77.3 mg, 598 μmol, 2 eq) in DMSO (1 mL) was added 2-chloropyrimidin-4-amine (50.3 mg, 388 μmol, 1.30 eq), and the mixture was stirred at 120° C. for 16 hours. 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% over 10 minutes]. This yielded 25 mg (32%) of the title compound as a colorless oil.

[1081] Analytical data: 1H NMR (400 MHz, CD3OD) δ7.72 (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).

[1082] Example B78: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[1083]

[1084] Step 1: Synthesis of racemic-cis-1-(4-methylthiopyrimidin-2-yl)piperidine-3,4-diol:

[1085] To a solution of racemic-cis-piperidine-3,4-diol (0.500 g, 3.26 mmol, 1 equivalent, HCl salt) and DIEA (1.68 g, 13.0 mmol, 2.27 mL, 4.00 equivalents) in DMSO (5 mL) was added 2-chloro-4-methylsulfanyl-pyrimidine (784 mg, 4.88 mmol, 1.50 equivalents) and the mixture was stirred at 100 ° C for 16 hours. 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 Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA=2:1). This produced 0.68 g (96%) of the title compound as an off-white solid.

[1086] Analyze the data: 1H NMR (400MHz, CDCl3) δ7.95(d,J=5.2Hz,1H),6.42(d,J=5.2Hz,1H),4.24-4.17(m,1H),4.16-4.07(m,1H ),3.96-3.86(m,2H),3.73(dd,J=13.6,3.2Hz,1H),3.64-3.52(m,1H),2.50(s,3H),1.94-1.73(m,2H).

[1087] Step 2: Synthesis of racemic-cis-4-(2-methoxyethoxy)-1-(4-methylthiopyrimidin-2-yl)piperidin-3-ol:

[1088] To a solution of rac-cis-1-(4-methylthiopyrimidin-2-yl)piperidine-3,4-diol (470 mg, 1.95 mmol, 1 eq) and NaI (29.2 mg, 194 μmol, 0.100 eq) in ACN (10 mL) was added 2-methoxyethyl 4-methylbenzenesulfonate (897 mg, 3.90 mmol, 2 eq) and CsCO (1.90 g, 5.84 mmol, 3 eq), 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% to 25% over 9 min]. This yielded 0.18 g (30%) of the title compound as a yellow solid.

[1089] Analyze the data: 1 H NMR(400MHz, CDCl3) δ7.95(d,J=5.2Hz,1H),6.39(d,J=5.2Hz,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).

[1090] Step 3: Synthesis of racemic-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol:

[1091] To a solution of rac-cis-4-(2-methoxyethoxy)-1-(4-methylthiopyrimidin-2-yl)piperidin-3-ol (160 mg, 534 μmol, 1 eq) in THF (8 mL) and H₂O (2 mL) was added potassium peroxymonosulfate (1.64 g, 2.67 mmol, 5.00 eq), and the mixture was stirred at 25° C. for 1 hour. The mixture was washed with saturated aqueous Na₂SO₃ (20 mL) and extracted with EA (30 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (EA). This yielded 85 mg (48%) of the title compound as a colorless oil.

[1092] Analyze the data: 1 H NMR (400MHz, CDCl3) δ8.58(d,J=4.8Hz,1H),7.07(d,J=4.8Hz,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).

[1093] Step 4: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[1094] A solution of rac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol (80.0 mg, 241 μmol, 1 equivalent) in NH / THF (8 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated in vacuo. The crude material was purified by preparative HPLC [column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mM NH HCO)-ACN]; B%: 1% to 30% over 10 minutes]. This yielded 5.0 mg (7%) of the title compound as a mixture of enantiomers as a colorless oil.

[1095] Analyze the data: 1H NMR (400MHz, CDCl3) δ7.91(d,J=5.6Hz,1H),5.73(d,J=5.6Hz,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).

[1096] Example B79: Synthesis of trans-racemic (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[1097]

[1098] Step 1: Synthesis of racemic-trans-tert-butyl 3,4-dihydroxypiperidine-1-carboxylate:

[1099] To a solution of racemic tert-butyl 7-oxa-4-azabicyclo[4.1.0]heptane-4-carboxylate (2 g, 10.0 mmol, 1 equivalent) in dioxane (30 mL) was added a solution of KOH (1.13 g, 20.0 mmol, 2 equivalents) in water (15 mL) and the mixture was stirred at 100 ° C for 16 hours. 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 produced 2 g (90%) of the title compound as a colorless oil, which was used directly in the next step.

[1100] Step 2: Synthesis of (3S,4S)-piperidine-3,4-diol:

[1101] 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.

[1102] Step 3: Synthesis of racemic-trans-1-(4-methylthiopyrimidin-2-yl)piperidine-3,4-diol:

[1103] To a solution of rac-trans-piperidine-3,4-diol (1.20 g, 7.81 mmol, 1 eq., HCl salt) and DIEA (5.05 g, 39.1 mmol, 6.80 mL, 5.00 eq.) in DMSO (12 mL) was added 2-chloro-4-methylsulfanyl-pyrimidine (1.25 g, 7.81 mmol, 1 eq.), and the mixture was stirred at 100° C. for 16 hours. 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 yielded 1.30 g (69%) of the title compound as an off-white solid, which was used directly in the next step.

[1104] Step 4: Synthesis of racemic-trans-4-(2-methoxyethoxy)-1-(4-methylthiopyrimidin-2-yl)piperidin-3-ol:

[1105] To a solution of rac-trans-1-(4-methylthiopyrimidin-2-yl)piperidine-3,4-diol (700 mg, 2.90 mmol, 1 eq) and NaI (43.4 mg, 290 μmol, 0.100 eq) in ACN (10 mL) was added 2-methoxyethyl 4-methylbenzenesulfonate (1.34 g, 5.80 mmol, 2 eq) and CsCO (2.84 g, 8.70 mmol, 3 eq). The mixture was stirred at 80°C for 16 hours. 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% to 50%, 11.5 minutes]. This resulted in 300 mg (34%) of the title compound as a yellow solid.

[1106] Analyze the data: 1 H NMR (400MHz, CDCl3) δ8.00-7.93(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).

[1107] Step 5: Synthesis of racemic-trans-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol:

[1108] To a solution of rac-trans-4-(2-methoxyethoxy)-1-(4-methylthiopyrimidin-2-yl)piperidin-3-ol (300 mg, 1 mmol, 1 eq) in THF (10 mL) and H₂O (3 mL) was added potassium peroxymonosulfate (1.85 g, 3.01 mmol, 3 eq), and the mixture was stirred at 25° C. for 3 h. The mixture was washed with saturated aqueous Na₂SO₃ (60 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (EA). This yielded 120 mg (36%) of the title compound as a colorless oil.

[1109] Step 6: Synthesis of racemic-trans-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[1110] A solution of rac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol (120 mg, 362 μmol, 1 equivalent) in NH / THF (8 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated in vacuo. The crude material was purified by preparative HPLC [column: Xtimate C18 150*40 mm*10 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 10% to 20% over 10 minutes]. This yielded 10.0 mg (10%) of the title compound as a mixture of enantiomers as a colorless oil.

[1111] Analyze the data: 1 H NMR (400MHz, CDCl3) δ7.90(d,J=5.6Hz,1H),5.74(d,J=5.6Hz,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=13.2,9.6Hz,1H),2.03-2(m,1H),1.53-1.43(m,1H).

[1112] Example C1: Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine

[1113]

[1114] Step 1: Synthesis of 6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one:

[1115] 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 dried under vacuum to give the title compound (60 g, 70%) as a light yellow solid.

[1116] 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).

[1117] Step 2: Synthesis of 1,6-dichloro-4-iodo-2,7-naphthyridine:

[1118] A mixture of 6-chloro-4-iodo-1,2-dihydro-2,7-naphthyridine-1-one (60 g, 0.196 mol) in POCl (320 mL) was stirred at 100 ° C for 1.5 hours. LCMS showed that the starting material was consumed. The mixture was concentrated and neutralized with a cooled saturated aqueous NaHCO solution. The mixture was extracted with EA 3*300 mL. The combined organic layers were dried over Na SO, filtered and concentrated under reduced pressure to give 1,6-dichloro-4-iodo-2,7-naphthyridine 53 g (84%) as a yellow solid.

[1119] Analytical data: LC-MS: (ES, m / z) = 325 [M+1].

[1120] Step 3: Synthesis of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine:

[1121] 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 showed that the reaction was complete. The mixture was cooled to room temperature and diluted with 200 mL of water. The resulting solution was extracted with 2×300 mL of EA 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 under vacuum. The product was purified by chromatography using EA:PE (1:10). This resulted in 15 g (68.1%) of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine as a white solid.

[1122] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[1123] Step 4: Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine:

[1124] 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 PtO2 (5 g, 22 mmol). The resulting mixture was stirred at 25 ° C under an H2 atmosphere for 24 hours. The solid was filtered off. The filtrate was concentrated under vacuum. The residue was purified by chromatography (EA:PE=1:8) to give 3 g (75%) of 1,6-dichloro-4-(prop-2-yl)-2,7-naphthyridine as a white solid.

[1125] 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).

[1126] Example C2: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine

[1127]

[1128] Step 1: Synthesis of 5-bromo-N-tert-butyl-2-chloroisonicotinamide:

[1129] Into a 100 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere, 5-bromo-2-chloropyridine-4-carboxylic acid (4 g, 16.9 mmol) in DMF (30 mL), 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) were placed. The resulting solution was stirred at room temperature overnight. Water was added to the resulting solution and the suspension was extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by FLASH using PE / EA (2:1). This produced 3 g (60.9%) of 5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide as a white solid.

[1130] 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).

[1131] Step 2: Synthesis of (E)-N-tert-butyl-2-chloro-5-(2-ethoxyvinyl)isonicotinamide:

[1132] Into a 100 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was placed 5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide (2 g, 6.85 mmol) in dioxane (30 mL), H₂O (6 mL), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.49 g, 7.53 mmol), Cs₂CO₃ (4.46 g, 13.7 mmol), and Pd(dppf)Cl₂ (501 mg, 685 μmol). The resulting solution was stirred at 80° C. for 2 hours. The resulting solution was diluted with water and extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by FLASH using PE / EA (2:1). This resulted in 1.2 g (62.1%) of N-tert-butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyridine-4-carboxamide as a yellow solid.

[1133] Analytical 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).

[1134] Step 3: Synthesis of 7-chloro-2,6-naphthyridin-1(2H)-one:

[1135] Into a 20 mL vial was placed N-tert-butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyridine-4-carboxamide (1.2 g, 4.24 mmol) in TFA (20 mL). The resulting solution was stirred at 100 ° C overnight. The resulting mixture was concentrated under vacuum. This produced 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.

[1136] Analytical data: LC-MS: (ES, m / z) = 181 [M+1].

[1137] Step 4: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1(2H)-one:

[1138] Into a 250 mL round-bottom flask was placed 7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (3 g, 16.6 mmol) in DCM (40 mL) and NBS (3.54 g, 19.9 mmol). The resulting solution was stirred at room temperature for 1 hour. The solid was collected by filtration. This produced 3 g (69.7%) of the title compound as a white solid.

[1139] 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).

[1140] Step 5: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate:

[1141] Into a 50mL three-necked flask is placed DCM (15mL) and TEA (777mg, 7.70mmol) containing 4-bromo-7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (1g, 3.85mmol). The resulting mixture is cooled to -78 ° C, and then Tf2O (4.34g, 15.4mmol) is added dropwise over 10 minutes. The resulting solution is stirred at -78 ° C for 0.5 hours. The mixture is then warmed to room temperature and stirred at this temperature for 0.5 hours. The reaction is then quenched by adding 2mL water / ice, extracted with DCM, and the organic layers are then combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue is applied to a silica gel column with EA / PE (0 to 10%). This produces 1g (66.6%) of the title compound as a white solid.

[1142] Analytical data: LC-MS: (ES, m / z) = 393 [M+1]; 1 H NMR (300MHz, DMSO-d6) δ9.47 (s, 1H), 8.78 (s, 1H), 8.14 (d, 1H, J = 0.9Hz).

[1143] Step 6: Synthesis of 4-bromo-7-chloro-1-iodo-2,6-naphthyridine:

[1144] Into a 50mL three-necked flask is placed ACN (9mL) and NaI (952mg, 6.35mmol) containing 4-bromo-7-chloro-2,6-naphthyridine-1-ester of trifluoromethanesulfonic acid (500mg, 1.27mmol). The resulting mixture is cooled to 0 ° C and added dropwise over 10 minutes containing trifluoromethanesulfonic acid (381mg, 2.54mmol) ACN (1mL). The mixture is then stirred at room temperature for 1.5 hours. Afterwards, the resulting solution is extracted with EA, the organic layers are then combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This produces 500mg of the title compound as a black solid. The crude compound is used directly in the next step without further purification.

[1145] Analytical data: LC-MS: (ES, m / z) = 369 [M+1].

[1146] Step 7: Synthesis of 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine:

[1147] Into a 25 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere were placed 4-bromo-7-chloro-1-iodo-2,6-naphthyridine (500 mg, 1.35 mmol), 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) added to dioxane (5 mL) and H2O (1 mL). The resulting solution was stirred at 80 ° C for 2 hours. The resulting solution was extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC with PE / EA (8: 1). This produced 200 mg (52.3%) of the title compound as a light yellow oil.

[1148] Analytical data: LC-MS: (ES, m / z) = 285 [M+1].

[1149] Step 8: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine:

[1150] Into a 25 mL round-bottom flask purged and maintained with an inert hydrogen atmosphere was placed EA (6 mL) containing 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine (160 mg, 564 μmol) and PtO2 (166 mg, 733 μmol). The resulting solution was stirred at room temperature for 3 hours. The solid was filtered off. The resulting mixture was concentrated under vacuum. This produced 100 mg (62.1%) of the title compound as a yellow solid.

[1151] Analytical data: LC-MS: (ES, m / z) = 287 [M+1].

[1152] Example C3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine

[1153]

[1154] Step 1: Synthesis of 6-chloro-4-isobutyrylnicotinic acid:

[1155] At -78 ° C, TMP (40.1 g, 285 mmol) was added dropwise to a stirred solution of n-BuLi (100 mL) in THF. The mixture was allowed to warm to 0 ° C and stirred for 1 hour, and then cooled 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 hours. N-methoxy-N, 2-dimethylpropionamide (37.3 g 285 mmol) was then added and the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was quenched by NH4Cl aqueous solution and the pH was adjusted to 5 to 6 with citric acid, then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the target product in a yellow oily form without further purification.

[1156] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[1157] Step 2: Synthesis of 7-chloro-1-isopropylpyrido[3,4-d]pyridazin-4(3H)-one:

[1158] To a solution of 6-chloro-4-(2-methylpropanoyl)pyridine-3-carboxylic acid (11 g, 48.3 mmol) in IPA was added NH2NH2.HO (3.62 g, 72.4 mmol), and the mixture was stirred at 70°C for 3 hours. The mixture was filtered and the solid was collected. The filtrate was concentrated to 10 mL and then filtered. The solids were combined to give the desired product (6 g, crude) as a yellow solid.

[1159] Analytical data: LC-MS: (ES, m / z) = 224 [M+1].

[1160] Step 3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine:

[1161] To a solution of POCl3 (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 without further purification.

[1162] Analytical data: LC-MS: (ES, m / z) = 242 [M+1].

[1163] Example C4: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline

[1164]

[1165] Step 1: Synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate:

[1166] 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 naturally warmed to room temperature and stirred at room temperature for 1 hour. The mixture was concentrated under vacuum. The residue was purified by silica gel column using PE: EA = 5: 1 to give 18 g (85%) of the title compound as a white solid.

[1167] Analytical data: LC-MS: (ES, m / z) = 392 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ9.46 (d, 1H, J = 0.8Hz), 8.20 (d, 1H, J = 8.3Hz), 8.02 (d, 1H, J = 8.4Hz), 7.93 (d, 1H, J = 0.7Hz).

[1168] Step 2: Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline:

[1169] A mixture of KCO (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)Cl.CHCl (2.83 g, 3.48 mmol) in dioxane / H2O (200 / 20 mL) was stirred at 45°C for 3 hours. The mixture was diluted with 500 mL of EA and washed with brine (200 mL*2). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using PE:EA = 20:1 to give 8.0 g (67%) of the title compound as an off-white solid.

[1170] Analytical data: LC-MS: (ES, m / z) = 282 [M+1].

[1171] Step 3: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline:

[1172] Under a H2 balloon, PtO2 (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 for 1 hour. The solid was filtered off. The mother solvent was concentrated under vacuum. The crude product was purified by silica gel column with PE:EA = 10:1 to give 6.7 g (93%) of the title compound as a brown solid.

[1173] Analytical data: LC-MS: (ES, m / z) = 284 [M+1].

[1174] Example C5: Synthesis of racemic-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol

[1175]

[1176] Step 1: Synthesis of 2-(8-bromo-3-chloroisoquinolin-5-yl)prop-2-en-1-ol:

[1177] 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 hours. The resulting solution was diluted with 100 mL of water and extracted with 2 x 100 mL of EA. The organic phase was washed with brine, dried, and concentrated. The residue was purified by flash chromatography with PE:EA (1:1). This yielded 2.1 g (54.9%) of the title compound as a white solid.

[1178] Analytical data: LC-MS: (ES, m / z) = 298 [M+1].

[1179] Step 2: Synthesis of racemic 2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol:

[1180] 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 h. The resulting mixture was filtered. The filtrate was concentrated under vacuum. The product was purified by flash chromatography with PE:EA (10:1). This yielded 1.8 g (90%) of the title compound as a yellow solid.

[1181] Analytical data: LC-MS: (ES, m / z) = 300 [M+1].

[1182] Example C6: Synthesis of 8-bromo-3-chloro-5-methylisoquinoline

[1183]

[1184] 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-trioxatriborane (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:H2O=5:1, 4.8 mL) was stirred at 40°C under N2 atmosphere for 16 hours. The resulting solution was concentrated under vacuum. The residue was purified by preparative TLC with DCM / MeOH (20 / 1) to give 100 mg of the title compound as an off-white solid.

[1185] Analytical data: LC-MS: (ES, m / z) = 258 [M+1].

[1186] Example C7: Synthesis of 8-bromo-3-chloroisoquinoline

[1187]

[1188] A mixture of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (100.00 mg, 0.256 mmol, 1 eq., from Example C4, Step 1), [3-(diphenylphosphino)propyl]diphenylphosphine (2.11 mg, 0.005 mmol, 0.02 eq.), (acetoxy)palladium acetate (1.15 mg, 0.005 mmol, 0.02 eq.), and triethylsilane (74.43 mg, 0.640 mmol, 2.5 eq.) in DMF (3 mL) was stirred at 60° C. under N₂ atmosphere for 1 hour. Water was added, the mixture was extracted with EA, and concentrated. The residue was applied to a preparative TLC with DCM / MeOH (10:1). This yielded 50 mg (80.5%) of the title compound as a light yellow solid.

[1189] Analytical data: LC-MS: (ES, m / z) = 242 [M+1].

[1190] Example C8: Synthesis of rac-3-chloro-5-(1-fluoropropan-2-yl)-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[1191]

[1192] Step 1: Synthesis of rac-2-{3-chloro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]isoquinolin-5-yl}propan-1-ol:

[1193] Under nitrogen, to a solution of racemic-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol (150 mg, 0.4990 mmol, from Example C5) in 1,4-dioxane was added 3-(methylsulfonylmethyl)azetidine (74.4 mg, 0.499 mmol), Cs2CO3 (325 mg, 0.998 mmol) and XantPhos Pd G4 (44.3 mg, 49.9 μmol). The mixture was stirred at 100 ° C for 3 hours. The resulting solution was diluted with 20 mL of water and extracted with 2x20 mL of EA. The organic phase was washed with brine, dried and concentrated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH=10: 1). This produced 100 mg (54.3%) of the title compound as a yellow solid.

[1194] Analytical data: LC-MS: (ES, m / z) = 369 [M+1].

[1195] Step 2: Synthesis of racemic-3-chloro-5-(1-fluoropropan-2-yl)-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1196] To a solution of 2-{3-chloro-8-[3-(methylsulfonylmethyl)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 hours. The reaction solution was quenched with water and extracted with 2 x 20 mL of EA. The organic phase was washed with brine, dried and concentrated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH=15:1). This produced 80 mg (79.9%) of the title compound as a yellow solid.

[1197] Analytical data: LC-MS: (ES, m / z) = 371 [M+1].

[1198] Example C9: Synthesis of 8-bromo-3-chloro-5-ethoxyisoquinoline

[1199]

[1200] Step 1: Synthesis of 8-bromo-3-chloro-5-methoxyisoquinoline:

[1201] To a mixture of 3-chloro-5-methoxyisoquinoline (2 g, 10.3 mmol) in AcOH (20 mL) was added a solution of dibromide (1.80 g, 11.3 mmol) dissolved in 10 mL of AcOH over 10 minutes. 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 100 mL of H2O) 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.

[1202] Analytical data: LC-MS: (ES, m / z) = 272 [M+1]. 1 H-NMR (300MHz, 6d-DMSO) δppm 9.21 (s, 1H), 8.09 -7.81 (m, 2H), 7.20 (d, J = 8.3Hz, 1H), 4.00 (s, 3H).

[1203] Step 2: Synthesis of 8-bromo-3-chloroisoquinolin-5-ol:

[1204] 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 while stirring rapidly. The precipitate was collected by filtration. This yielded 1.8 g (89%) of the title compound as a yellow solid.

[1205] Analytical data: LC-MS: (ES, m / z) = 258 [M+1].

[1206] Step 3: Synthesis of 8-bromo-3-chloro-5-ethoxyisoquinoline:

[1207] 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 hours. The resulting solution was cooled to room temperature, diluted with water and extracted with EA. The organic phase was concentrated under vacuum and purified by chromatography with PE:EA (1:1). This yielded 800 mg (80.2%) of the title compound as a yellow solid.

[1208] Analytical data: LC-MS: (ES, m / z) = 286 [M+1]; 1H-NMR(400MHz,6d-DMSO)δppm 9.23 (d, 1H, J = 0.8Hz), 8.03 (d, 1H, J = 0.8Hz), 7.91 (d, 1H, J = 8.3Hz), 7.20 (d, 1H, J = 8.4Hz), 4.25 (q, 2H, J = 7.0Hz), 1.47 (t, 3H, J = 6.9Hz).

[1209] Example C10: Synthesis of 3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline

[1210]

[1211] Step 1: Synthesis of (1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanol:

[1212] 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 Cs 2 CO 3 (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.

[1213] Analytical data: LC-MS: (ES, m / z) = 291 [M+1].

[1214] Step 2: Synthesis of 3-chloro-8-(3-(iodomethyl)azetidin-1-yl)-5-isopropylisoquinoline:

[1215] 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.

[1216] Analytical data: LC-MS: (ES, m / z) = 401 [M+1].

[1217] Step 3: Synthesis of 3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline:

[1218] A mixture of 3-chloro-8-[3-(iodomethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (100 mg, 249 μmol) and sodium cyclopropylsulfinate (127 mg, 996 μmol) in DMF (15 mL) was stirred at 80° C. for 2 h. 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.

[1219] Analytical data: LC-MS: (ES, m / z) = 379 [M+1].

[1220] Example C11: Synthesis of 8-bromo-3-chloro-5-cyclopropylisoquinoline

[1221]

[1222] To a solution of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (240 mg, 614 μmol) in dioxane / HO (10 mL / 2 mL) was added 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). The mixture was stirred at 80° C. under an N atmosphere for 16 hours. Water was added to the mixture and extracted with EA. The organic phase was concentrated and purified by FLASH (50% EA / PE) to give 90 mg (52%) of the title compound as a yellow solid.

[1223] Analytical data: LC-MS: (ES, m / z) = 284 [M+1].

[1224] Example C12: Synthesis of 3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[1225]

[1226] Step 1: Synthesis of 7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1227] To a solution of 3-chloro-8-[3-(methylsulfonylmethyl)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 / DCM) to give 170 mg (81.7%) of the title compound as a yellow solid.

[1228] Analytical data: LC-MS: (ES, m / z) = 431 [M+1].

[1229] Step 2: Synthesis of 3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1230] A mixture of 7-bromo-3-chloro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (75 mg, 173 μmol), trimethyl-1,3,5,2,4,6-trioxatriborane (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 / DCM) to give 55 mg (87%) of the title compound as a yellow solid.

[1231] Analytical data: LC-MS: (ES, m / z) = 367 [M+1].

[1232] Example C13: Synthesis of 3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[1233]

[1234] Step 1: Synthesis of 7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1235] NBS (163 mg, 918 μmol) was added portionwise to 3-chloro-8-[3-(methylsulfonylmethyl)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 under vacuum. The residue was purified by preparative TLC with PE:EA=1:1 to give 350 mg of the title compound as a yellow solid.

[1236] Analytical data: LC-MS: (ES, m / z) = 431 [M+1].

[1237] Step 2: Synthesis of 3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1238] At -78 ° C., under N2 atmosphere, n-BuLi (2.5M, 2.29 mmol, 916 μL) was added dropwise to THF (20 mL) containing 7-bromo-3-chloro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (330 mg, 764 μmol) and N-(phenylsulfonyl)-N-fluorobenzenesulfonamide (479 mg, 1.52 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with H2O, diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC with DCM:MeOH=30:1 to give 80 mg of the title compound as a yellow solid.

[1239] Analytical data: LC-MS: (ES, m / z) = 371 [M+1].

[1240] Example C14: Synthesis of 3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline

[1241]

[1242] Step 1: Synthesis of 3-chloro-5-iodo-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1243] To a solution of 3-chloro-8-[(2R,3S)-3-(methylsulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline (100 mg, 307 μmol) in AcOH (5 mL) was added iodo(thio)amine (58.6 mg, 337 μmol) and stirred at room temperature for 1 hour. Water was added and the reaction 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.

[1244] Analytical data: LC-MS: (ES, m / z) = 451 [M+1].

[1245] Step 2: Synthesis of 3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline:

[1246] Under N2 atmosphere, a mixture of 3-chloro-5-iodo-8-[(2R,3S)-3-(methylsulfonylmethyl)-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. for 2 hours. The reaction 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 light yellow solid.

[1247] Analytical data: LC-MS: (ES, m / z) = 393 [M+1].

[1248] 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

[1249]

[1250] Step 1: Synthesis of 6-chloro-4-iodo-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridine:

[1251] A mixture of 1,6-dichloro-4-iodo-2,7-naphthyridine (300 mg, 923 μmol), (2R, 3S)-3-(methylsulfonylmethyl)-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 Na2SO4 and concentrated under vacuum. The residue was purified by TLC (PE:EA=1:1). This produced 300 mg (72.1%) of the title compound as a light yellow solid.

[1252] Analytical data: LC-MS: (ES, m / z) = 452 [M+1].

[1253] 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:

[1254] Under N2 atmosphere, a 50 mL sealed tube was placed with 6-chloro-4-iodo-1-[(2R,3S)-3-(methylsulfonylmethyl)-2-methylazetidin-1-yl]-2,7-naphthyridine (200 mg, 663 μmol), 2-(4,4,5,5-tetramethyl-1,4-dinitrofuran (122 mg, 663 μmol), K2CO3 (122 mg, 884 μmol) and Pd(dppf)Cl2 (64.6 mg, 88.3 μmol) in dioxane (20 mL) and H2O (4 mL). 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 Na2SO4 and concentrated under vacuum. The residue was purified by Flash Column Silica-CS (DCM:MeOH=10:1). This gave 150 mg (89.2%) of the title compound as a white solid.

[1255] Analytical data: LC-MS: (ES, m / z) = 382 [M+1].

[1256] 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:

[1257] To a solution of 2-{6-chloro-1-[(2R,3S)-3-(methylsulfonylmethyl)-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 produced 110 mg of the title compound as a yellow solid.

[1258] Analytical data: LC-MS: (ES, m / z) = 384 [M+1].

[1259] Example C16: Synthesis of 3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline:

[1260]

[1261] Step 1: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-ol:

[1262] To a solution of 3-chloro-5,7-difluoro-8-methoxy-isoquinoline (300 mg, 1.31 mmol, 1 eq) in DCM (5 mL) was added BBr (982 mg, 3.92 mmol, 3 eq) at -78 °C, and the mixture was 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 yielded 0.22 g (77%) of the title compound as a brown solid.

[1263] Analytical data: LC-MS: (ES, m / z): RT = 0.645 min, LCMS: m / z = 215.8 [M+1].

[1264] Step 2: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-yl trifluoromethanesulfonate:

[1265] 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 h. The mixture was concentrated and the residue was purified by silica gel chromatography (PE to PE / EA = 50 / 1). This yielded 0.26 g (76%) of the title compound as a white solid.

[1266] 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, 10.4Hz, 1H), 8.28 (s, 1H).

[1267] Step 3: Synthesis of 3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline:

[1268] To a mixture of (3-chloro-5,7-difluoro-8-isoquinolinate) (140 mg, 403 μmol, 1 eq), 3-(methylsulfonylmethyl)azetidine (159 mg, 604 μmol, 1.50 eq, TFA salt) and CsCO (393 mg, 1.21 mmol, 3 eq) 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 eq), BINAP (201 mg, 322 μmol, 0.8 eq) and Pd(OAc) (18.1 mg, 80.5 μmol, 0.2 eq), the mixture was degassed and purged with N three times, and then stirred at 90° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=20:1 to 1:1). This resulted in 10 mg (7%) of the title compound as a yellow solid.

[1269] 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).

[1270] Example 1, Compound 55: 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

[1271]

[1272] Step 1: Synthesis of 3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1273] A mixture of CsCO (8.21 g, 25.2 mmol), 3-(methylsulfonylmethyl)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 N atmosphere for 16 hours. The mixture was diluted with EA (200 mL) and washed with brine. The organic layer was dried over NaSO and concentrated under vacuum. The residue was purified by FLASH (DCM:MeOH=30:1) to give 5.0 g (67%) of the title compound as a yellow solid.

[1274] Analytical data: LC-MS: (ES, m / z) = 353 [M+1].

[1275] 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:

[1276] CsCO (3.81 g, 11.7 mmol) was added to a solution of 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-(methylsulfonylmethyl)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 an N atmosphere for 16 hours. The mixture was diluted with EA (500 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC: XBridge Prep OBD C18 column 30×150 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 minutes; 254; 220 nm to give 2.80 g (70%) of the title compound as a yellow solid.

[1277] 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

[1278]

[1279] To a solution of 3-chloro-8-[3-(methylsulfonylmethyl)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 μmol). The mixture was stirred at 100° C. under N2 for 2 hours. The reaction mixture was cooled to room temperature and diluted with 20 mL of water. The resulting solution was extracted with 2×20 mL of EA and the organic layers were combined. The resulting mix...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: Z is O or NH; Each A 1 , A 2 and A 3 are independently N or CR; wherein each R is independently H, halogen or CH3; Ring A is a 4- to 12-membered heterocyclic group; 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, wherein R 1 Represented by or represented by R 1 The alkyl, alkoxy or cycloalkyl in the group represented by is optionally selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy groups; and / or 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, wherein R 2 The alkyl, alkoxy or cycloalkyl represented by is optionally substituted by 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 heterocyclic group, wherein R 5 The alkyl, cycloalkyl or heterocyclic group represented by is optionally selected from halogen, CN, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy groups; R 6 is H or is optionally selected from halogen, CN, OH, NR a R b and C1-C4 alkyl substituted with 1 to 3 groups of C1-C2 alkoxy; and Each R a and R b are independently H or C1-C4 alkyl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by structural formula (II-A), (II-B), (II-C), (II-D) or (II-E):

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (II-A):

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Z is O.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluorine, C1-C4 alkyl, C1-C4 alkoxy or C3-C6 cycloalkyl, wherein R 2 The alkyl, alkoxy or cycloalkyl represented by is optionally substituted by 1 to 3 groups selected from halogen and OH.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 6 It is H, methyl, ethyl, C1-C2 haloalkyl or C1-C2 aminoalkyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 5 is H; optionally selected from halogen, CN and NR a R b C1-C4 alkyl substituted with 1 to 3 groups; C3-C6 cycloalkyl; or a 4- to 6-membered monocyclic heterocyclic group optionally substituted with C1-C4 alkyl; and wherein R a and R b Each is independently selected from H, methyl and ethyl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 6 R 1 Substituted 4- to 7-membered monocyclic heterocyclyl.

9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 6 R 1 Substituted 7- to 12-membered bicyclic heterocyclyl.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, 4 or 5; and Each R 1 are independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, -O-C3-C6 cycloalkyl, wherein R 1 Represented by or represented by R 1 The alkyl, alkoxy or cycloalkyl in the group represented by is optionally selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 2 It is H, F, methyl, ethyl, isopropyl, CH(CH3)CH2F, CH(CH3)CH2OH, CF3, OCH3, OCH2CH3 or cyclopropyl.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 6 It is H, CH3 or CH2NH2.

13. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted by 1 to 6 R 1 substituted, and Ring A is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 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]dec-8-yl or 1,4-dioxa-9-azaspiro[5.5]undec-9-yl.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein at least one R 1 is OH, C1-C4 alkoxy or -O-C3-C6 cycloalkyl, wherein R 1 Represented by or represented by R 1 The alkoxy or cycloalkyl group in the group represented by is optionally selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently are F, CN, OH, NH2, CH3, CH2CH3, CHF2, CH(OH)CH3, CH2OH, CH2NH2, CH2CH2NH2, OCH3, OCD3, OCH2CH2OH, OCH2CH(OH)CH3, OCH2C(OH)(CH3)2, OCH2CH2OCH3, OCH2CH2NH2, OCH2CH2NHCH3, OCH2CH2N(CH3)2, -O-cyclopropyl, NHCH3, N(CH3)2.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein for 17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 2 is H or isopropyl.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 6 R 1 Substituted piperidinyl.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

20. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating cancer.

21. The use according to claim 20, wherein the cancer is non-small cell lung cancer.

22. The use according to claim 20 or 21, wherein the cancer has metastasized.

23. The use according to claim 20 or 21, wherein the cancer is characterized by: i) epidermal growth factor receptor EGFR L858R mutation and / or exon 19 deletion; and ii) T790M mutation.

24. The use according to claim 23, wherein the cancer is further characterized by an epidermal growth factor receptor (EGFR) C797S mutation.

25. The use according to claim 20 or 21, wherein the medicament is administered in combination with afatinib, osimertinib, erlotinib or gefitinib.

26. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for inhibiting epidermal growth factor receptor (EGFR).

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