Inhibitors of mutated form of EGFR

Abstract

The present disclosure relates to inhibitors of mutant forms of EGFR. Specifically, the present disclosure provides a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, which is useful in the treatment of cancer. # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of December 22, 2020, an application number of 2020800972399, and an invention title of "Inhibitors of EGFR Mutant Forms".

[0002] Cross-reference to related applications

[0003] This application claims the priority of U.S. Provisional Application No. 62 / 953,030, filed on December 23, 2019. The entire content of the foregoing application is incorporated herein by reference. Background art

[0004] The epidermal growth factor receptor (EGFR) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. By binding to its ligands, such as epidermal growth factor (EGF), EGFR can form homodimers on the cell membrane or 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 cells. These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis. Disruptions of the EGFR signaling pathway (including increased ligand and receptor expression), EGFR gene amplification and alterations (such as mutations, deletions, etc.) can promote the malignant transformation of cells and play important roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. For example, alterations of the EGFR gene, such as mutations and deletions, are found in non-small cell lung cancer (NSCLC) tumors. The two most frequent EGFR alterations found in NSCLC tumors are the short in-frame deletion in exon 19 (del19) and L858R, a single missense mutation in exon 21 (Cancer Discovery 2016 6(6)601). These two alterations cause ligand-independent EGFR activation and are called primary or activating mutations of EGFR mutant NSCLC (EGFR M+). Clinical experience shows an objective response rate (ORR) of approximately 60% to 85% in patients with EGFR M+ NSCLC treated with first-line (1L) therapy with the EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib (Lancet Oncol. 2010 Vol. 11, 121; Lancet Oncol. 2016 Vol. 17, 577; N. Engl. J. Med. November 18, 2017 Doi:10.1056 / NEJMoa1713137; Lancet Oncol. 2011 Vol. 12, 735), thus confirming that EGFR mutant NSCLC tumors rely on oncogenic EGFR activity for survival and proliferation and establishing del19 and L858R mutant EGFR as the oncogenic driver of the disease and thus validating the drug target and biomarker for the treatment of NSCLC.

[0005] However, after treatment with first-generation (erlotinib and gefitinib) and second-generation (afatinib) EGFR TKIs for an average of 10 to 12 months, drug resistance to these small molecule inhibitors was observed in almost all NSCLC patients (Lancet Oncol. February 2010; 11(2): 121-8; Lancet Oncol. May 2016; 17(5): 577-89; Lancet Oncol. August 2011; 12(8): 735-42). The most prominent mechanism of resistance to first- and second-generation EGFR TKIs is due to secondary mutations of T790M in EGFR, and progression occurs in 50% to 70% of patients with first- and second-generation EGFR inhibitors (Blakely, 2012; Kobayashi, 2005). This secondary mutation reduces the affinity of the drug for the target, thereby generating drug resistance and leading to tumor recurrence or disease progression.

[0006] Given the prevalence of this mutation in the development of drug resistance in EGFR-targeted lung cancer therapies, many companies have attempted to develop new small molecule EGFR inhibitors that treat these patients with drug-resistant lung cancer by inhibiting the drug-resistant mutant EGFR-T790M. For example, third-generation EGFR TKIs (osimertinib ) have been developed to treat NSCLC patients if the cancer cells are positive for primary EGFR mutations del19 or L858R with or without the T790M mutation in the gene encoding EGFR.

[0007] Although the third-generation EGFR TKI osimertinib has shown efficacy in NSCLC patients, unfortunately, drug resistance mediated by exon 20 C797 mutations in EGFR typically develops within approximately 10 months (European Journal of Medicinal Chemistry 2017 Volume 142: 32-47) and accounts for the majority of osimertinib drug resistance events (Cancer Letters 2016 Volume 385: 51-54). The EGFR del19 / L858R T790M C797S cis mutant kinase variant typically appears in second-line (2L) patients after treatment with osimertinib, which is commonly referred to as the "triple mutant" EGFR and is no longer inhibited by first-, second-, or third-generation EGFR inhibitors.

[0008] There is no approved EGFR TKI 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 mutation del19 / L858R T790M C797S and have no or low activity against wild-type EGFR. In addition to treating the mutant forms of EGFR for which there is currently no therapy, these selective EGFR inhibitors may be more suitable as therapeutic agents, especially for treating cancer, because of the reduction in toxicology (diarrhea, rash) associated with wild-type EGFR inhibition. SUMMARY OF THE INVENTION

[0009] The applicant has discovered novel compounds that are effective inhibitors of certain mutant forms of EGFR (see Synthesis Examples 1 to 43). In particular, the compounds of the present disclosure have been shown to 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 having one or more alterations, 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 having L858R and / or exon 19 deletion mutations, T790M mutations, and C797S mutations (hereinafter "EGFR having LRTMCS mutations" or "triple mutant EGFR") (see Biological Example 1) and can be used to treat various cancers, such as lung cancer (see Biological Example 2). Importantly, the compounds of the present disclosure are selective EGFR inhibitors, i.e., the compounds of the present disclosure have no or low activity against wild-type EGFR and the kinome. Advantages associated with such selectivity may include facilitating effective dosing and reducing on-target toxicity mediated by EGFR. Some of the compounds of the present disclosure exhibit good penetration of the brain and blood-brain barrier (e.g., PGP efflux ratio less than 5). Thus, it is expected that the compounds of the present disclosure or pharmaceutically acceptable salts thereof can be effectively used to treat metastatic cancers, including brain metastases (including leptomeningeal disease and other systemic metastases). Some of the compounds of the present disclosure also have the advantage of high microsomal stability. The compounds of the present disclosure may also have favorable toxicity characteristics associated with other non-kinase targets.

[0010] In one aspect, the present invention provides a compound represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] The definitions of each variable are provided as follows.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof (“the pharmaceutical composition of the present disclosure”).

[0014] The present disclosure provides a method of treating a subject having cancer, which comprises 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 the 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.

[0015] 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 particular embodiment, the cancer is non-small cell lung cancer with brain metastases.

[0016] The treatment method disclosed herein further comprises administering to the subject an effective amount of afatinib, osimertinib, erlotinib, or gefitinib.

[0017] The present disclosure also provides a method of inhibiting epidermal growth factor receptor (EGFR) in a subject in need thereof, which comprises 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 the pharmaceutical composition of the present disclosure.

[0018] The present disclosure also provides the use of an effective amount of a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure in the preparation of a medicament for treating cancer.

[0019] In another aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure for treating cancer. Detailed Description

[0020] Definitions

[0021] As used herein, the term “halo” means halogen and includes chlorine, fluorine, bromine, and iodine.

[0022] The term "alkyl", as used alone or as part of a larger moiety, such as "alkoxy" or "haloalkyl", means a saturated aliphatic straight or branched chain monovalent hydrocarbon radical. Unless otherwise specified, alkyl generally has 1 to 4 carbon atoms, i.e., (C1-C4)alkyl. As used herein, a "(C1-C4)alkyl" group means a group having 1 to 4 carbon atoms in a straight or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, etc.

[0023] The term "alkenyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by double bonds.

[0024] The term "alkoxy" means an alkyl group linked through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0025] The term "aminoalkyl" means an alkyl group substituted with -NH2.

[0026] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy group, respectively, which may be substituted by one or more halogen atoms, as the case may be.

[0027] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyl has 3 to 6 carbon atoms. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise stated, "cycloalkyl" has 3 to 6 carbon atoms.

[0028] The term "heterocyclic group" or "heterocycle" refers to a group 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, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones ("4- to 12-membered heterocyclic group"). In some embodiments, the heterocyclic group 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 heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, provided that the valence permits. The heterocyclic group may be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., bicyclic system ("bicyclic heterocyclic group") or tricyclic system ("tricyclic heterocyclic group"); polycyclic ring systems include fused, bridged, or spiro systems). Exemplary monocyclic heterocyclic groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridyl, etc. The polycyclic ring system of the heterocyclic group 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 of the polycyclic ring system.

[0029] A bridged bicyclic system has two non-aromatic rings (heterocyclic or cycloalkyl) containing 7 to 12 ring atoms and sharing three or more atoms, wherein the two bridgehead atoms are separated by a bridge containing at least one atom. "Bridged heterocyclic group" 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.

[0030] A fused bicyclic system has two non-aromatic rings (heterocyclic or cycloalkyl) containing 7 to 12 ring atoms and sharing two adjacent ring atoms. Examples of fused bicyclic systems include hexahydro-1H-furo[3,4-b]pyrrolyl and hexahydro-1H-furo[3,4-c]pyrrolyl.

[0031] A spiro bicyclic system has two non-aromatic rings (heterocyclic or cycloalkyl) containing 7 to 12 ring atoms and sharing one ring atom. Examples of spiro bicyclic systems include 1-oxa-7-azaspiro[3.5]non-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl, and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl.

[0032] The compounds of the present invention

[0033] Embodiments of compounds having the general structure of formula (I) are disclosed herein. These compounds are selective inhibitors of LRTM and LRTMCS EGFR. Contrary to other EGFR inhibitors (such as osimertinib) that irreversibly bind to EGFR, the compounds disclosed herein are non-covalent inhibitors.

[0034] In a first embodiment, the present invention provides a compound represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0035]

[0036] Wherein:

[0037] Z is O or NH;

[0038] Each A 1 、A 2 and A 3 is independently N or CR; wherein each R is independently H, halogen, or CH3;

[0039] Ring A is a 4- to 12-membered heterocyclic group;

[0040] Each R 1Independently being halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or -O-C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl in the group represented by R 1 or in the group represented by R 1 is optionally substituted by 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy; and / or

[0041] m is 0, 1, 2, 3, 4, 5 or 6;

[0042] R 2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy or C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl in the group represented by R 2 is optionally substituted by 1 to 3 groups selected from halogen and OH;

[0043] R 3 is H or methyl;

[0044] R 4 is H or methyl;

[0045] R 5 is H, C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered monocyclic heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group in the group represented by R 5 is optionally substituted by 1 to 3 groups selected from halogen, CN, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy;

[0046] R 6 is H or C1-C4 alkyl optionally substituted by 1 to 3 groups selected from halogen, CN, OH, NR a R b and C1-C2 alkoxy; and

[0047] each R a and R b is independently H or C1-C4 alkyl.

[0048] In an alternative first embodiment, the present invention provides a compound represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0049]

[0050] Wherein:

[0051] Z is O or NH;

[0052] Each A 1 、A 2 and A 3 is independently N or CR; wherein each R is independently H, halogen or CH3;

[0053] Ring A is a 4- to 10-membered heterocyclic group;

[0054] Each R 1 is independently halogen, CN, OH, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or -O-C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl represented by R 1 or represented by R 1 is optionally substituted by 1 to 3 groups selected from deuterium, halogen, OH, NRR a R b 、C1-C2 alkyl and C1-C2 alkoxy;

[0055] m is 0, 1, 2, 3, 4, 5 or 6;

[0056] R 2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy or C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl represented by R 2 is optionally substituted by 1 to 3 groups selected from halogen, OR a and NR a R b ;

[0057] R 3 is H or methyl;

[0058] R 4 is H or methyl;

[0059] R 5 is H, C1-C4 alkyl, C3-C6 cycloalkyl or a 4- to 6-membered monocyclic heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group represented by R 5 is optionally substituted by 1 to 3 groups selected from halogen, CN, OH, NRR a R b 、C1-C2 alkyl and C1-C2 alkoxy;

[0060] R 6 is H or C1-C4 alkyl optionally substituted by 1 to 3 groups selected from halogen, CN, OH, NRR a R b and C1-C2 alkoxy; and

[0061] Each R a and Rb Independently H or C1-C4 alkyl.

[0062] 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:

[0063]

[0064]

[0065] wherein the variables are as defined in the first embodiment.

[0066] In a third embodiment, the present disclosure provides a compound represented by structural formula (II-A) or a pharmaceutically acceptable salt thereof:

[0067]

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

[0069] In a fourth embodiment, the present disclosure provides a compound according to structural formula (I), (II-A), (II-B), (II-C), (II-D) or (II-E) or a pharmaceutically acceptable salt thereof, wherein Z is O, and the remaining variables among these are as defined in the first embodiment.

[0070] 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 the alkyl, alkoxy or cycloalkyl represented by R 2 is optionally substituted by 1-3 groups selected from halogen and OH, and the remaining variables among these 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 the alkyl, alkoxy or cycloalkyl represented by R 2 is optionally substituted by 1-3 groups selected from halogen, OH and NH2, and the remaining variables among these are as defined in the first or fourth embodiment.

[0071] 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 remaining variables among these variables are as defined in the first, fourth or fifth embodiment.

[0072] 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; C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen, CN and NR a R b ; C3-C6 cycloalkyl; or a 4- to 6-membered monocyclic heterocyclic group optionally substituted with C1-C4 alkyl; wherein R a and R b are each independently selected from H, methyl and ethyl; and wherein the remaining variables among these variables are as defined in the first, fourth, fifth or sixth embodiment.

[0073] In an eighth 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 a 4- to 7-membered monocyclic heterocyclic group optionally substituted with 1 to 6 R 1 ; wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth or seventh embodiment.

[0074] In a ninth 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 a 7- to 12-membered bicyclic heterocyclic group optionally substituted with 1 to 6 R 1 ; wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth or seventh embodiment.

[0075] 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 is independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, -O-C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl in the group represented by R 1 or the group represented by R 1 is optionally substituted with a group selected from deuterium, halogen, OH, NR a R b, substituted with 1 to 3 groups of C1-C2 alkyl and C1-C2 alkoxy; and the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0076] In the eleventh embodiment, the present disclosure 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, F, methyl, ethyl, isopropyl, CH(CH3)CH2F, CH(CH3)CH2OH, CF3, OCH3, OCH2CH3, or cyclopropyl, and the remaining variables among these 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 formula (I), (II-A), (II-B), (II-C), (II-D), or (II-E) or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, methyl, ethyl, isopropyl, CH(CH3)CH2F, CH(CH3)CH2OH, CF3, OCH3, OCH2CH3, C(CH3)2NH2, or cyclopropyl, and the remaining variables among these variables are as defined in the first, fourth, fifth (or alternative fifth), sixth, seventh, eighth, ninth, or tenth embodiment.

[0077] In the twelfth embodiment, the present disclosure 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 6 is H, CH3, or CH2NH2, and the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0078] In the thirteenth embodiment, the present disclosure 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 with 1 to 6 R 1is replaced, 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]non-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl, wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, tenth, eleventh or twelfth embodiment.

[0079] In a fourteenth embodiment, the present disclosure 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 at least one R 1 is OH, C1-C4 alkoxy or -O-C3-C6 cycloalkyl, wherein the alkoxy or cycloalkyl in the group represented by R 1 or in the group represented by R 1 is optionally substituted with 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy, wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0080] 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 1Independently 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, and wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiments. In a specific embodiment, each R 1 Independently F, OH, Me, Et, OMe, OCD3 or OCH2CH2OH. In another specific embodiment, each R 1 Independently F, OH, Me or OCD3.

[0081] In the 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 is wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiments. In a specific embodiment, is

[0082] In the seventeenth 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 R 2 is H or isopropyl, and wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiments.

[0083] In the 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 a piperidinyl group optionally substituted with 1 to 6 R 1 substituents, wherein R 2is H or isopropyl, wherein the remaining variables among these variables are as defined in the first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth embodiment.

[0084] In one embodiment, the compounds of the present disclosure are any of the compounds disclosed in the Examples and Table 1, or a pharmaceutically acceptable salt thereof.

[0085] The term "pharmaceutically acceptable salt" refers to a medicinal salt that is applicable to contact with the tissues of humans and lower animals within the scope of reasonable medical judgment without undue toxicity, irritation, allergic reaction, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described by S.M. Berge et al. in J. Pharm. Sci., 1977, 66, 1-19.

[0086] Included within the teachings of the present invention are the 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 (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the teachings of the present invention having an acidic group (such as a carboxylic acid) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0087] Compounds having 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 both. Stereoisomers refer to compounds that differ only in their spatial arrangement. Stereoisomers include all diastereoisomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereoisomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0088] 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 denoted by "R" or "S" in the chemical name) or structure (e.g., the configuration is represented by a "wedge" bond), the depicted configuration is enriched by more than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% relative to the opposite configuration (except when "racemic" or "racemate" is specified in connection with the structure or name, as explained in the following two paragraphs). "The enrichment of the depicted configuration relative to the opposite configuration" is in mole percentage and is determined by dividing the number of compounds having the specified stereochemical configuration at the chiral center by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0089] When the stereochemical configuration at a chiral center in a compound is described by its chemical name (e.g., where the configuration is specified by "R" or "S" in the name) or structure (e.g., the configuration is specified by a "wedge" bond) and the term "racemic" or "racemate" is associated with the structure or named in the chemical name, it means a racemic mixture.

[0090] When two stereoisomers are described by their chemical name or structure and the chemical name or structure is joined by "and", it means a mixture of the two stereoisomers.

[0091] When two stereoisomers are described by their chemical name or structure and the name or structure is joined by "or", it means one or the other of the two stereoisomers, but not both.

[0092] When a disclosed compound having a chiral center is represented by a structure without showing the configuration at the chiral center, the structure is intended to include a compound having the S configuration at the chiral center, a compound having the R configuration at the chiral center, or a compound that is a mixture of the R and S configurations at the chiral center. When a disclosed compound having a chiral center is described by its chemical name without denoting the configuration at the chiral center with "S" or "R", the name is intended to include a compound having the S configuration at the chiral center, a compound having the R configuration at the chiral center, or a compound that is a mixture of the R and S configurations at the chiral center.

[0093] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. This teaching encompasses all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures and diastereomeric mixtures of the compounds disclosed herein.

[0094] A mixture of enantiomers and diastereomers can be separated into its component enantiomers or stereoisomers by well-known methods (e.g., chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent). Enantiomers and diastereomers can also be obtained from diastereomer- or enantiomer-pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0095] "Peak 1" in the experimental section refers to the expected reaction product compound obtained by chromatographic separation / purification that elutes earlier than the second expected reaction product compound from the same previous reaction. The second expected product compound is referred to as "peak 2".

[0096] When a compound of the present disclosure is named or structured to represent a single enantiomer, unless otherwise stated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the enantiomers being named or described divided by the total weight of the mixture of the two enantiomers.

[0097] 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 pair of diastereomers), it should be understood that, unless otherwise stated, it includes one or any mixture of the stereoisomers contained. It should be further understood that the stereoisomer purity of the named or described stereoisomers is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomer purity is determined by dividing the total weight of the mixture of the stereoisomers contained by the name or structure by the total weight of the mixture of all stereoisomers.

[0098] In the compounds of the present disclosure, any position specifically designated as "D" or "deuterium" should be understood to have a deuterium enrichment of 50%, 80%, 90%, 95%, 98%, or 99%. "Deuterium enrichment" is the mole percentage and is determined by dividing the number of compounds having 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 about the presence of hydrogen or deuterium, that position has hydrogen at its natural abundance. A specific alternative embodiment relates to the compounds of the present disclosure that have a deuterium enrichment of at least 5%, 10%, 25%, 50%, 80%, 90%, 95%, 98%, or 99% at one or more positions not specifically designated as "D" or "deuterium".

[0099] As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl or heterocyclic group) are referred to as "substituted" or "optionally substituted". When a moiety is modified by one of these terms, unless otherwise stated, it means that any part of the moiety known to those skilled in the art to be capable of being substituted can be substituted, including one or more substituents. If there are more than one substituent, each substituent can be selected independently. These methods for substitution are well known in the art and / or taught by the present disclosure. The optional substituents can be any substituents suitable for attachment to the moiety.

[0100] The compounds of the present disclosure are selective EGFR inhibitors. As used herein, the term "selective EGFR inhibitor" refers to a compound that selectively inhibits certain mutant EGFR kinases relative to wild-type EGFR and the kinome. In other words, the selective EGFR inhibitor has no activity or low activity against wild-type EGFR and the kinome. When compared with the inhibitory activity of the selective EGFR inhibitor against wild-type EGFR and many other kinases, in terms of the IC 50 value (i.e., the IC 50 value is sub-nanomolar), the inhibitory activity of the selective EGFR inhibitor against certain mutant EGFR kinases is more potent. The potency can be measured using known biochemical assays.

[0101] Some compounds of the present disclosure have the advantage of good brain penetration. The ability of a particular compound to cross the BBB and penetrate the brain can be evaluated using various known methods or combinations of these methods. An in vitro method frequently used to predict the in vivo brain penetration of a compound is the P-gp efflux ratio. P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) and limits the penetration of its substrates into the central nervous system (CNS). Compounds found to be good P-gp substrates in vitro (i.e., having a high efflux ratio) are predicted to have poor in vivo brain penetration. To measure the P-gp efflux ratio, the apparent apical-to-basolateral permeability (Papp[A-B]) and the apparent basolateral-to-apical permeability (Papp[B-A]) of the compound in Madin-Darby canine kidney cells overexpressing P-gp (MDCK-MDR1 cells) are determined. The P-gp efflux ratio is a measure of the ratio of Papp[B-A] / Papp[A-B]. In some embodiments, the compounds of the present disclosure have a P-gp efflux ratio less than 2, less than 3, less than 4, less than 5.

[0102] Some compounds of the present disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Hepatic metabolism is the major elimination route for small molecule drugs. The clearance of a compound by hepatic metabolism can be evaluated in vitro using human liver microsomes (HLM) or human hepatocytes. The compound is incubated with HLM plus appropriate cofactors or human hepatocytes, and the depletion of the compound is measured to determine the in vitro intrinsic clearance (Clint). Clint is scaled to the total body clearance (CL), and the hepatic extraction ratio (ER) is determined by dividing CL by the standard human liver blood flow rate. Compounds with a low hepatic extraction ratio are considered to have good metabolic stability. In some embodiments, the compounds of the present disclosure have calculated ER values of <0.3, <0.4, <0.5, <0.6.

[0103] Pharmaceutical composition

[0104] The pharmaceutical compositions of the present disclosure (also referred to herein as "the disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carriers or diluents and a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof.

[0105] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that facilitate the formulation and / or administration and / or absorption by a subject of an active agent and 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, flavorants, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, sugars (such as lactose, amylose or starch), hydroxypropylmethylcellulose, fatty acid esters, polyvinylpyrrolidone, and coloring agents, etc. These formulations can be sterilized and (if desired) mixed with adjuvants (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, coloring and / or aromatic substances) and those similar that do not react adversely with or interfere with the activity of the compounds provided herein. Those skilled in the art will appreciate that other pharmaceutical excipients are suitable for use with the compounds of the present disclosure or their pharmaceutically acceptable salts.

[0106] The pharmaceutical compositions of the present disclosure optionally comprise one or more pharmaceutically acceptable carriers and / or diluents, such as lactose, starch, cellulose, and dextrose. Other excipients may also be included, such as flavoring agents, sweetening agents, and preservatives, such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben. A more complete list of suitable excipients can be found in the Pharmaceutical Excipients Handbook (5th Edition, Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th Edition) and The United States Pharmacopeia: The National Formulary (USP24NF19) published in 1999. A carrier, diluent, and / or excipient is “acceptable” insofar as it is compatible with the other ingredients of the pharmaceutical composition and not harmful to its recipient.

[0107] Method of treatment

[0108] The present disclosure provides a method of inhibiting certain mutant forms of epidermal growth factor receptor (EGFR) in a subject in need thereof, which comprises administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Mutant forms of EGFR include, for example, EGFR having LRTMCS mutations (exon 19 deletion (del19) or exon 21 (L858R) substitution mutation, T790M mutation, and C797S mutation). Subjects “in need of inhibiting EGFR” are those suffering from a disease in which a beneficial therapeutic effect can be achieved by inhibiting at least one mutant EGFR, such therapeutic effect being, for example, slowing disease progression, alleviating one or more symptoms associated with the disease, or prolonging the life of the subject in view of the disease.

[0109] In some embodiments, the present disclosure provides a method of treating a disease / condition / cancer associated with or regulated by mutant EGFR in a subject in need thereof, wherein inhibition of the mutant EGFR has a 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.

[0110] In another embodiment, the present disclosure provides a method of treating a subject having cancer, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. Cancers to be treated according to the disclosed method include lung cancer, colon cancer, urothelial carcinoma, breast cancer, prostate cancer, brain cancer, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, including metastases of all cancers listed (particularly brain metastases). Generally, the cancer is characterized by one or more of the EGFR mutations described herein. In a specific embodiment, the 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.

[0111] 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.

[0112] In another embodiment, a disease / condition / cancer associated with or regulated 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 (the 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):

[0113] EGFR Genotype

[0114]

[0115]

[0116]

[0117]

[0118] In another embodiment, a 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 del19.

[0119] In another embodiment, a 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 del19 T790M.

[0120] In another embodiment, a 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 del19 C797S.

[0121] In another embodiment, a 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 del19 C797X (C797G or C797N).

[0122] In another embodiment, a 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 del19 T790M C797S.

[0123] In another embodiment, a 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 del19 T790M (C797G or C797N).

[0124] In another embodiment, a 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 del19 L792X (L792F, L792H, or L792Y).

[0125] In another embodiment, the disease / condition / 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 T790M L792X (L792F, L792H, or L792Y).

[0126] In another embodiment, the disease / condition / 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 G796R (G796S).

[0127] In another embodiment, the disease / condition / 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 L792R (L792V or L792P).

[0128] In another embodiment, the disease / condition / 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 L718Q (L718V).

[0129] In another embodiment, the disease / condition / 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 T790M G796R (G796S).

[0130] In another embodiment, the disease / condition / 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 T790M L792R (L792V or L792P).

[0131] In another embodiment, the disease / condition / 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 T790M L718Q (L718V).

[0132] In another embodiment, the disease / condition / 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.

[0133] In another embodiment, a 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 T790M.

[0134] In another embodiment, a 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 C797S.

[0135] In another embodiment, a 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).

[0136] In another embodiment, a 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 T790M C797S.

[0137] In another embodiment, a 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 T790M C797X (797G or C797N).

[0138] In another embodiment, a 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).

[0139] In another embodiment, a 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 L790M L792X (L792F, L792H or L792Y).

[0140] In another embodiment, a 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 G796R (G796S).

[0141] In another embodiment, a 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).

[0142] In another embodiment, a 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 L718Q (L718V).

[0143] In another embodiment, a 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 T790M G796R (G796S).

[0144] In another embodiment, a 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 T790M L792R (L792V or L792P).

[0145] In another embodiment, a 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 T790M L718Q (L718V).

[0146] In another embodiment, a 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 del18.

[0147] In another embodiment, a 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 that includes EGFR G719X (G719A, G719S, G719C, G719R, G719D, or G719V).

[0148] In another embodiment, a 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 that includes EGFR E709X (E709K, E709H, or E709A).

[0149] In another embodiment, a 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 that includes EGFR E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).

[0150] In another embodiment, a 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 that includes EGFR G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.

[0151] In another embodiment, a 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 that includes EGFR ex20ins.

[0152] In another embodiment, a 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 that includes EGFR ex20ins L718Q.

[0153] In another embodiment, a 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 that includes EGFR ex20ins T790M.

[0154] In another embodiment, a 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 that includes EGFR ex20ins C797S.

[0155] In another embodiment, a 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 that includes EGFR S7681I.

[0156] In another embodiment, a 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 that includes EGFR T790M.

[0157] In another embodiment, a 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 that includes EGFR T790M C797S / GL792X (L792F, L792H, L792R, or L792Y).

[0158] In another embodiment, a 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.

[0159] In another embodiment, a 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.

[0160] In another embodiment, a 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.

[0161] In another embodiment, a 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.

[0162] In another embodiment, a 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 gefitinib.

[0163] In another embodiment, a 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 erlotinib.

[0164] In another embodiment, a 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.

[0165] In another embodiment, a 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.

[0166] In another embodiment, a 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.

[0167] In another embodiment, a 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.

[0168] Another embodiment is treating a subject with metastatic NSCLC, wherein the tumor has an activating exon 19 deletion or L858R EGFR mutation as detected by an approved molecular testing method and a resistance mutation disclosed herein. Another embodiment is a compound disclosed herein used in combination with a first-generation or third-generation TKI designated for treating a subject with metastatic NSCLC, wherein the tumor has T790M and C797S mutations as detected by an approved test, and the subject's disease has progressed during or after at least 2 prior EGFR TKI therapies.

[0169] Another embodiment is a compound of the present disclosure for treating a subject with metastatic NSCLC, wherein the disease of the subject with on-target EGFR resistance has progressed at or after any EGFR TKI. In a specific embodiment, the compound of the present disclosure is used in combination with a first-generation or third-generation TKI designated for treating a subject with metastatic NSCLC.

[0170] Another embodiment is a compound of the present disclosure for treating a subject with metastatic EGFRC797S mutation-positive NSCLC as detected by an approved molecular test, wherein the disease of the subject has progressed at or after first-line osimertinib. In a specific embodiment, the compound of the present disclosure is used in combination with a first-generation or third-generation TKI designated for treating a subject with metastatic NSCLC.

[0171] In a specific embodiment, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.

[0172] Those skilled in the art can easily determine certain EGFR alterations in a subject in cells, cancer, genes, or gene products using detection methods selected from those known in the art (e.g., hybridization-based methods, amplification-based methods, microarray analysis, flow cytometry analysis, DNA sequencing, next-generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescence in situ hybridization, dot blot, and Southern blot), e.g., whether a subject has one or more of the mutations or deletions described herein.

[0173] To detect one or more EGFR deletions and / or mutations, a primary tumor sample, circulating tumor DNA (ctDNA), circulating tumor cells (CTC), and / or circulating exosomes can be collected from a subject. The sample is processed, nucleic acids are isolated using techniques known in the art, and then the nucleic acids are sequenced using methods known in the art. The sequences are then aligned to the respective exons, and a measure of transcriptional expression (e.g., RPKM, or reads per kilobase per million mapped reads) is quantified. The raw sequence and exon array data can be obtained from sources such as TCGA, ICGC, and the NCBI Gene Expression Omnibus (GEO). For a given sample, the respective exon coordinates are annotated with gene identifier information, and the exons belonging to the kinase domain are marked. The exon levels are then z-score normalized across all tumor samples.

[0174] The compounds of the present disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be used to treat a subject who has become refractory to treatment with one or more other EGFR inhibitors. "Refractory" means that the subject's cancer previously responded to the drug but has subsequently responded poorly or not at all. In some embodiments, the subject has become refractory to 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.

[0175] Combination

[0176] The compounds of the present disclosure, their pharmaceutically acceptable salts or the pharmaceutical compositions disclosed herein can be used in combination with one or more additional pharmacologically active substances. For example, the present disclosure includes methods of treating a condition / disease / or cancer, which include administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein in combination with an EGFR (or EGFR mutant) inhibitor (such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, afatinib (AST 2818), amitinib (HS10296), BBT-176, BI-4020, CH7233163, gilteritinib, JND-3229, lazertinib, nazartinib (EGF 816), PCC-0208027, regorafenib (BPI-7711), TQB3804, zorifertinib (AZ-3759) or DZD9008); or an EGFR antibody (such as cetuximab, panitumumab, necitumumab, HLX07, JMT101); or a bispecific EGFR and MET antibody (such as amivantamab (JNJ-61186372, JNJ-372)). For treating cancer (e.g., NSCLC), using 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 an initial treatment before the cancer becomes refractory) can prevent or delay the cancer from becoming refractory. Generally, the cancer is characterized by one of the EGFR genotypes described herein.

[0177] Alternatively, the compounds of the present disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein may be administered in combination with other anti-cancer agents that are not EGFR inhibitors. For example, they may be administered in combination with the following: 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, abemacicilb, 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, such as 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);Multi-kinase protein inhibitors (e.g., anlotinib, midostaurin); PARP inhibitors (e.g., niraparib); platinum-based therapies (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 therapies (e.g., oncoprex).;

[0178] A "subject" is a human in need of treatment.

[0179] Methods and dosage forms of administration

[0180] The precise amount of a compound administered to a subject in an "effective amount" 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. Those skilled in the art will be able to determine an appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti-cancer agent, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Appropriate doses of approved therapeutic agents are known and can be adjusted by those skilled in the art based on the condition of the subject, the type of condition being treated, and the amount of the compound of formula (I) used in accordance with, e.g., the dosages reported in the literature and as recommended in the Physician's Desk Reference (57th edition, 2003).

[0181] "Treating" or "treatment" refers to obtaining the desired pharmacological and / or physiological effect. The effect can be therapeutic, including partially or substantially achieving one or more of the following results: partially or substantially reducing the degree of a disease, condition or cancer; alleviating or improving clinical symptoms or parameters 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.

[0182] The term "effective amount" means an amount that, when administered to a subject, results in a beneficial or desired outcome, including a clinical outcome, e.g., inhibition, suppression, or reduction of the symptoms of a condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be provided in unit dosage forms (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 g per day and in another alternative 10 mg to 1 g per day).

[0183] As used herein, the terms "administer", "administering", "administration", etc. refer to methods that can be used to enable a composition to be delivered to a desired site of biological action. These methods include, but are not limited to, intra-articular (into the joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, etc. Administration techniques useful for the agents and methods described herein are found, e.g., in Goodman & Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0184] In addition, the compounds of the present disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention can be co-administered with other therapeutic agents. As used herein, the terms "co-administer", "administer in combination with", and their grammatical equivalents are intended to include the administration of 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 simultaneously or at different times. In some embodiments, one or more compounds of the present disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present disclosure will be co-administered with other agents. These terms include the administration of two or more agents to a subject such that the two agents and / or their metabolites are present in the subject at the same time. They include co-administration in separate compositions simultaneously, co-administration in separate compositions at different times, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and other agents are administered in a single composition. In some embodiments, the compounds described herein and other agents are mixed in a composition.

[0185] 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., the subject, the disease, the disease state involved, the specific treatment). The treatment may involve daily or multiple-day or less-than-daily (e.g., weekly or monthly, etc.) dosages over a period of several days to several months or even years. However, those skilled in the art will immediately know the appropriate and / or equivalent dosage of the disclosed EGFR inhibitor upon looking up the dosage of an approved composition for treating the disease, as a guide.

[0186] The compounds of the present disclosure or their pharmaceutically acceptable salts can be administered to a patient in various forms, which depend on the selected route of administration, as understood by those skilled in the art. The compounds of this teaching can be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally and formulated into pharmaceutical compositions accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intralung, intrathecal, rectal, and topical modes of administration. Parenteral administration can be carried out by continuous infusion over a selected period of time.

[0187] 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 into a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0188] Generally, for oral therapeutic administration, the compounds of the present disclosure or their pharmaceutically acceptable salts can be combined with excipients and used in the form of edible tablets, lozenges, troches, capsules, elixirs, suspensions, syrups, wafers, etc.

[0189] Generally, for parenteral administration, solutions of the compounds of the present disclosure or solutions of their pharmaceutically acceptable salts can typically be prepared in water appropriately mixed with a surfactant (e.g., hydroxypropylcellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and their mixtures (with or without ethanol) and oils. Under the conditions of general storage and use, these formulations contain preservatives to prevent microbial growth.

[0190] Generally, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the compounds of the present disclosure for the temporary preparation of sterile injection solutions or dispersions are suitable.

[0191] The following examples are illustrative and not intended to limit the scope of the present disclosure in any way.

[0192] Examples

[0193] Examples

[0194] Preparation of Exemplary Compounds

[0195] Definition

[0196] TsOH 4-Methylbenzenesulfonic acid

[0197] TEA Triethylamine

[0198] THF Tetrahydrofuran

[0199] MsCl Methanesulfonyl chloride

[0200] DCM Dichloromethane

[0201] NH4Cl Ammonium chloride

[0202] MgSO4 Magnesium sulfate

[0203] NaN3 Sodium azide

[0204] DMF N,N-Dimethylformamide

[0205] EA Ethyl acetate

[0206] Na2SO4 Sodium sulfate

[0207] MeOH Methanol

[0208] N2 Nitrogen

[0209] H2 Hydrogen

[0210] LiAlH4 Lithium aluminum hydride

[0211] NaHCO3 Sodium bicarbonate

[0212] CbzCl Benzyl chloroformate

[0213] PE Petroleum ether

[0214] DAST N-Ethyl-N-(trifluorothio)ethylamine

[0215] HCl Hydrochloride

[0216] ACN Acetonitrile

[0217] DIPEA Diisopropylethylamine

[0218] DMSO Dimethyl sulfoxide

[0219] DMA N,N-Dimethylacetamide

[0220] h Hour

[0221] HPLC High performance liquid chromatography

[0222] min Minute

[0223] °C Degree Celsius

[0224] IC 50 50% inhibitory concentration

[0225] IPA Isopropyl alcohol

[0226] MTBE Methyl tert-butyl ether

[0227] rt Room temperature

[0228] TFA Trifluoroacetic acid

[0229] The method for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. The suitable solvent should not substantially react with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out (e.g., a temperature within the range from the freezing temperature to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0230] 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, for example, in Wuts & Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons: New Jersey, (2014), the entire content of which is incorporated herein by reference.

[0231] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by 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 for compound characterization:

[0232] LC-MS: Liquid chromatography - mass spectrometry (LC-MS) data (for analyzing the purity and identity of the sample) were obtained at 22.4 °C using an Agilent 1260 LC system with an Agilent 6120 mass spectrometer equipped with an ES-API ionization and a reversed-phase column with an Agilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0 x 50 mm dimensions). The mobile phase consisted of a mixture of 0.1% formic acid aqueous solution and 0.1% formic acid acetonitrile solution. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase over a 4-minute process was used. The flow rate was a constant 1 mL / min.

[0233] Alternatively, liquid chromatography - mass spectrometry (LC-MS) data (for analyzing the purity and identity of the sample) were obtained at 22.4 °C using a Shimadzu LCMS system with a Shimadzu LCMS mass spectrometer equipped with an ESI ionization and a reversed-phase column with an Agilent (Poroshel HPH-C18 2.7 μm particle size, 3.0 x 50 mm dimensions). The mobile phase consisted of 5 mM NH4HCO3 (or 0.05% TFA) aqueous solution and acetonitrile. A constant gradient of 90% aqueous / 10% organic to 5% aqueous / 95% organic mobile phase over a 2-minute process was used. The flow rate was a constant 1.5 mL / min.

[0234] Preparative LC-MS : Preparative HPLC was carried out at 22.4 °C on a Shimadzu Discovery Preparative system with a reversed-phase column with a Luna 5u C18(2) 100A, AXIA-packed 250 x 21.2 mm column. The mobile phase consisted of a mixture of 0.1% formic acid aqueous solution and 0.1% formic acid acetonitrile solution. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase over a 25-minute process was used. The flow rate was a constant 20 mL / min. The reaction carried out in the microwave was also carried out in a Biotage Initiator microwave device.

[0235] Alternatively, preparative HPLC was performed on a Waters Preparative system equipped with a column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm. The mobile phase consisted of a mixture of solvent water (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 over an 11-minute process was utilized. The flow rate was a constant 60 mL / min. The reaction carried out in the microwave was also performed in a Biotage Initiator microwave device.

[0236] Silica gel chromatography : On a Teledyne Isco Rf device, Isolera Four device or Isolera Prime device, silica gel chromatography was performed.

[0237] Proton NMR : 1H NMR spectra were obtained using a Varian 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.5 seconds, with a 1-second delay; 16 to 64 scans) or an Avance 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.99 seconds, with a 1-second delay; 4 to 64 scans) or an Avance 300MHz Unity Inova 300MHz NMR instrument (acquisition time = 5.45 seconds, with a 1-second delay; 4 to 64 scans). Unless otherwise stated, all protons were reported in parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent. 1 1H NMR spectra. Unless otherwise stated, all protons were reported in parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent.

[0238] SFC : Waters preparative system.

[0239] Chiral HPLC was performed on an Agilent 1260 preparative system.

[0240] Those skilled in the art should be aware that changes in gradient, column length, and flow rate are possible, and some conditions may be more suitable for compound characterization than others, depending on the chemical being analyzed.

[0241] General synthesis reaction formula:

[0242] Reaction Scheme 1:

[0243]

[0244] In certain embodiments, an optionally substituted bicyclic heteroaromatic A1 (where X = C or N, R = H, halogen, optionally substituted alkyl or -O-alkyl) is reacted with an optionally substituted azetidine 1 (where R1 = H, alkyl and R2 = optionally substituted methylsulfone or sulfonimide) using standard Buchwald coupling conditions to form an optionally substituted condensed product B1. The resulting material is further homogenized with an optionally substituted pyrimidine or triazine (where Y = C, N, O; n = 0, 1, 2; and either or both of R3 and R4 are H, halogen, optionally substituted alkyl, O-alkyl or N-alkyl) by a second Buchwald coupling to obtain the final product C1.

[0245] Synthesis example:

[0246] Example A1: Synthesis of 3-(ethylsulfonylmethyl)azetidine trifluoroacetate

[0247]

[0248] Step 1: Synthesis of tert-butyl 3-(ethylthiomethyl)azetidine-1-carboxylate:

[0249] tert-Butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol, 1 equiv) and sodium (ethylthio) (1.12 g, 13.4 mmol, 2 equiv) were dissolved in a mixed solvent (CH3CN / H2O = 3:1, 20 mL). The resulting solution was stirred at 60 °C for 18 h. The resulting solution was concentrated in vacuo. The residue was purified by chromatography using DCM / MeOH (30 / 1). 1.4 g (90%) of the title compound as an off-white solid was produced.

[0250] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56].

[0251] Step 2: Synthesis of tert-butyl 3-(ethylsulfonylmethyl)azetidine-1-carboxylate:

[0252] tert-Butyl 3-[(ethylthio)methyl]azetidine-1-carboxylate (1.4 g, 6.05 mmol, 1 equiv) was dissolved in a mixed solvent (THF:EtOH = 1:1, 10 mL), then potassium peroxymonosulfate (Oxone, 11.1 g, 18.1 mmol, 3 equiv) was added in 0.5 mL of water. The resulting solution was stirred at 0 °C for 10 min and then at room temperature for 2 h. The resulting solution was concentrated in vacuo and purified by chromatography using DCM / MeOH (20:1) to give 1.3 g (81%) of the title compound as a white solid.

[0253] Analytical data: LC-MS: (ES, m / z) = 286 [M+23].

[0254] Step 3: Synthesis of 3-(ethylsulfonylmethyl)azetidine trifluoroacetate:

[0255] 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 afford 800 mg of the title compound as a white solid.

[0256] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0257] Example A2: Synthesis of 3-(isopropylsulfonylmethyl)azetidine

[0258]

[0259] Step I: Synthesis of tert-butyl 3-(isopropylthiomethyl)azetidine-1-carboxylate:

[0260] 3-(Iodomethyl)azetidine-1-carboxylate tert-butyl ester (200 mg, 673 μmol, 1 equiv) and sodium (propan-2-ylthio) (66.0 mg, 673 μmol, 1 equiv) were dissolved in ACN (3 mL). The resulting solution was stirred at 80 °C for 16 hours. The resulting solution was extracted with DCM, then the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. 150 mg (90%) of the title compound was produced.

[0261] Step 2: Synthesis of tert-butyl 3-(isopropylsulfonylmethyl)azetidine-1-carboxylate:

[0262] Tert-butyl 3-[(propan-2-ylthio)methyl]azetidine-1-carboxylate (140 mg, 570 μmol, 1 equiv) and potassium peroxymonosulfate bisulfate (525 mg, 855 μmol, 1.50 equiv) 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. A sodium sulfite solution was added to the resulting solution to terminate the reaction, and then it was extracted with EA. The organic layers were combined and concentrated under vacuum. 130 mg (82%) of the title compound as an off-white solid was produced.

[0263] Analytical data: LC-MS: (ES, m / z) = 300 [M+23].

[0264] Step 3: Synthesis of 3-(isopropylsulfonylmethyl)azetidine trifluoroacetate:

[0265] Put DCM (4 mL) / TFA (1 mL) containing tert-butyl 3-[(propan-2-ylsulfonyl)methyl]azetidine-1-carboxylate (120 mg, 432 μmol) into an 8 mL tube. Stir the resulting solution at room temperature for 2 hours. Concentrate the resulting solution under vacuum. 70 mg of the title compound as a white solid is produced.

[0266] Analysis data: LC-MS: (ES, m / z) = 178 [M+1].

[0267] Example A3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidine

[0268]

[0269] Step 1: Synthesis of benzyl 3-((trifluoromethylthio)methyl)azetidine-1-carboxylate:

[0270] Stir a mixture of benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (100 mg, 0.450 mmol, 1 equiv), AgSCF3 (420 mg, 1.8 mmol, 4.00 equiv) and nBu4NI (1725 mg, 5.4 mmol, 12 equiv) in toluene (8 mL) at 80 °C for 12 hours. Filter out the solid. Concentrate the resulting mixture. Apply the residue to a silica gel column with EA / PE (3:1). 50 mg (36.4%) of the title compound as a light yellow solid is produced.

[0271] Analysis data: LC-MS: (ES, m / z = 306 [M+1].

[0272] Step 2: Synthesis of benzyl 3-((trifluoromethylsulfonyl)methyl)azetidine-1-carboxylate:

[0273] Add potassium peroxymonosulfate (330.5 mg, 1.97 mmol, 3 equiv) to a solution of benzyl 3-[[(trifluoromethyl)thio]methyl]azetidine-1-carboxylate (200 mg, 0.66 mmol, 1 equiv) in THF (1 mL) / EtOH (1 mL) / H2O (1 mL). Stir the resulting solution at 60 °C for 2 hours. Then quench the reaction by adding 1 mL of Na2S2O3 and extract with 3 x 5 mL of EA. Apply the residue to a silica gel column with EA / PE (3:1). 120 mg (54.5%) of the title compound as a light yellow oil is produced.

[0274] Analytical data: LC-MS: (ES, m / z) = 338 [M+1].

[0275] Step 3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidine hydrobromide:

[0276] 3-(Trifluoromethylsulfonylmethyl)azetidine-1-carboxylic acid benzyl ester (50 mg, 0.148 mmol, 1 equiv) was added to ethanepropionyl bromide (30% in AcOH, 1 mL). The resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated and gave 20 mg (66.4%) of 3-(trifluoromethylsulfonylmethyl)azetidine hydrobromide as a pale yellow solid. The crude product was used directly in the next step without further purification.

[0277] Analytical data: LC-MS: (ES, m / z): = 204 [M+1].

[0278] Example A4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0279]

[0280] Step 1: Synthesis of (2R,3S)-1-dibenzyl-2-methylazetidin-3-yl methanesulfonate:

[0281] (2R,3S)-1-Dibenzyl-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 warmed to room temperature and stirred 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.

[0282] Analytical data: LC-MS: (ES, m / z) = 332 [M+1].

[0283] Step 2: Synthesis of (S)-methyl 2-((2R,3S)-1-dibenzyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate

[0284] (2R,3S)-1-Dibenzyl-2-methylazetidin-3-yl methanesulfonate (26 g, 78.4 mmol) and methyl 2-(methylsulfonyl)acetate (15.3 g, 101 mmol) were dissolved in 260 mL of DMF, then NaH (3.75 g of 60% dispersion in mineral oil, 6.63 mmol) was added and stirred for about 15 minutes until hydrogen evolution ceased. The reaction mixture was heated at 80 °C overnight. The reaction was cooled, then diluted with about 200 mL of water and extracted with EA. The combined organic matter was washed with water and brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The residue was purified by chromatography (0 to 7% MeOH / DCM). The pure fractions were combined and evaporated to give 24 g (80%) of the title compound as a pale yellow foam.

[0285] Step 3: Synthesis of (2R,3S)-1-dibenzyl-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0286] (S)-Methyl 2-((2R,3S)-1-dibenzyl-2-methylazetidin-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. The flask was placed in a preheated block maintained at 150 °C. LC / MS indicated consumption of the starting material after 1.5 hours. It was cooled to room temperature and diluted with water, extracted with EA and the combined organic matter was washed with water and brine, 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 fractions were combined and evaporated to give 19 g (93%) of the title compound as a pale yellow foam.

[0287] Analytical data: LC-MS: (ES, m / z) = 330 [M+1].

[0288] Step 4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0289] To a solution of (2R,3S)-1-(diphenylmethyl)-3-(methylsulfonylmethyl)-2-methylazetidine (19 g, 57.3 mmol) in MeOH (270 mL) was added TFA (9 mL) and Pd(OH)2 (5.7 g). The reaction was stirred overnight at room temperature under a H2 atmosphere. The reaction mixture was filtered and evaporated to give the crude title compound as a light brown oil (17 g).

[0290] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0291] Example A5: Synthesis of 3-Methyl-3-(methylsulfonylmethyl)azetidine

[0292]

[0293] Step I: Synthesis of tert-Butyl 3-Methyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate:

[0294] At 0 °C, 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. The mixture was stirred at room temperature for 4 h. The mixture was diluted with DCM and washed with brine. The organic layer was dried and concentrated in vacuo to afford 350 mg (95%) of the title compound as a colorless oil.

[0295] Analytical data: LC-MS: (ES, m / z) = 224 [M+1-56].

[0296] Step 2: Synthesis of tert-Butyl 3-Methyl-3-(methylsulfonylmethyl)azetidine-1-carboxylate:

[0297] At room temperature, sodium methyl sulfide (175 mg, 2.50 mmol) was added to a solution of tert-butyl 3-[(methylsulfonyloxy)methyl]-3-methylazetidine-1-carboxylate (350 mg, 1.25 mmol) in ACN (30 mL). The resulting mixture was heated to reflux for 16 h. The mixture was diluted with DCM and washed with brine. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography with PE:EA = 1:1. This gave 250 mg (75%) of the title compound as a white solid.

[0298] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56].

[0299] Step 3: Synthesis of 3-Methyl-3-(methylsulfonylmethyl)azetidine:

[0300] At room temperature, potassium peroxymonosulfate (362 mg, 2.16 mmol) was added to a solution of tert-butyl 3-methyl-3-[(methylthio)methyl]azetidine-1-carboxylate (250 mg, 1.08 mmol) in THF / H2O / EtOH (5 / 5 / 5 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography with DCM:MeOH = 20:1. This gave 200 mg (88%) of the colorless title compound.

[0301] Analytical data: LC-MS: (ES, m / z) = 208 [M+1-56].

[0302] Step 4: Synthesis of 3-methyl-3-(methylsulfonylmethyl)azetidine:

[0303] At room temperature, TFA (5 mL) was added to a solution of 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 in vacuo to afford 100 mg of the title compound as a colorless oil.

[0304] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0305] Example A6: Synthesis of N-((azetidin-3-ylmethyl)(methyl)(oxo)-l6-sulfinyl)benzamide

[0306]

[0307] Step 1: Synthesis of tert-butyl 3-(methylthiomethyl)azetidine-1-carboxylate:

[0308] A mixture of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (5.05 g, 17 mmol, 1 equiv) and NaSMe (3.56 g, 25.5 mmol, 1.50 equiv) in MeCN (30 mL) and H2O (10 mL) was heated to 60 °C for 18 h. After cooling to room temperature, the mixture was concentrated and the residue was diluted with EA. The organic solution was washed with water and dried over Na2SO4. The solution was concentrated to afford the title compound as a pale yellow oil (3.69 g, quantitative).

[0309] Step 2: Synthesis of tert-butyl 3-(methylsulfinylmethyl)azetidine-1-carboxylate:

[0310] At 0 °C, mCPBA (2.92 g, 17 mmol, 1 equiv) was added portionwise to a solution of tert-butyl 3-[(methylthio)methyl]azetidine-1-carboxylate (3.69 g, 17 mmol, 1 equiv) in DCM (50 mL). The reaction was carried out at 0 °C for 2 h and then quenched by the addition of saturated NaHCO3 (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 afford the title compound as a pale yellow syrup (2.7 g, 68.2%).

[0311] Step 3: Synthesis of tert-butyl 3-(S-methylsulfinimidoylmethyl)azetidine-1-carboxylate:

[0312] A mixture of tert-butyl 3-(methylsulfinylmethyl)azetidine-1-carboxylate (2.68 g, 11.5 mmol, 1 equiv) contained in MeCN (60 mL), ammonium acetate (4.41 g, 57.4 mmol, 5.00 equiv), and PhI(OAc)2 (5.53 mg, 17.2 mmol, 1.50 equiv) was stirred at 35 °C for 18 h. 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 as a pale yellow syrup (1.5 g, 52.63%).

[0313] Analytical data: LC-MS: (ES, m / z) = 249 [M+1].

[0314] Step 4: Synthesis of tert-butyl 3-((N-benzoyl-S-methylsulfinimidoyl)methyl)azetidine-1-carboxylate:

[0315] At 0 °C, BzCl (281 mg, 2 mmol, 1.33 equiv) was added to a mixture of tert-butyl 3-{[imino(methyl)oxido-λ 6 -sulfanyl]methyl}azetidine-1-carboxylate (372 mg, 1.50 mmol, 1 equiv) and DMAP (366 mg, 3 mmol, 2 equiv) contained in DCM (6 mL). The reaction was carried out at room temperature for 3 h and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give the title compound as a yellow syrup (440 mg, 83.3%).

[0316] Analytical data: LC-MS: (ES, m / z) = 375 [M+23].

[0317] Step 5: Synthesis of N-((azetidin-3-ylmethyl)(methyl)(oxido)-λ6-sulfanyl)benzamide:

[0318] tert-Butyl 3-((N-benzoyl-S-methylsulfinimidoyl)methyl)azetidine-1-carboxylate (440 mg, 1.25 mmol, 1 equiv) contained 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 as a yellow syrup (315 mg, quantitative) trifluoroacetate.

[0319] Example A7: Synthesis of (2R,3S)-3-(ethylsulfinylmethyl)-2-methylazetidine

[0320]

[0321] Step 1: Synthesis of methyl 2-(ethylthio)acetate:

[0322] A solution of methyl 2-mercaptoacetate (20 g, 188 mmol), iodoethane (87.9 g, 564 mmol), and K2CO3 (39.5 g, 282 mmol) in THF (300 mL) was refluxed for 5 h. Water was added and the reaction mixture was extracted with EA. The organic layer was concentrated in vacuo to afford the title compound (20 g) as a pale yellow oil.

[0323] Analytical data: LC-MS: (ES, m / z) = 157 [M+23].

[0324] Step 2: Synthesis of methyl 2-(ethylsulfonyl)acetate:

[0325] At 0 °C, m-CPBA (76.7 g, 446 mmol) was added to a solution of methyl 2-(ethylthio)acetate (20 g, 149 mmol) in DCM (500 mL), and the reaction was stirred at room temperature overnight. The reaction mixture was washed with water and concentrated in vacuo. The residue was applied to a silica gel column with EA / PE (1:3) to afford the title compound (13.5 g) as a pale yellow oil.

[0326] Step 3: Synthesis of methyl 2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(ethylsulfonyl)acetate:

[0327] (2R,3S)-1-Diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (13 g, 39.2 mmol, Step 1, Example A4) and methyl 2-(ethylsulfonyl)acetate were dissolved in 130 mL of DMF, then NaH (1.12 g of 60% dispersion in mineral oil, 47.0 mmol) was added and stirred for about 15 min until hydrogen evolution ceased. The reaction mixture was heated at 80 °C overnight. The reaction was cooled, then diluted with water and extracted with EA. The combined organics were washed with water, brine, dried over sodium sulfate. Filtered and evaporated to give the crude product. The crude product was purified by chromatography (0 to 7% MeOH / DCM) to afford 8 g of the title compound as a pale yellow foam.

[0328] Analytical data: LC-MS: (ES, m / z) = 402 [M+1].

[0329] Step 4: Synthesis of (2R,3S)-1-diphenylmethyl-3-(ethylsulfonylmethyl)-2-methylazetidine:

[0330] 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 the mixture was heated to 150 °C for 1.5 h. After cooling to room temperature, it was diluted with 150 mL of water and extracted with EA (x3). The combined organic layers were washed with water (x3) and brine and dried over sodium sulfate. After filtration and evaporation, the crude product was obtained and purified by chromatography (0 to 5% MeOH / DCM) to give 6 g of the title compound as a pale yellow foam.

[0331] Analytical data: LC-MS: (ES, m / z) = 344 [M+1].

[0332] Step 5: Synthesis of (2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidine:

[0333] 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 overnight at room temperature under a H2 atmosphere. After filtration and concentration of the reaction under vacuum, 3.8 g of the title compound (trifluoroacetate) was obtained as a light brown oil.

[0334] Analytical data: LC-MS: (ES, m / z) = 178 [M+1].

[0335] Example A8: Synthesis of racemic-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxo)-l6-sulfinyl)benzamide

[0336]

[0337] Step 1: Synthesis of racemic-(trans)-tert-butyl 3-(hydroxymethyl)-2-methylazetidine-1-carboxylate:

[0338] At 0 °C, BH3 (21.0 mL, 21.0 mmol, 3 equiv., 1 M in THF) was added to a solution of racemic-(trans)-1-[(tert-butoxy)carbonyl]-2-methylazetidine-3-carboxylic acid (1.50 g, 7 mmol, 1 equiv.) contained in THF (20 mL). The reaction was carried out at room temperature for 18 h and then quenched with 1 N HCl (10 mL). The mixture was neutralized with 10% Na2CO3. The mixture was extracted with EA (30 mL * 3). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / EA = 1:1) to give the title compound as a colorless syrup (1.2 g, 85.7%).

[0339] Analysis data: 1 H-NMR (300 MHz, CD3Cl) δ ppm 4.09 - 3.99 (m, 1H), 3.91 (t, 1H, J = 8.5 Hz), 3.76 (dd, 2H, J = 6.5, 5.2 Hz), 3.60 (dd, 1H, J = 8.6, 6.0 Hz), 2.33 - 2.21 (m, 1H), 1.54 (t, 1H, J = 5.3 Hz), 1.46 (s, 9H), 1.41 (d, 3H, J = 6.3 Hz)

[0340] Step 2: Synthesis of racemic-(trans)-2-methyl-3-(methylsulfanylmethyl)azetidine-1-carboxylic acid tert-butyl ester:

[0341] At 0 °C, TEA (1.21 g, 12.0 mmol, 2 equiv.) was added to a solution of racemic-(trans)-3-(hydroxymethyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester (1.20 g, 6 mmol, 1 equiv.) contained in DCM (35 mL), followed by the addition of MsCl (889 mg, 7.80 mmol, 1.3 equiv.). The reaction was carried out at 0 °C for 1 h and then quenched with saturated NaHCO3 (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 equiv.) was added. The reaction was carried out at 60 °C for 18 h. After cooling to room temperature, EA (100 mL) was added. The mixture was washed with water (50 mL) and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 4:1) to give the title compound as a yellow oil (1.38 g, quantitative).

[0342] Analysis data: 1H-NMR (300 MHz, CD3Cl) δ ppm 3.96 (dd, 2H, J = 9.8, 7.0 Hz), 3.51 (dd, 1H, J = 8.7, 6.1 Hz), 2.69 (d, 2H, J = 7.8 Hz), 2.34 - 2.23 (m, 1H), 2.12 (s, 3H), 1.46 (s, 9H), 1.42 (d, 3H, J = 6.2 Hz).

[0343] Step 3: Synthesis of tert-butyl (rac)-(trans)-2-methyl-3-(methylsulfinylmethyl)azetidine-1-carboxylate:

[0344] At 0 °C, mCPBA (1.08 g, 6.30 mmol, 1.05 equiv) was added portionwise to a solution of tert-butyl (rac)-(trans)-2-methyl-3-[(methylthio)methyl]azetidine-1-carboxylate (1.38 g, 6 mmol, 1 equiv) in DCM (30 mL) over 2 h, and then quenched with saturated NaHCO3 (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 afford the title compound as a pale yellow oil (1.2 g, 81.1%).

[0345] Analytical data: 1 H-NMR (300 MHz, CD3Cl) δ ppm 4.15 - 4.02 (m, 2H), 3.66 (td, 1H, J = 9.0, 6.2 Hz), 3.11 - 2.79 (m, 2H), 2.74 - 2.65 (m, 1H), 2.61 (d, 3H, J = 3.9 Hz), 1.51 - 1.40 (m, 12H).

[0346] Step 4: Synthesis of tert-butyl (rac)-(2R,3S)-2-methyl-3-(S-methylsulfinimidomethyl)azetidine-1-carboxylate:

[0347] A mixture of tert-butyl (rac)-(trans)-3-(methylsulfinylmethyl)-2-methylazetidine-1-carboxylate (1.23 g, 5 mmol, 1 equiv), PhI(OAc)2 (2.41 g, 7.50 mmol, 1.5 equiv), and ammonium acetate (2.31 g, 30.0 mmol, 6 equiv) in ACN (30 mL) was stirred at 35 °C for 18 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 15:1) to afford the title compound as a pale yellow syrup (600 mg, 45.8%).

[0348] Analytical data: LC-MS: (ES, m / z) = 263 [M+1].

[0349] Step 5: Synthesis of racemic-(trans)-3-((N-benzoyl-S-methylsulfinimidoyl)methyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester:

[0350] At 0 °C, benzoyl chloride (274 mg, 1.95 mmol, 1.3 eq) was added to a mixture of racemic-(trans)-3-{[imino(methyl)oxido-λ 6 -sulfanyl]methyl}-2-methylazetidine-1-carboxylic acid tert-butyl ester (393 mg, 1.5 mmol, 1 eq) and DMAP (292 mg, 2.40 mmol, 1.6 eq) in DCM (5 mL). The reaction was carried out at 0 °C for 2 h, then quenched with saturated NaHCO3 (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 as a colorless syrup (400 mg, 72.9%).

[0351] Analytical data: LC-MS: (ES, m / z) = 367 [M+1].

[0352] Step 5: Synthesis of racemic-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxido)-l6-sulfinyl)benzamide:

[0353] A solution of racemic-(trans)-3-((N-benzoyl-S-methylsulfinimidoyl)methyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester (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 as a colorless syrup (370 mg, 69.6%).

[0354] Analytical data: LC-MS: (ES, m / z) = 267 [M+1].

[0355] 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

[0356]

[0357] Step 1: Synthesis of tert-butyl 3-methyl-4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate:

[0358] At 0 °C, trimethylsilyl trifluoromethanesulfonate (12.50 g, 56.25 mmol, 1.20 eq) was added dropwise to a pre-cooled solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (10 g, 46.88 mmol, 1 eq) and TEA (11.38 g, 112.5 mmol, 2.40 eq) in toluene (100 mL). The resulting mixture was stirred at 0 °C for 4 h. The solution was quenched with water (50 mL) and extracted twice with EA. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (10.5 g, 78.5%).

[0359] Analysis data: 1 H-NMR (400 MHz, 6d-DMSO) δ ppm 3.68 - 3.66 (m, 2H), 3.43 (t, 2H, J = 5.8 Hz), 2.05 (tq, 2H, J = 6.0, 2.0 Hz), 1.53 - 1.47 (m, 3H), 1.41 (s, 9H), 0.15 (s, 9H).

[0360] Step 2: Synthesis of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate:

[0361] 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 h. The solution was diluted with water (100 mL) and extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This gave 8 g (98.8%) of the title compound as a pale yellow oil.

[0362] Step 3: Synthesis of tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate:

[0363] A mixture of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (7 g, 30.2 mmol, 1 equiv) and NaBH4 (1.37 g, 36.2 mmol, 1.12 equiv) in methanol (70 mL) was stirred at room temperature for 3 h. 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 compound of the title compound as a pale yellow oil.

[0364] Step 4: Synthesis of 3-fluoro-3-methylpiperidin-4-ol hydrochloride:

[0365] To a reaction vessel was added tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (7 g, 30.0 mmol), DCM (70 mL) and hydrochloric acid (4 M in dioxane, 50 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction precipitate was collected by filtration to give the title compound as a white solid (4.5 g).

[0366] Step 5: Synthesis of 1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol:

[0367] A mixture of 2-chloropyrimidin-4-amine (2.7 g, 20.8 mmol, 1 equiv), 3-fluoro-3-methylpiperidin-4-ol hydrochloride (3.86 g, 22.8 mmol, 1.10 equiv) and TEA (6.30 g, 62.4 mmol, 3 equiv) in isopropanol (45 mL) was stirred in a sealed vial at 130 °C for 5 h. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated in vacuo to give the crude compound of the title compound as a yellow oil (6 g).

[0368] 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 NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 10% B to 30% B in 35 min; 254 / 220 nm; Rt: 21.12 min). The eluate containing the desired compound was evaporated to dryness to give the cis racemate (1.3 g, 26.1%) as a white solid and the trans racemate (500 mg, 10.0%) as a white solid.

[0369] 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 eluate 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).

[0370] Analytical data: LC-MS: (ES, m / z) = 227 [M + 1]; 1 ¹H-NMR (400 MHz, 6d-DMSO) δ ppm 7.71 (d, 1H, J = 5.6 Hz), 6.37 (s, 2H), 5.69 (d, 1H, J = 5.6 Hz), 4.93 (d, 1H, J = 6.5 Hz), 4.66 (ddd, 1H, J = 14.1, 9.1, 2.2 Hz), 4.60 - 4.50 (m, 1H), 3.44 (ddt, 1H, J = 24.8, 11.0, 5.6 Hz), 3.02 - 2.78 (m, 2H), 1.69 - 1.53 (m, 2H), 1.31 (d, 3H, J = 21.2 Hz).

[0371] 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 eluate 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 as a white solid (180 mg) (peak 1) and (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol as a white solid (190 mg) (peak 2).

[0372] Analytical data: LC-MS: (ES, m / z) = 227 [M+1]; 1 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H J = 5.7 Hz), 6.40 (s, 2H), 5.70 (d, 1H, J = 5.6 Hz), 5.24 (d, 1H, J = 4.5 Hz), 3.83 - 3.56 (m, 5H), 1.78 (ddt, 1H, J = 12.9, 10.0, 4.7 Hz), 1.48 - 1.36 (m, 1H), 1.24 (d, 3H, J = 22.5 Hz).

[0373] 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

[0374]

[0375] Step 1: Synthesis of tert-butyl 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate:

[0376] Dissolve / suspend tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (2 g, 8.50 mmol, 1 equiv), trimethylsulfonium iodide (5.61 g, 25.5 mmo, 3 equiv) and t-BuOK (2.85 g, 25.5 mmol, 3 equiv) in t-BuOH. Stir the mixture at 50 °C for 2 days. Add water to the reaction mixture and extract with EA. Concentrate the organic layer in vacuo. This gives 2 g (89%) of the title compound.

[0377] Step 2: Synthesis of 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane:

[0378] Add TFA (3 mL) to DCM (10 mL) containing tert-butyl 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 7.59 mmol). Stir the reaction at room temperature for 2 h. Concentrate the mixture in vacuo to give 2.1 g of the title compound as the trifluoroacetate salt. Use the crude product directly in the next step.

[0379] Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0380] Step 3: Synthesis of (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine and (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine:

[0381] TEA (12.3 g, 122 mmol, 2 equiv) was added to DMSO (100 mL) containing 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane (10 g, 61.2 mmol, 1 equiv) and 2-chloropyrimidin-4-amine (8.41 g, 61.2 mmol, 1 equiv). The reaction was stirred at 100 °C for 2 h. Water was added to the mixture and extracted with EA. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by FLASH (5% MeOH / DCM) to give the title compound (2.1 g).

[0382] 2.1 g of the product was separated by preparative SFC-HPLC using the following conditions (column: CHIRALART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: EtOH; flow rate: 40 mL / min; gradient: 35% B; 254 nm). The eluate containing the desired compound was evaporated to dryness to give 800 mg of peak 1: (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine and 805 mg of peak 2: (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine.

[0383] Peak 1: (S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or (R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine:

[0384] Analytical data: LC-MS: (ES, m / z) = 257 [M+1]; 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.74 (d, 1H, J = 5.6 Hz), 6.52 (s, 2H), 5.77 (d, 1H, J = 5.7 Hz), 4.46 (t, 2H, J = 7.8 Hz), 4.23 (td, 1H, J = 14.1, 7.2 Hz), 3.93 - 3.74 (m, 2H), 3.53 (ddd, 1H, J = 13.2, 8.9, 3.5 Hz), 2.74 (dt, 1H, J = 11.4, 7.5 Hz), 2.50 - 2.39 (m, 1H), 2.10 - 1.97 (m, 1H), 1.90 (ddt, 1H, J = 13.4, 8.9, 4.3 Hz).

[0385] 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:

[0386] Analysis data: LC-MS: (ES, m / z) = 257 [M+1]; 1 H-NMR (300 MHz, 6d-DMSO) δ ppm 7.75 (d, 1H, J = 5.7 Hz), 6.52 (s, 2H), 5.77 (d, 1H, J = 5.6 Hz), 4.46 (t, 2H, J = 7.8 Hz), 4.23 (td, 1H, J = 14.2, 7.2 Hz), 3.93 - 3.74 (m, 2H), 3.53 (ddd, 1H, J = 13.1, 8.8, 3.5 Hz), 2.74 (dt, 1H, J = 11.4, 7.5 Hz), 2.50 - 2.41 (m, 1H), 2.10 - 1.97 (m, 1H), 1.91 (ddt, 1H, J = 13.4, 8.8, 4.3 Hz).

[0387] Example B3: Synthesis of 2-(4-methylpiperazin-1-yl)pyrimidin-4-amine

[0388]

[0389] A mixture of 2-chloropyrimidin-4-amine (300 mg, 2.31 mmol, 1 equiv), 1-methylpiperazine (231 mg, 2.31 mmol, 1 equiv) and TEA (466 mg, 4.62 mmol, 2 equiv) in IPA (3 mL) was heated to 100 °C for 1.5 h. LCMS showed complete reaction. The mixture was diluted with water and extracted with EA. The organic phase was dried, concentrated and purified by FLASH (DCM:MeOH = 5%). This gave 270 mg (60%) of the title compound as a yellow solid.

[0390] Analytical data: LC-MS: (ES, m / z) = 194 [M+1].

[0391] Example B4: Synthesis of 2-(4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0392]

[0393] 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 afford 1.12 g (53%) of the title compound as a pale yellow solid.

[0394] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0395] Example B5: Synthesis of 2-morpholinopyrimidin-4-amine

[0396]

[0397] A mixture of 2-chloropyrimidin-4-amine (296 mg, 2.3 mmol, 1 equiv), morpholine (200 mg, 2.3 mmol, 1 equiv) and TEA (460 mg, 4.6 mmol, 2.0 equiv) in IPA (5 mL) was stirred at 100 °C for 5 h. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative TLC to afford 360 mg (87%) of the title compound as a yellow solid.

[0398] Analytical data: LC-MS: (ES, m / z) = 181 [M+1].

[0399] Example B6: Synthesis of racemic-2-(1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-amine

[0400]

[0401] A mixture of 1-oxa-7-azaspiro[3.5]nonane (1.27 g, 10 mmol, 1 equiv), DIPEA (2.6 g, 20 mmol, 2 equiv), and 2-chloropyrimidin-4-amine (1.29 g, 10 mmol, 10.00 equiv) in DMSO (12 mL) was stirred 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 afford 1.3 g (59%) of the title compound as a pale yellow solid.

[0402] Analytical data: LC-MS: (ES, m / z) = 221 [M+1].

[0403] Example B7: Synthesis of 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrimidin-4-amine

[0404]

[0405] 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), and the mixture was heated to 100 °C and stirred overnight. LCMS showed the reaction was complete. Water was added to the mixture and it was extracted with EA. The organic phase was concentrated and purified by FLASH (5% MeOH / DCM). This gave 500 mg (37%) of the title compound as a pale yellow solid.

[0406] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0407] Example B8: Synthesis of 2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrimidin-4-amine

[0408]

[0409] In a 20 mL sealed tube, IPA (10 mL) containing 2-chloropyrimidin-4-amine (600 mg, 4.63 mmol, 1 equiv), (3R,4S)-3,4-difluoropyrrolidine (495 mg, 4.63 mmol, 1 equiv), and TEA (1.39 g, 13.8 mmol, 3 equiv) was added under nitrogen and heated to 100 °C for 12 h. The reaction mixture was filtered and evaporated to afford 800 mg (86%) of the title compound as a yellow solid.

[0410] Analytical data: LC-MS: (ES, m / z) = 201 [M+1].

[0411] Example B9: Synthesis of 1-(4-aminopyrimidin-2-yl)-4-methylpiperidin-4-ol

[0412]

[0413] A mixture of 4-methylpiperidin-4-ol (230 mg, 2 mmol, 1 equiv), 2-chloropyrimidin-4-amine (258 mg, 2 mmol, 1 equiv) and TEA (300 mg, 3 mmol, 1.5 equiv) in IPA (5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was purified by preparative TLC (6% MeOH / DCM) to give the title compound 210 mg (50%).

[0414] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0415] 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

[0416]

[0417] Step 1: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol:

[0418] A mixture of cis-4-methoxypiperidin-3-ol (1.7 g, 13 mmol, 1 equiv), 2-chloropyrimidin-4-amine (1.7 g, 13 mmol, 1 equiv) and TEA (2.6 g, 26 mmol, 2.0 equiv) in IPA (15 mL) was stirred overnight at 100 °C. The mixture was concentrated and the residue was purified by FLASH (5% MeOH / DCM) to give the title compound as a yellow solid 2.4 g (82.7%).

[0419] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0420] 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:

[0421] 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 eluate 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).

[0422] 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

[0423]

[0424] Step 1: Synthesis of cis-5-fluoro-3,3-dimethylpiperidin-4-ol:

[0425] cis-5-Fluoro-4-hydroxy-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (4.7 g, 19.0 mmol) was added to an HCl solution (30 mL) in 1,4-dioxane, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to obtain 3.6 g of the title compound as the hydrochloride as a white solid.

[0426] Step 2: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol:

[0427] 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). The resulting mixture was stirred at 100 °C for 3 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC: column: XBridge 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 min; 254 / 220 nm; Rt: 6.92 min; The eluate containing the desired compound was evaporated to dryness to give the title compound as a white solid (1.8 g, 39.4%).

[0428] Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[0429] 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:

[0430] 1.8 g of the cis racemate was separated on column by preparative chiral HPLC: 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 eluate containing the desired compound was 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%).

[0431] (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:

[0432] Analytical data: LC-MS: (ES, m / z) = 241 [M+1]; 1 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.69 (d, 1H, J = 5.7 Hz), 6.36 (s, 2H), 5.67 (d, 1H, J = 5.6 Hz), 5.00 (d, 1H, J = 5.4 Hz), 4.75 - 4.47 (m, 1H), 4.09 - 3.93 (m, 1H), 3.86 - 3.67 (m, 1H), 3.62 (d, 1H, J = 12.9 Hz), 3.37 (ddd, 1H, J = 22.0, 5.5, 2.9 Hz), 3.31 - 3.18 (m, 1H), 0.95 - 0.78 (m, 6H).

[0433] 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

[0434]

[0435] Step 1: Synthesis of racemic-cis-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0436] At -78 °C, 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). The mixture was stirred overnight at room temperature. 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, evaporated to give 4.8 g (crude) of the title compound as a yellow solid.

[0437] Analytical data: LC-MS: (ES, m / z) = 178 [M+1 - 56].

[0438] Step 2: Synthesis of racemic-cis-3-fluoro-4-methylpiperidin-4-ol:

[0439] 3-Fluoro-4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (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.

[0440] Analytical data: LC-MS: (ES, m / z) = 134 [M+1].

[0441] Step 3: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol:

[0442] 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 overnight at 120 °C. 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 (1.3 g) as a light yellow solid.

[0443] Analytical data: LC-MS: (ES, m / z) = 227 [M+1].

[0444] 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:

[0445] 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 as a white solid (450 mg, stereochemistry determined by X-ray crystallography of compound 117) and peak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol as a white solid (470 mg).

[0446] Peak 1: (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol:

[0447] Analytical data: 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.73 (d, 1H, J = 5.6 Hz), 6.40 (s, 2H), 5.72 (d, 1H, J = 5.6 Hz), 4.71 (s, 1H), 4.39 - 3.92 (m, 3H), 3.38 (dddd, 2H, J = 40.5, 13.6, 10.3, 4.6 Hz), 1.62 (q, 1H, J = 6.2 Hz), 1.42 (td, 1H, J = 13.6, 12.0, 4.3 Hz,), 1.20 (s, 3H).

[0448] Peak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

[0449] Analysis data: 1 H-NMR (300 MHz, 6d-DMSO) δ ppm 7.73 (d, 1H, J = 5.6 Hz), 6.40 (s, 2H), 5.72 (d, 1H, J = 5.6 Hz), 4.71 (s, 1H), 4.36 - 4.07 (m, 2H), 4.07 - 3.95 (m, 1H), 3.44 (ddd, 1H, J = 13.2, 9.4, 4.8 Hz), 3.31 (ddd, 1H, J = 13.4, 8.3, 3.2 Hz), 1.61 (ddt, 1H, J = 14.1, 7.2, 3.9 Hz), 1.41 (ddd, 1H, J = 13.9, 10.3, 4.4 Hz), 1.20 (s, 3H).

[0450] 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

[0451]

[0452] Step 1: Synthesis of 1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol:

[0453] 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.

[0454] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0455] 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:

[0456] 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, held at 50% for 2.0 minutes; back pressure (psi): 1500.000; flow rate: 2 mL / min to obtain 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 are light yellow solids.

[0457] Analytical data: 1 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.74 (d, 1H, J = 5.6 Hz), 6.45 (s, 2H), 5.74 (d, 1H, J = 5.7 Hz), 5.41 (s, 1H), 4.58 (dt, 1H, J = 13.4, 9.4 Hz), 4.29 (d, 1H, J = 13.3 Hz), 3.59 - 3.38 (m, 1H), 3.23 (ddd, 1H, J = 13.8, 9.6, 4.7 Hz), 1.62 (q, 2H, J = 5.8, 4.8 Hz), 1.22 (d, 3H, J = 1.6 Hz)

[0458] Example B14: Synthesis of racemic-(trans)-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

[0459]

[0460] To a solution of 2-chloropyrimidin-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). The mixture was heated to 100 °C and stirred overnight. LCMS showed complete reaction. Water was added to the mixture and it was extracted with EA. The organic phase was concentrated and purified by FLASH. This gave 180 mg (65%) of the title compound as a yellow solid.

[0461] Analytical data: LC-MS: (ES, m / z) = 213 [M+1].

[0462] Example B15: Synthesis of racemic-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol

[0463]

[0464] Step 1: Synthesis of (1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-ol:

[0465] A mixture of commercially available racemic-(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.

[0466] Analytical data: LC-MS: (ES, m / z) = 128 [M+1].

[0467] Step 2: Synthesis of racemic-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol:

[0468] A mixture of racemic-(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 h. 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.

[0469] Analytical data: LC-MS: (ES, m / z) = 221 [M+1].

[0470] Example B16: Synthesis of racemic - 1 - (1 - (4 - aminopyrimidin - 2 - yl) - 3 - fluoropyrrolidin - 3 - yl)ethanol

[0471]

[0472] Step 1: Synthesis of racemic - tert - butyl 3 - fluoro - 3 - (methoxy(methyl)carbamoyl)pyrrolidine - 1 - carboxylate:

[0473] A solution of racemic - 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 organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with EA / PE (1:6) to afford 900 mg (76%) of the title compound as a pale yellow oil.

[0474] Analytical data: LC - MS: (ES, m / z) = 221 [M + 1 - 56].

[0475] Step 2: Synthesis of racemic - tert - butyl 3 - acetyl - 3 - fluoropyrrolidine - 1 - carboxylate:

[0476] At - 60 °C, under N2, bromo(methyl)magnesium (7.7 mL, 2.5 M, 16.2 mmol) was added 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). The reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous NH4Cl solution (10 mL), extracted with EA and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 780 mg (crude) of the title compound as a pale yellow oil.

[0477] Step 3: Synthesis of racemic - tert - butyl 3 - fluoro - 3 - (1 - hydroxyethyl)pyrrolidine - 1 - carboxylate:

[0478] At 0 °C, NaBH4 (191 mg, 5.05 mmol) was added to a solution of racemic - tert - butyl 3 - acetyl - 3 - fluoropyrrolidine - 1 - carboxylate (780 mg, 3.37 mmol) in MeOH (10 mL), and the mixture was stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo and extracted with EA, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 700 mg of the product as a pale yellow oil.

[0479] Step 4: Synthesis of racemic - 1 - (3 - fluoropyrrolidin - 3 - yl)ethanol:

[0480] To a solution of racemic 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 the mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo to give 500 mg of the product as a pale yellow solid.

[0481] Step 5: Synthesis of racemic - 1 - (1 - (4 - aminopyrimidin - 2 - yl)-3 - fluoropyrrolidin - 3 - yl)ethanol:

[0482] A solution of racemic - 1 - (3 - fluoropyrrolidin - 3 - yl)ethan - 1 - ol (550 mg, 4.13 mmol), 2 - chloropyrimidin - 4 - amine (535 mg, 4.13 mmol) and TEA (1.24 g, 12.3 mmol) in IPA (6 mL) was heated to 100 °C and stirred overnight. The reaction was concentrated in vacuo and purified by TLC (DCM:MeOH = 15:1) to give 800 mg of the product as a pale yellow solid.

[0483] Analytical data: LC - MS: (ES, m / z)=227 [M + 1].

[0484] Example B17: Synthesis of racemic - 2 - (4 - aminopyrimidin - 2 - yl)-2 - azabicyclo[2.2.1]heptan - 5 - ol

[0485]

[0486] Step 1: Synthesis of racemic - 2 - azabicyclo[2.2.1]heptan - 5 - ol:

[0487] To a solution of racemic 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 h. LCMS showed complete reaction and the solution was concentrated to give 450 mg of the product, which was used directly in the next step.

[0488] Analytical data: LC - MS: (ES, m / z)=114 [M + 1].

[0489] Step 2: Synthesis of racemic - 2 - (4 - aminopyrimidin - 2 - yl)-2 - azabicyclo[2.2.1]heptan - 5 - ol:

[0490] Stir a mixture of 2-chloropyrimidin-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) at 110 °C overnight. LCMS showed the reaction was complete. Add water to the mixture and extract with EA. Concentrate the organic phase and purify by FLASH. This gave 180 mg of the title compound as a yellow solid.

[0491] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0492] Example B18: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

[0493]

[0494] Step 1: Synthesis of cis-4-fluoropiperidin-3-ol:

[0495] Dissolve (cis)-tert-butyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (300 mg) in dioxane (1 mL). Add dioxane containing HCl (4 M, 2 mL) and stir for 1 hour. Concentrate the reaction mixture to give the title compound as a white solid (140 mg).

[0496] Analytical data: LC-MS: (ES, m / z) = 120 [M+1].

[0497] Step 2: Synthesis of cis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol:

[0498] Stir a mixture of 2-chloropyrimidin-4-amine (129 mg), cis-4-fluoropiperidin-3-ol (118 mg), and DIPEA (384 mg) in DMSO at 120 °C for 12 hours. Add water, extract the mixture with EA and purify by preparative TLC (5% MeOH / DCM) to give the title compound as a yellow solid (95 mg).

[0499] Analytical data: LC-MS: (ES, m / z) = 213 [M+1].

[0500] Example B19: Synthesis of 2-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)pyrimidin-4-amine

[0501]

[0502] To a solution of 2-chloropyrimidin-4-amine (1 g, 7.71 mmol) in IPA (12 mL) was added 1,4-dioxo-8-azaspiro[4.5]decane (1.10 g, 7.71 mmol) and TEA (1.55 g, 15.4 mmol). The mixture was 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 was obtained as a yellow solid, 1.5 g (82.8%).

[0503] Analytical data: LC-MS: (ES, m / z) = 237 [M+1].

[0504] Example B20: Synthesis of racemic tert-butyl 4-(4-aminopyrimidin-2-yl)-2-(difluoromethyl)piperazine-1-carboxylate

[0505]

[0506] A mixture of racemic 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 h. 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 as a yellow solid (200 mg, 72%).

[0507] Analytical data: LC-MS: (ES, m / z) = 330 [M+1].

[0508] 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

[0509]

[0510] To a solution of racemic trans-3-methylpiperidin-4-ol (800 mg, 6.94 mmol) in IPA (10 mL) was added 2-chloropyrimidin-4-amine (1.34 g, 10.4 mmol) and TEA (2.1 g, 20.8 mmol). The mixture was stirred at 100 °C for 8 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash using the following conditions: DCM:MEOH = 10:1. This gave 1.2 g (83.3%) of the title compound as a white solid.

[0511] The 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.

[0512] Analytical data: LC - MS: (ES, m / z) = 209[M + 1].

[0513] Example B22: Synthesis of racemic - (cis)-1-(4 - aminopyrimidin - 2 - yl)-3 - fluoro - 3,4 - dimethylpiperidin - 4 - ol and racemic - (trans)-1-(4 - aminopyrimidin - 2 - yl)-3 - fluoro - 3,4 - dimethylpiperidin - 4 - ol

[0514]

[0515] Step 1: Synthesis of tert - butyl 3 - fluoro - 4 - hydroxy - 3,4 - dimethylpiperidine - 1 - carboxylate:

[0516] At 0 °C, LiMe (27 mL, 43.2 mmol) was added to a mixture of racemic - tert - butyl 3 - fluoro - 3 - methyl - 4 - oxopiperidine - 1 - carboxylate (5 g, 21.6 mmol, from step 2 of Example B1) in THF. 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) and used directly in the next step.

[0517] Step 2: Synthesis of 3 - fluoro - 3,4 - dimethylpiperidin - 4 - ol:

[0518] 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 a crude product.

[0519] Step 3: Synthesis of racemic-(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol and racemic-(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol:

[0520] 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 h. Water was added and the suspension was extracted with EA. The organic phase was concentrated and the residue was purified by FLASH (EA in 50% PE) to give the title compound (1.5 g) as a pale yellow solid.

[0521] 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 give 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.

[0522] Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[0523] Example B23: 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

[0524]

[0525] Step 1: Synthesis of racemic-3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester:

[0526] At room temperature, TEA (7.07 g, 70.0 mmol, 2 eq) was added to a solution of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate (7.95 g, 35 mmol, 1 eq) contained in DMF (35 mL), and then TMSCl (5.67 g, 52.5 mmol, 1.50 eq) was added. The reaction was carried out at 120 °C for 18 h and then quenched with saturated NaHCO3. The mixture was extracted with MTBE. The organic layers were combined and concentrated. The residue was dissolved in DMF (70 mL), and Selectfluor (12.3 g, 35 mmol, 1 eq) was added at 0 °C. The mixture was stirred at room temperature for 2 h and then quenched with brine. The mixture was extracted with EA. The organic layers were combined and concentrated to give a mixture (6.5 g) 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.

[0527] Step 2: Synthesis of methyl (±)-3-ethyl-3-fluoro-4-oxopiperidine-1-(9H-fluoren-9-yl)carboxylate:

[0528] A solution of tert-butyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate (6.5 g, 26.4 mmol, 1 eq) in TFA (20 mL) and DCM (60 mL) was stirred at room temperature for 2 h. The mixture was concentrated and redissolved in DCM (120 mL), TEA (13.3 g, 132 mmol, 5.00 eq) was added, and then methyl chloroformate (9H-fluoren-9-yl) (10.2 g, 39.5 mmol, 1.50 eq) was added. The reaction was carried out at room temperature for 2 h. Saturated NaHCO3 was added. The mixture was extracted with DCM. The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / EA = 30:1) to give the title compound as a colorless syrup (3.7 g, 30.53% over 2 steps).

[0529] Analytical data: LC-MS: (ES, m / z) = 390 [M+23].

[0530] Step 3: Synthesis of methyl (±)-cis-3-ethyl-3-fluoro-4-hydroxypiperidine-1-(9H-fluoren-9-yl)carboxylate and methyl (±)-trans-3-ethyl-3-fluoro-4-hydroxypiperidine-1-(9H-fluoren-9-yl)carboxylate:

[0531] Place 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (500 mg, 1.361 mmol, 1 equiv), methanol (10 mL), and NaBH4 (102.97 mg, 2.722 mmol, 2 equiv) into a 25 mL round-bottom flask. Stir the resulting solution at 0 °C for 1 h. Then quench the reaction by adding 1 mL of water. Concentrate the resulting mixture. Apply the residue to a silica gel column with EA / PE (1:1). This yields 200 mg of peak 1: racemic-cis-3-ethyl-3-fluoro-4-hydroxypiperidine-1-(9H-fluoren-9-yl)carboxylic acid methyl ester (identified as cis by 2D NMR) and 100 mg of peak 2: racemic-trans-3-ethyl-3-fluoro-4-hydroxypiperidine-1-(9H-fluoren-9-yl)carboxylic acid methyl ester (identified as trans by 2D NMR).

[0532] Analytical data: LC-MS: (ES, m / z) = 370 [M+1].

[0533] Step 4: Synthesis of racemic-cis-3-ethyl-3-fluoropiperidin-4-ol and racemic-trans-3-ethyl-3-fluoropiperidin-4-ol:

[0534] Add diethylamine (3 mL) to a solution of racemic-cis-3-ethyl-3-fluoro-4-hydroxypiperidine-1-(9H-fluoren-9-yl)carboxylic acid methyl ester (200.0 mg, 0.54 mmol) in methanol (15 mL). Stir the resulting solution at 0 °C for 2 h. Concentrate the resulting mixture. This yields 60 mg (75%) of the title compound as a pale yellow oil.

[0535] Analytical data: LC-MS: (ES, m / z) = 148 [M+1].

[0536] 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:

[0537] Stir a mixture of racemic-cis-3-ethyl-3-fluoropiperidin-4-ol (1 g, 6.794 mmol, 1 equiv), 2-chloropyrimidin-4-amine (0.88 g, 6.794 mmol, 1 equiv), and TEA (2.06 g, 20.38 mmol, 3 equiv) in IPA (10.00 mL) at 100 °C for 12 h. Concentrate the resulting mixture. Apply the residue to a silica gel column with DCM / MeOH (5:1). This yields 1 g (61.3%) of racemic-cis-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol as a pale yellow solid.

[0538] Analysis data: LC-MS: (ES, m / z) = 241 [M+1]; 1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J = 5.6 Hz), 6.35 (s, 2H), 5.69 (d, 1H, J = 5.6 Hz), 4.88 (d, 1H, J = 6.5 Hz), 4.62 (ddd, 1H, J = 14.0, 9.0, 1.9 Hz), 4.52 - 4.40 (m, 1H), 3.63 - 3.42 (m, 1H), 3.08 - 2.86 (m, 2H), 1.84 (ddt, 1H, J = 15.1, 9.4, 7.5 Hz), 1.75 - 1.49 (m, 3H), 0.92 (t, 3H, J = 7.6 Hz)

[0539] Stir a mixture of racemic - trans - 3 - ethyl - 3 - fluoropiperidin - 4 - ol (900 mg, 6.114 mmol, 1 equiv), 2 - chloropyrimidin - 4 - amine (792.12 mg, 6.114 mmol, 1 equiv) and TEA (1856.15 mg, 18.343 mmol, 3 equiv) in IPA (10.00 mL) at 100 °C for 12 h. Concentrate the resulting mixture. Apply the residue onto a silica gel column with DCM / MeOH (5:1). This gives 500 mg (34.03%) of racemic - trans - 1 - (4 - aminopyrimidin - 2 - yl) - 3 - ethyl - 3 - fluoropiperidin - 4 - ol as a pale yellow solid.

[0540] Analysis data: LC-MS: (ES, m / z) = 241 [M+1].

[0541] 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

[0542]

[0543] Stir 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) at 100 °C for 2 h. Concentrate the mixture and purify the residue by preparative TLC with DCM / MeOH (20:1). This gives 700 mg (56%) of racemic-(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a yellow solid. Purify this racemic-(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol by preparative HPLC using the following conditions: column: CHIRALPAK ID-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; Evaporate the eluate containing the desired compound to dryness to obtain 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%).

[0544] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0545] Example B25: Synthesis of 2-(1,4-dioxo-9-azaspiro[5.5]undec-9-yl)pyrimidin-4-amine

[0546]

[0547] Stir a mixture of 2-chloropyrimidin-4-amine (80 mg, 617 μmol), 1,4-dioxo-9-azaspiro[5.5]undecane (97.0 mg, 617 μmol) and TEA (186 mg, 1.85 mmol) in IPA (2 mL) at 100 °C for 3 h. Dilute the reaction mixture with water, extract with EA and wash with brine. Dry the organic layer, evaporate and purify by preparative TLC (DCM:MeOH = 20:1) to give the title compound as a yellow solid (85 mg, 55%).

[0548] Analytical data: LC-MS: (ES, m / z) = 251 [M+1].

[0549] 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

[0550]

[0551] Step 1: Synthesis of racemic-5-fluoro-5-methyl-4-(triethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester:

[0552] At -70 °C, to a solution of racemic-3-fluoro-3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (4.7 g, 20.3 mmol) in THF (30 mL) was added LiHDMS (30.4 mL, 30.4 mmol) and the mixture was stirred at -30 °C to -20 °C for 1 h. Then TESCl (6.11 g, 40.6 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EA. The organic layer was dried and concentrated. The residue was purified on a silica gel column with 10% EtOAc / PE to give the title compound as a colorless oil (6.2 g, 88%).

[0553] Step 2: Synthesis of racemic-3,5-difluoro-3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester:

[0554] At 10 °C, to a solution of racemic-3-fluoro-3-methyl-4-[(triethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (6.2 g, 17.9 mmol) in DMF (30 mL) was added SelectFluor (12.6 g, 35.8 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EA. The organic layer was dried and concentrated. The residue was purified on a silica gel column with 30% EtOAc / PE to give the title compound as a pale yellow oil (3 g, 67%).

[0555] Step 3: Synthesis of racemic-3,5-difluoro-4-hydroxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0556] Under an ice - cream bath, NaBH4 (1.06 g, 28 mmol) was added to a solution of racemic tert - butyl 3,5 - difluoro - 3 - methyl - 4 - oxopiperidine - 1 - carboxylate (3.5 g, 14.0 mmol) in MeOH. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with EA and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 2.9 g (82.6%) of the title compound as a colorless oil.

[0557] Analytical data: LC - MS: (ES, m / z) = 196 [M + 1 - 56].

[0558] Step 4: Synthesis of racemic 3,5 - difluoro - 3 - methylpiperidin - 4 - ol:

[0559] 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 in vacuo to give the title compound as a salt (1.6 g).

[0560] Analytical data: LC - MS: (ES, m / z) = 152 [M + 1].

[0561] 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:

[0562] 3,5-Difluoro-3-methylpiperidin-4-ol (900 mg, 5.95 mmol) contained in DMSO (10 mL), 2-chloropyrimidin-4-amine (1.6 g, crude, TFA salt), and DIEA (3.07 g, 23.8 mmol) were placed into three 40 mL sealed tubes. The resulting solution was stirred at 120 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with water, extracted with EA, and concentrated under vacuum. The residue was purified by preparative HPLC with 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 in 7 min; 254; 220 nm. This yielded 380 mg of (3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol and (3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol as a white solid, 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. The isomers were further separated by SFC to obtain 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 obtain 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.

[0563] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0564] Example B27: Synthesis of racemic - 2-(6 - fluoro - 1,4 - dioxo - 8 - azaspiro[4.5]dec - 8 - yl)pyrimidin - 4 - amine

[0565]

[0566] Step 1: Synthesis of benzyl 1,4 - dioxo - 8 - azaspiro[4.5]decane - 8 - carboxylate:

[0567] At 0 °C, benzyl chloroformate (386 mg, 3.83 mmol) was added to a solution of 1,4 - dioxo - 8 - azaspiro[4.5]decane (500 mg, 3.49 mmol) and TEA (386 mg, 3.83 mmol) in THF (10 mL), and the mixture was 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.

[0568] Analysis data: LC - MS: (ES, m / z) = 278 [M + 1].

[0569] Step 2: Synthesis of racemic - 6 - fluoro - 1,4 - dioxo - 8 - azaspiro[4.5]decane - 8 - carboxylate benzyl ester:

[0570] At room temperature, H2SO4 (14.1 mg, 144 μmol) was added to a mixture of benzyl 1,4 - dioxo - 8 - azaspiro[4.5]decane - 8 - carboxylate (800 mg, 2.88 mmol) and SelectFluor (2.04 g, 5.76 mmol) in ACN (10 mL), and the mixture was 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.

[0571] Analysis data: LC - MS: (ES, m / z) = 296 [M + 1].

[0572] Step 3: Synthesis of racemic - 6 - fluoro - 1,4 - dioxo - 8 - azaspiro[4.5]decane:

[0573] At room temperature, a mixture of racemic - benzyl 6 - fluoro - 1,4 - dioxo - 8 - azaspiro[4.5]decane - 8 - carboxylate (600 mg, 2.03 mmol) and Pd / C (239 mg, 2.03 mmol) in MeOH (20 mL) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, evaporated to afford the title compound (340 mg) as a brown oil.

[0574] Analytical data: LC - MS: (ES, m / z) = 162 [M + 1].

[0575] Step 4: Synthesis of racemic - 2 - (6 - fluoro - 1,4 - dioxo - 8 - azaspiro[4.5]dec - 8 - yl)pyrimidin - 4 - amine:

[0576] A mixture of 2 - chloropyrimidin - 4 - amine (180 mg, 1.38 mmol), racemic - 6 - fluoro - 1,4 - dioxo - 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 afford the title compound (200 mg) as a yellow solid.

[0577] Analytical data: LC - MS: (ES, m / z) = 255 [M + 1].

[0578] 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

[0579]

[0580] 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) contained in IPA (20 mL). The mixture was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column with DCM:MeOH = 20:1. This gave 1.2 g of trans-(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a colorless oil. trans-(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (1.2 g, 5.35 mmol) was purified by chiral SFC using the following conditions: column: CHIRALPAK IC, 2*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: EtOH(8 mmol / L NH3.MeOH)-HPLC; flow rate: 40 mL / min; gradient: 25% B; 254 nm. This gave 450 mg of peak 1: (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a white solid and 460 mg of peak 2: (3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a white solid.

[0581] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0582] Example B29: Synthesis of 2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethanamine

[0583]

[0584] Step 1: Synthesis of tert-butyl 3-((2-hydroxyethylthio)methyl)azetidine-1-carboxylate:

[0585] To a 50 mL flask was added tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (3 g, 10.0 mmol) dissolved in THF (10 mL). To this was added 2-mercaptoethanol (781 mg, 10.0 mmol), K2CO3 (4.20 g, 30.0 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EA. The organic layer was dried and concentrated to give the title compound (2.8 g) as a brown oil (crude).

[0586] Analytical data: LC-MS: (ES, m / z) = 248 [M+1].

[0587] Step 2: Synthesis of tert-butyl 3-((2-hydroxyethylsulfonyl)methyl)azetidine-1-carboxylate:

[0588] Add tert-butyl 3-{[(2-hydroxyethyl)thio]methyl}azetidine-1-carboxylate (2.7 g, 1.2 mmol) dissolved in THF / EtOH / H2O (10 mL) to a 50 mL flask. To this, add potassium peroxymonosulfate (744 mg, 1.2 mmol). Stir the mixture at room temperature for 3 hours. Extract the reaction with EA. Dry the organic layer and concentrate to obtain the title compound as a yellow solid (2.4 g crude).

[0589] Step 3: Synthesis of tert-butyl 3-(vinylsulfonylmethyl)azetidine-1-carboxylate:

[0590] At 0 °C, add methanesulfonyl chloride (1.8 g) to a solution of tert-butyl 3-[(2-hydroxyethylsulfonyl)methyl]azetidine-1-carboxylate (2.2 g) and TEA (2.5 g) in DCM (10 mL). Stir the mixture at room temperature for 3 hours. Add water and extract with EA. Dry the organic layer and concentrate to obtain the title compound as a brown solid (1.8 g).

[0591] Analytical data: LC-MS: (ES, m / z) = 206 [M+1-56].

[0592] Step 4: Synthesis of tert-butyl 3-((2-(dimethylamino)ethylsulfonyl)methyl)azetidine-1-carboxylate:

[0593] Add tert-butyl 3-[(vinylsulfonyl)methyl]azetidine-1-carboxylate (1.8 g) dissolved in DCM (10 mL) to a 50 mL flask. To this, add dimethylamine hydrochloride (1.2 g), TEA (2.3 g). Stir the mixture at room temperature for 3 hours. Add water and extract with DCM. Combine the organic layers and purify using DCM / MeOH (20 / 1) to obtain the title compound as a brown solid (1.5 g).

[0594] Analytical data: LC-MS: (ES, m / z) = 307 [M+1].

[0595] Step 5: Synthesis of 2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethylamine:

[0596] 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 h. The solvent was removed under reduced pressure to afford 1.2 g (crude) of the title compound as the trifluoroacetate salt as a yellow solid.

[0597] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0598] Example B30: Synthesis of 3-(1-oxa-7-azaspiro[3.5]non-7-yl)-1,2,4-triazin-5-amine

[0599]

[0600] Step 1: Synthesis of 3,5-dichloro-1,2,4-triazine:

[0601] At room temperature, DIEA (17.1 g, 132.7 mmol) and POCl3 (27.1 g, 176.8 mmol) were added 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). The solution was then heated at 120 °C for 3 h. Excess POCl3 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 Na2SO4 and concentrated to dryness to afford the crude product which was used in the next step without further purification (200 mg, crude).

[0602] Step 2: Synthesis of 3-chloro-1,2,4-triazin-5-amine:

[0603] NH3 / MeOH (20 mL, 7.0 M) was added to a solution of 3,5-dichloro-1,2,4-triazine (200 mg, 1.33 mmol) in THF (5 mL) and the resulting mixture was stirred at room temperature for 30 min; LC-MS showed the reaction was complete. Evaporation to dryness and purification by preparative HPLC afforded the title compound (50 mg, 20% yield over 2 steps).

[0604] Analytical data: LC-MS: (ES, m / z) = 131 [M+1].

[0605] Step 3: Synthesis of 3-(1-oxa-7-azaspiro[3.5]non-7-yl)-1,2,4-triazin-5-amine:

[0606] At room temperature, 1-oxa-7-azaspiro[3.5]nonane (29.1 mg, 229 μmol) was added to a solution of 3-chloro-1,2,4-triazin-5-amine (30 mg, 229 μmol) and DIPEA (88.4 mg, 686 μmol) in DMSO (1 mL). The mixture was stirred at 120 °C for 2 h. 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 gave 30 mg (59%) of the title compound as a pale yellow solid.

[0607] Analytical data: LC-MS: (ES, m / z) = 222 [M+1].

[0608] Example B31: Synthesis of 3-(4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

[0609]

[0610] At room temperature, 4-methoxypiperidine (26.3 mg, 229 μmol) was added to a solution of 3-chloro-1,2,4-triazin-5-amine (30 mg, 229 μmol) and DIEA (59 mg, 458 μmol) in DMSO (1 mL). The mixture was stirred at 120 °C for 2 h. 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 gave 30 mg (62%) of the title compound as a pale yellow solid.

[0611] Analytical data: LC-MS: (ES, m / z) = 210 [M+1].

[0612] Example B32: Synthesis of 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0613]

[0614] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylate:

[0615] At 0 °C, NaH (152 mg, 3.82 mmol) was added to a solution of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (700 mg, 3.19 mmol) in THF (5 mL). MeI (497 mg, 3.5 mmol) was added and the mixture was warmed to room temperature and stirred for 2 h. 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 as a yellow oil (750 mg, crude).

[0616] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56].

[0617] Step 2: Synthesis of (3R,4S)-3-fluoro-4-methoxypiperidine:

[0618] TFA (2 mL) was added to a solution of tert-butyl (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylate (750 mg, 3.21 mmol) in DCM (10 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated to give the title compound as a brown oil (700 mg crude).

[0619] Step 3: Synthesis of 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine:

[0620] 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 h. The reaction mixture was diluted with water, extracted with EA and washed with brine. The organic layer was dried over Na2SO4, filtered, evaporated and purified by column chromatography (50% EA / PE) to give the title compound as a yellow solid (550 mg).

[0621] Example B33: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0622]

[0623] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate:

[0624] At 0 °C, sodium hydride (218.90 mg, 9.122 mmol, 4 eq) was added to (3S,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.280 mmol, 1 eq) contained in THF (10 mL). After stirring for 20 minutes, methyl iodide (1294.73 mg, 9.122 mmol, 4 eq) was added. The resulting solution was stirred at 0 °C for an additional 1 hour. Then the reaction was quenched by adding 10 mL of water. The solid was filtered off. The resulting solution was extracted with EA and concentrated in vacuo. This gave 500 mg (94.1%) of the title compound as a pale yellow oil.

[0625] Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56].

[0626] Step 2: Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine:

[0627] A solution of (3S,4R)-tert-butyl 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 in vacuo to give 500 mg (crude) of the title compound as a solid.

[0628] Step 3: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine:

[0629] 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 hours. The solvent was removed in vacuo and the residue was purified by FLASH (5% MeOH / DCM) to give 3.3 g (66%) of the title compound as a pale yellow solid.

[0630] Analytical data: LC-MS: (ES, m / z) = 227 [M+1]. 1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J = 5.6 Hz), 6.39 (s, 2H), 5.71 (d, 1H, J = 5.6 Hz), 4.83 (d, 1H, J = 49.3 Hz), 4.60 - 4.49 (m, 1H), 4.29 (d, 1H, J = 13.3 Hz), 3.55 - 3.42 (m, 1H), 3.28 (d, 1H, J = 13.3 Hz), 3.20 - 3.04 (m, 1H), 1.76 - 1.48 (m, 2H)

[0631] Example B34: Synthesis of 2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)pyrimidin-4-amine

[0632]

[0633] 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 at 100 °C overnight. The solvent was removed and the residue was purified by preparative TLC (5% MeOH / DCM) to give the title compound as a yellow solid (300 mg, 73.8%).

[0634] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0635] Example B35: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol

[0636]

[0637] Step 1: Synthesis of racemic-4-hydroxy-2,4-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

[0638] At 0 °C, methyllithium (822 mg, 37.4 mmol) was added dropwise to racemic-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (4 g, 18.7 mmol) in THF. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water / ice and extracted with EA. The organic layers were combined and concentrated in vacuo. This gave 4.2 g (98.1%) of the title compound as a yellow solid.

[0639] Analytical data: LC-MS: (ES, m / z) = 230 [M+1].

[0640] Step 2: Synthesis of racemic-2,4-dimethylpiperidin-4-ol

[0641] To a stirred solution of racemic 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 h. The reaction was concentrated in vacuo. The crude product was used directly in the next step.

[0642] Analytical data: LC-MS: (ES, m / z) = 130 [M+1].

[0643] Step 3: Synthesis of racemic 1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol:

[0644] To a stirred solution of racemic 2,4-dimethylpiperidin-4-ol (2 g, 15.4 mmol) and 2-chloropyrimidin-4-amine (2.18 g, 16.9 mmol) in NMP was added DIEA (3.97 g, 30.8 mmol). The mixture was stirred at 150 °C overnight. After cooling to room temperature, the reaction was extracted with DCM / MeOH (10:1). The residue was purified by preparative TLC with DCM / MeOH (10:1). This gave 0.2 g of the title compound as a white solid.

[0645] Analytical data: LC-MS: (ES, m / z) = 223 [M+1].

[0646] Example B36: Synthesis of racemic 2-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-4-amine

[0647]

[0648] A mixture of 2-chloropyrimidin-4-amine (100 mg, 0.7719 mmol), racemic 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 h. 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.

[0649] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0650] Example B37: Synthesis of tert-butyl 3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate

[0651]

[0652] Step 1: Synthesis of benzyl 3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate:

[0653] Into a 100 mL round-bottom flask were placed benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.2 g, 5.42 mmol), TEA (822 mg, 8.13 mmol), and methanesulfonyl chloride (620 mg, 5.42 mmol) contained in DCM (20 mL). The resulting solution was stirred at room temperature for 6 hours. The solution was washed with water and purified by preparative TLC (20% EA / PE). This gave 1.0 g of the title compound as a white solid.

[0654] Analytical data: LC-MS: (ES, m / z) = 300 [M+1].

[0655] Step 2: Synthesis of tert-butyl 3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylthio)azetidine-1-carboxylate:

[0656] 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 Cs2CO3 (1.15 g, 3.54 mmol) contained in DMF (2 mL) was stirred at 100 °C for 2 hours. Water was added and the mixture was extracted with EA. The organic phase was concentrated to give 480 mg of the title compound as a white solid.

[0657] Analytical data: LC-MS: (ES, m / z) = 293 [M+1-100].

[0658] Step 3: Synthesis of tert-butyl 3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylsulfonyl)azetidine-1-carboxylate:

[0659] Potassium peroxymonosulfate (4.21 g, 6.86 mmol) was added to a solution of tert-butyl 3-[({1-[(tert-butoxy)carbonyl]azetidin-3-yl}thio)methyl]azetidine-1-carboxylate (900 mg, 2.29 mmol) contained in EtOH / THF / H2O (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.

[0660] Analytical data: LC-MS: (ES, m / z) = 325 [M+1-100].

[0661] Step 4: Synthesis of tert-butyl 3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate:

[0662] Under a hydrogen atmosphere, a mixture of 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) was stirred at room temperature for 4 hours. The solid was filtered off and the mother solvent was concentrated under reduced pressure to afford the title compound (480 mg) as a white solid.

[0663] Analytical data: LC-MS: (ES, m / z) = 291 [M+1].

[0664] Example B38: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)azepan-4-ol

[0665]

[0666] A mixture of racemic-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 hours. The reaction mixture was concentrated and purified by preparative TLC (DCM:MeOH = 5:1) to afford the title compound (90 mg) as a yellow solid.

[0667] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0668] 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

[0669]

[0670] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-methoxypiperidine-1-carboxylate:

[0671] At 0 °C, NaH (20.23 mg, 0.843 mmol, 2 equiv) was added to a solution of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (100 mg, 0.422 mmol, 1 equiv) in DMF (5 mL). After stirring for 30 min, MeI (89.74 mg, 0.632 mmol, 1.5 equiv) was added and the mixture was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with EA and concentrated. This gave 150 mg (crude) of the title compound as a pale yellow solid.

[0672] Analytical data: LC-MS: (ES, m / z) = 252 [M+1].

[0673] Step 2: Synthesis of 3,3-difluoro-4-methoxypiperidine:

[0674] A solution of tert-butyl 3,3-difluoro-4-methoxypiperidine-1-carboxylate (300 mg, 1.194 mmol) in 4 M HCl / dioxane (5 mL) and DCM (15 mL) was stirred at room temperature for 12 h. The resulting mixture was concentrated. This gave 280 mg (crude) of the title compound as the HCl salt as a pale yellow solid.

[0675] Analytical data: LC-MS: (ES, m / z) = 152 [M+1].

[0676] 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:

[0677] A mixture of 3,3-difluoro-4-methoxypiperidine (1.5 g, 9.923 mmol, 1 equiv), 2-chloropyrimidin-4-amine (1.29 g, 9.923 mmol, 1 equiv) and TEA (3.01 g, 29.77 mmol, 3 equiv) in IPA (10 mL) was stirred at 100 °C for 3 h. The resulting mixture was concentrated. The residue was subjected to silica gel column with EA / PE (1:1). This gave 1.1 g (45.4%) of the title compound as a yellow solid.

[0678] The 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, held at 50% for 2 minutes; backpressure (psi): 1500.000; flow rate (mL / min) to obtain peak 1: (S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine or (R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine as a pale yellow solid (500 mg) 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 as a pale yellow solid (500 mg).

[0679] Analysis data: LC-MS: (ES, m / z) = 245 [M+1].

[0680] Example B40: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-5,5-dimethylpiperidin-4-ol

[0681]

[0682] Step 1: Synthesis of racemic-5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester:

[0683] At 0 °C, under a N2 atmosphere, TMSOTf (14.6 g, 65.8 mmol) was added 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. 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 in vacuo. The crude product was used directly in the next step.

[0684] At 0 °C, Selectfluor (1.55 g, 4.4 mmol) was added 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, 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 with PE / EA (5:1). This gave 500 mg (51%) of the title compound as a pale yellow solid.

[0685] Analytical data: LC-MS: (ES, m / z) = 246 [M+1].

[0686] Step 2: Synthesis of tert-butyl 3,3-difluoro-5,5-dimethyl-4-oxopiperidine-1-carboxylate:

[0687] At -78 °C, under a N2 atmosphere, lithium bis(trimethylsilyl)amide (LiHMDS, 46.4 mg, 814 μmol) was added to a solution of racemic tert-butyl 5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylate (100 mg, 407 μmol) in THF. The mixture was stirred at -78 °C for 10 minutes and N-fluorobenzenesulfonimide (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 gave 60 mg (56%) of the title compound as a pale yellow solid.

[0688] Analytical data: LC-MS: (ES, m / z) = 208 [M+1-56].

[0689] Step 3: Synthesis of racemic tert-butyl 3,3-difluoro-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate:

[0690] At room temperature, sodium borohydride (NaBH4, 45.9 mg, 1.21 mmol) was added to a solution of tert-butyl 3,3-difluoro-5,5-dimethyl-4-oxopiperidine-1-carboxylate (80 mg, 303 μmol) in MeOH. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA and water. The organic layer was concentrated in vacuo. The crude product (75 mg) was used directly in the next step.

[0691] Analytical data: LC-MS: (ES, m / z) = 210 [M+1-56].

[0692] Step 4: Synthesis of racemic 3,3-difluoro-5,5-dimethylpiperidin-4-ol:

[0693] 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 in vacuo to give 40 mg (86%) of the title compound as a brown liquid.

[0694] Analytical data: LC-MS: (ES, m / z) = 166 [M+1].

[0695] Step 5: Synthesis of racemic - tert - butyl 2-(3,3 - difluoro - 4 - hydroxy - 5,5 - dimethylpiperidin - 1 - yl)pyrimidin - 4 - ylcarbamate:

[0696] A mixture of racemic - 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 K3PO4 (383 mg, 1.81 mmol) in DMSO was stirred at 100 °C under N2 atmosphere for 2 h. Water was added and the mixture was extracted with EA. The organic phase was concentrated and the residue was purified by preparative TLC with DCM / MeOH (20:1). This gave 100 mg (36%) of the product as a yellow solid.

[0697] Analytical data: LC - MS: (ES, m / z) = 359 [M + 1].

[0698] Step 6: Synthesis of racemic - 1-(4 - aminopyrimidin - 2 - yl)-3,3 - difluoro - 5,5 - dimethylpiperidin - 4 - ol:

[0699] 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) in DCM / TFA (10 / 3 mL) was stirred 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.

[0700] Analytical data: LC - MS: (ES, m / z) = 259 [M + 1].

[0701] Example B41: Synthesis of racemic - 1-(5 - amino - 1,2,4 - triazin - 3 - yl)-3 - fluoro - 3 - methylpiperidin - 4 - ol

[0702]

[0703] At room temperature, 3-fluoro-3-methylpiperidin-4-ol (Step 4, B1; 284 mg, 2.14 mmol) was added to a solution of 3-chloro-1,2,4-triazin-5-amine (280 mg, 2.14 mmol) and TEA (648 mg, 6.42 mmol) in IPA (5 mL). The mixture was stirred at 100 °C for 2 h. The solvent was removed and the residue was purified by preparative TLC with PE / EA (5:1). This gave 260 mg (53%) of 1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol as a yellow solid. The product was purified by column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5B to 10B in 7 min; 254 / 220 nm. This gave 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.

[0704] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[0705] Example B42: 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

[0706]

[0707] Step 1: Synthesis of racemic-(cis)-3,4-dihydroxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0708] 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 K2OsO4.2H2O (37.4 mg, 101.2 μmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with EA. The organic layer was dried over Na2SO4. Filtered and concentrated to dryness to give the title compound (180 mg) as a dark yellow oil.

[0709] Analytical data: LC-MS: (ES, m / z) = 176 [M+1-56].

[0710] Step 2: Synthesis of racemic-(cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0711] At room temperature, MeI (367 mg, 2.59 mmol) was added to a mixture of Ag2O (399 mg, 1.72 mmol) and (cis)-3,4-dihydroxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester (200 mg, 864 μmol) in DMF (20 mL). The mixture was stirred at room temperature for 2 days. The solid was filtered off and the filtrate was diluted with EA and washed with H2O. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 160 mg of racemic-(cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester mixed with racemic-(cis)-4-hydroxy-3-methoxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester as a colorless oil, which was used in the next step without further purification.

[0712] Analytical data: LC-MS: (ES, m / z) = 190 [M+1-56].

[0713] Step 3: Synthesis of racemic-(cis)-4-methoxy-3-methylpiperidin-3-ol:

[0714] 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) and racemic-(cis)-4-hydroxy-3-methoxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester in DCM (15 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo 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.

[0715] Analytical data: LC-MS: (ES, m / z) = 146 [M+1].

[0716] 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:

[0717] At room temperature, 2-chloropyrimidin-4-amine (100 mg, 771 μmol) was added to TEA (388 mg, 3.85 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 was heated to 100 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by preparative TLC with DCM:MeOH = 25:1. This gave 120 mg of racemic-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-ol mixed with racemic-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol as a brown oil.

[0718] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0719] Example B43: Synthesis of 3-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

[0720]

[0721] At room temperature, 3-chloro-1,2,4-triazin-5-amine (64.6 mg, 495 μmol) was added 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). The mixture was stirred at 120 °C for 2 h. 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.

[0722] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[0723] Example B44: Synthesis of 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethanol

[0724]

[0725] Stir 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) at 100 °C for 12 h. Dilute the reaction mixture with water and extract with EA. Dry the organic layer over Na2SO4, filter, evaporate and purify by column chromatography (DCM:MeOH = 20:1) to give the title compound (270 mg) as a yellow solid.

[0726] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0727] Example B45: Synthesis of racemic-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol

[0728]

[0729] Step 1: Synthesis of racemic-4-methoxypiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester:

[0730] At 0 °C, add NaH (1.3 g, 34.5 mmol) to a solution of racemic-4-hydroxypiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester (6.0 g, 23.0 mmol) in DMF (50 mL). After stirring for 10 min, add methyl iodide (4.8 g, 34.5 mmol). Stir the mixture at room temperature overnight. Add water and extract the mixture with EA. Wash the organic phase with water, dry and concentrate. Purify the residue by FLASH (20% EA / PE) to give 3.0 g (47%) of the title compound as a colorless oil.

[0731] Analytical data: LC-MS: (ES, m / z) = 274 [M+1].

[0732] Step 2: Synthesis of racemic-3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester:

[0733] At 0 °C, add LiBH4 (2 M in THF, 15 mmol) to a solution of racemic-4-methoxypiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester (2 g, 7.3 mmol) in THF (40 mL). Stir the mixture at room temperature for 2 h. Add water and extract the mixture with EA. Wash the organic phase with water, dry and concentrate to give 1.2 g (67%) of the title compound as a colorless oil.

[0734] Analytical data: LC-MS: (ES, m / z) = 246 [M+1].

[0735] Step 3: Synthesis of racemic-(4-methoxypiperidin-3-yl)methanol:

[0736] 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 h. The solvent was removed under reduced pressure to give 700 mg of the title compound trifluoroacetate as a yellow oil.

[0737] Analytical data: LC-MS: (ES, m / z) = 146 [M+1].

[0738] Step 4: Synthesis of racemic-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol:

[0739] A mixture of racemic-(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 racemic-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol as a pale yellow solid.

[0740] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0741] Example B46: Synthesis of (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol

[0742]

[0743] Step 1: Synthesis of (4-methoxypiperidin-4-yl)methanol:

[0744] 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 h. 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 400 mg of the title compound as a colorless oil (crude).

[0745] Analytical data: LC-MS: (ES, m / z) = 146 [M+1].

[0746] Step 2: Synthesis of (1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol:

[0747] Stir 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) at 100 °C for 2 h. Concentrate the mixture and purify the residue on preparative TLC (EA:PE = 2:1) to afford the title compound (35 mg) as a pale yellow solid.

[0748] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[0749] Example B47: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-2-methylpiperidin-4-ol

[0750]

[0751] Stir a mixture of racemic-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) at 100 °C overnight. Remove the solvent under reduced pressure. Purify the residue by preparative TLC (5% MeOH / DCM) to afford 200 mg of the title compound as a yellow solid.

[0752] Analytical data: LC-MS: (ES, m / z) = 209 [M+1].

[0753] Example B48: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate

[0754]

[0755] Step 1: Synthesis of tert-butyl 2-(piperidin-4-yloxy)ethylcarbamate:

[0756] Stir a mixture of tert-butyl 2-(pyridin-4-yloxy)ethylcarbamate (200 mg, 0.84 mmol) and PtO2 (30 mg) in AcOH (5 mL) at 50 °C under 5 atm H2 atmosphere overnight. Remove the solvent under reduced pressure and dilute the residue with MeOH. Filter off the solid and concentrate the filtrate to afford 250 mg of the title compound as a colorless oil.

[0757] Analytical data: LC-MS: (ES, m / z) = 245 [M+1].

[0758] Step 2: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate:

[0759] 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.

[0760] Analytical data: LC-MS: (ES, m / z) = 338 [M+1].

[0761] 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

[0762]

[0763] Step 1: Synthesis of racemic-tert-butyl 3-carbamoyl-4-methoxypiperidine-1-carboxylate:

[0764] A solution of racemic-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.

[0765] Analytical data: LC-MS: (ES, m / z) = 259 [M+1].

[0766] Step 2: Synthesis of racemic-tert-butyl 3-cyano-4-methoxypiperidine-1-carboxylate:

[0767] TFAA (810 mg, 3.86 mmol) was added to a solution of racemic-tert-butyl 3-carbamoyl-4-methoxypiperidine-1-carboxylate (500 mg, 1.93 mmol) and TEA (585 mg, 5.79 mmol) in DCM (25 mL). The mixture was stirred at room temperature for 2 hours. The resulting solution was washed with water and dried over Na2SO4. This gave the title compound (400 mg) as a colorless oil.

[0768] Analytical data: LC-MS: (ES, m / z) = 185 [M+1-56].

[0769] Step 3: Synthesis of racemic-4-methoxypiperidine-3-carbonitrile:

[0770] To a solution of racemic-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 pale yellow oil.

[0771] Analytical data: LC-MS: (ES, m / z) = 141 [M+1].

[0772] 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:

[0773] 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 by preparative HPLC, column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13B to 23B in 7 minutes; 254 / 220 nm. This gave racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile (35 mg) as a colorless oil and racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile (50 mg) as a colorless oil.

[0774] Racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile:

[0775] Analytical data: LC-MS: (ES, m / z) = 234 [M+1]; 1H-NMR (300 MHz, 3d-CD3Cl) δ ppm 7.94 (d, 1H, J = 5.6 Hz), 5.81 (d, 1H, J = 5.7 Hz), 4.68 (s, 2H), 4.37 (dd, 1H, J = 13.4, 7.0 Hz), 4.14 - 4.00 (m, 1H), 3.85 (dd, 1H, J = 13.1, 3.6 Hz), 3.68 - 3.57 (m, 2H), 3.49 (s, 3H), 3.04 (dtd, 1H, J = 6.7, 3.8, 2.0 Hz), 1.99 - 1.71 (m, 2H)

[0776] Racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile:

[0777] Analytical data: LC-MS: (ES, m / z) = 234 [M+1]; 1 H-NMR (300 MHz, 3d-CD3Cl) δ ppm 7.93 (d, 1H, J = 5.6 Hz), 5.82 (d, 1H, J = 5.6 Hz), 4.78 - 4.71 (m, 1H), 4.69 (s, 2H), 4.51 - 4.37 (m, 1H), 3.61 - 3.51 (m, 1H), 3.49 (s, 3H), 3.40 (dd, 1H, J = 13.4, 9.5 Hz), 3.19 (ddd, 1H, J = 13.6, 10.4, 3.1 Hz), 2.64 (td, 1H, J = 9.1, 4.0 Hz), 2.21 - 2.07 (m, 1H), 1.53 - 1.34 (m, 1H)

[0778] Example B50: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-3-methoxypiperidin-4-ol

[0779]

[0780] Step 1: Synthesis of racemic-tert-butyl 4-hydroxy-3-methoxypiperidine-1-carboxylate:

[0781] At 0 °C, NaBH4 (395 mg, 10.4 mmol) was added to a solution of racemic tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate (2 g, 8.72 mmol) in THF (50 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted with EA and washed with brine. The organic layer was dried over Na2SO4, filtered, evaporated to give the title compound as a yellow semi-solid (2 g, crude).

[0782] Analytical data: LC-MS: (ES, m / z) = 232 [M+1].

[0783] Step 2: Synthesis of racemic - 3 - methoxypiperidin - 4 - ol:

[0784] A solution of racemic - 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 as a yellow semi - solid (700 mg, crude).

[0785] Analytical data: LC - MS: (ES, m / z) = 132 [M + 1].

[0786] Step 3: Synthesis of racemic - 1 - (4 - aminopyrimidin - 2 - yl) - 3 - methoxypiperidin - 4 - ol:

[0787] A mixture of racemic - 2 - chloropyrimidin - 4 - amine (200 mg, 1.54 mmol), 3 - methoxypiperidin - 4 - ol (700 mg, 5.33 mmol) and TEA (1.24 g, 12.3 mmol) in IPA (8 mL) was stirred at 100 °C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (150 mL×3) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered, evaporated and purified by column chromatography (EA) to give the title compound as a yellow solid (220 mg).

[0788] Analytical data: LC - MS: (ES, m / z) = 225 [M + 1].

[0789] Example B51: Synthesis of 2 - ((3R,4S) - 1 - (4 - aminopyrimidin - 2 - yl) - 3 - fluoropiperidin - 4 - yloxy)ethanol

[0790]

[0791] Step 1: Synthesis of (3R,4S) - 3 - fluoro - 4 - (2 - hydroxyethoxy)piperidine - 1 - carboxylate tert - butyl ester:

[0792] At 0 °C, NaH (455 mg, 11.4 mmol) was added to 10 mL of DMF containing (3R,4S) - 3 - fluoro - 4 - hydroxypiperidine - 1 - carboxylate tert - butyl ester (1.0 g, 4.56 mmol). After stirring for 20 min, (2 - bromoethoxy)(tert - butyl)dimethylsilane (3.25 g, 13.6 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by FLASH with PE:EA = 10:1 to give 1.1 g of the title compound as a colorless oil.

[0793] Step 2: Synthesis of 2-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol:

[0794] At room temperature, TFA (5 mL) was added to DCM (20 mL) containing tert-butyl (3R,4S)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoropiperidine-1-carboxylate (1.1 g, 2.91 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was mixed with DMSO (10 mL) containing 2-chloropyrimidin-4-amine (317 mg, 2.45 mmol) and DIEA (1.26 mg, 9.80 mmol). The mixture was heated to 100 °C and stirred for 16 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by FLASH with MeOH:EA = 1:15 to give 450 mg of the title compound as a yellow solid.

[0795] Analytical data: LC-MS: (ES, m / z) = 257 [M+1]; 1 1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J = 5.6 Hz), 6.41 (s, 2H), 5.71 (d, 1H, J = 5.6 Hz), 4.91 - 4.73 (m, 1H), 4.67 - 4.50 (m, 2H), 4.34 (d, 1H, J = 13.0 Hz), 3.69 - 3.46 (m, 5H), 3.30 - 3.17 (m, 1H), 3.06 (d, 1H, J = 11.3 Hz), 1.80 - 1.54 (m, 2H).

[0796] Example B52: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

[0797]

[0798] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxyethoxy)piperidine-1-carboxylate:

[0799] At 0 °C, NaH (1.35 g, 33.9 mmol) was added portionwise to DMF (10 mL) containing (3S,4R)-tert-butyl 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 the mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by FLASH with PE:EA = 10:1 to give 3.0 g of the title compound as a colorless oil.

[0800] Step 2: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol:

[0801] At room temperature, TFA (15 mL) was added to DCM (20 mL) containing (3S,4R)-tert-butyl 4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoropiperidine-1-carboxylate (3.0 g, 7.94 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was mixed with DMSO (10 mL) containing 2-chloropyrimidin-4-amine (873 mg, 6.74 mmol) and DIEA (629 mg, 4.88 mmol). The mixture was stirred at 100 °C overnight. The mixture was diluted with 50 mL of EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by FLASH with MeOH:EA = 1:15 to give 1.1 g of the title compound as a yellow solid.

[0802] Analytical data: LC-MS: (ES, m / z) = 257 [M+1]; 1 H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J = 5.6 Hz), 6.41 (s, 2H), 5.71 (d, 1H, J = 5.6 Hz), 4.94 - 4.69 (m, 1H), 4.67 - 4.52 (m, 2H), 4.34 (d, 1H, J = 13.3 Hz), 3.72 - 3.45 (m, 5H), 3.31 - 3.19 (m, 1H), 3.07 (t, 1H, J = 11.4 Hz), 1.77 - 1.44 (m, 2H).

[0803] Example B53: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl carbamate and racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl carbamate

[0804]

[0805] Step 1: Synthesis of racemic - 1 - (tert - butoxycarbonyl) - 4 - methoxypiperidine - 3 - carboxylic acid:

[0806] A mixture of racemic - 4 - methoxypiperidine - 1,3 - dicarboxylic acid 1 - tert - butyl 3 - methyl ester (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 Na2SO4 and concentrated to dryness to give the title compound as a pale yellow oil (2.7 g, 95%).

[0807] Analytical data: LC - MS: (ES, m / z) = 282 [M + 23].

[0808] Step 2: Synthesis of racemic - 4 - methoxypiperidine - 3 - carboxylic acid:

[0809] TFA (7 mL) was added to a solution of racemic - 1 - [(tert - butoxy)carbonyl] - 4 - methoxypiperidine - 3 - carboxylic acid (1.5 g, 5.78 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration to dryness to give the title compound as a pale yellow oil (1.5 g, crude).

[0810] Analytical data: LC - MS: (ES, m / z) = 160 [M + 1].

[0811] Step 3: Synthesis of racemic - 1 - (benzyloxycarbonyl) - 4 - methoxypiperidine - 3 - carboxylic acid:

[0812] CbzCl (1.49 g, 8.74 mmol) was added to a solution of racemic - 4 - methoxypiperidine - 3 - carboxylic acid (1.5 g, crude) and NaOH (931 mg, 23.3 mmol) in water (20 mL). 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 Na2SO4 and concentrated to dryness to give the title compound as a colorless oil (1.2 g, 70% over two steps).

[0813] Analytical data: LC - MS: (ES, m / z) = 294 [M + 1].

[0814] Step 4: Synthesis of racemic - 3 - (tert - butoxycarbonylamino) - 4 - methoxypiperidine - 1 - carboxylic acid benzyl ester:

[0815] To a solution of racemic - 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 h. 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.

[0816] Analytical data: LC - MS: (ES, m / z) = 387 [M + 23].

[0817] Step 5: Synthesis of racemic - tert - butyl 4 - methoxypiperidin - 3 - ylcarbamate:

[0818] A mixture of racemic - 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 under a H2 atmosphere at room temperature 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.

[0819] Analytical data: LC - MS: (ES, m / z) = 231 [M + 1].

[0820] Step 6: Synthesis of racemic - cis - 1 - (4 - aminopyrimidin - 2 - yl) - 4 - methoxypiperidin - 3 - ylcarbamate and racemic - trans - 1 - (4 - aminopyrimidin - 2 - yl) - 4 - methoxypiperidin - 3 - ylcarbamate:

[0821] A mixture of racemic - 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 h. The resulting mixture was purified on preparative HPLC to give peak 2: racemic - cis - 1 - (4 - aminopyrimidin - 2 - yl) - 4 - methoxypiperidin - 3 - ylcarbamate (18 mg) as an off - white solid and peak 1: racemic - trans - 1 - (4 - aminopyrimidin - 2 - yl) - 4 - methoxypiperidin - 3 - ylcarbamate (55 mg) as an off - white solid.

[0822] Analytical data: LC - MS: (ES, m / z) = 324 [M + 1].

[0823] 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

[0824]

[0825] Step 1: Synthesis of tert-butyl 5,5-difluoro-5,6-dihydropyridine-1(2H)-carboxylate:

[0826] At 0 °C, DMAP (274 mg, 2.25 mmol, 1.5 eq) was added to a solution of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (355 mg, 1.5 mmol, 1 eq) in DCM (6 mL), followed by addition of trifluoromethanesulfonic anhydride (550 mg, 1.95 mmol, 1.3 eq). The reaction was carried out at 0 °C for 1 h, and then quenched with saturated NaHCO3 (30 mL). The mixture was extracted with DCM (10 mL * 3). The organic layers were combined and concentrated. The residue was dissolved in toluene (5 mL). DBU (569 mg, 3.75 mmol, 2.5 eq) was added. The reaction was carried out at 70 °C for 18 h. 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 as a pale yellow oil (260 mg, 79.3%).

[0827] Analysis data: 1 1H-NMR (400 MHz, CD3Cl) δ ppm 6.23 - 6.17 (m, 1H), 5.98 - 5.92 (m, 1H), 4.06 - 4.00 (m, 2H), 3.91 - 3.65 (m, 2H), 1.51 (s, 9H).

[0828] Step 2: Synthesis of cis-3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylate tert-butyl ester:

[0829] At room temperature, K2OsO4·2H2O (12.8 mg, 35 μmol, 0.05 eq) and NMO (244 mg, 2.1 mmol, 3 eq) were added 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). The reaction was carried out at 40 °C for 18 h. After cooling to room temperature, the mixture was diluted with EA (50 mL) and washed with 10% 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 as a white solid (71 mg, 40.1%).

[0830] Analysis data: 1 1H-NMR (400 MHz, DMSO-d6) δ ppm 5.88 (d, 1H, J = 5.1 Hz), 5.18 (d, 1H, J = 5.9 Hz), 3.96 - 3.60 (m, 3H), 3.60 - 3.44 (m, 1H), 3.34 - 3.19 (m, 1H), 3.10 - 2.76 (m, 1H), 1.40 (s, 9H).

[0831] Step 3: Synthesis of cis-3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylic acid tert-butyl ester:

[0832] At 0 °C, NaH (10.9 mg, 275 μmol, 1 eq, 60%) was added to a solution of cis-3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylic acid tert-butyl ester (69.6 mg, 275 μmol, 1 eq) in THF (2 mL). After 30 min, MeI (39.0 mg, 275 μmol, 1 eq) was added. The reaction was carried out at 0 °C for 1 h and at room temperature for 18 h. After quenching with saturated NH4Cl (10 mL), the mixture was extracted with EA (5 mL × 3). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / EA = 2:1) to give the title compound as a colorless syrup (22 mg, 30%).

[0833] Step 4: Synthesis of cis-5,5-difluoro-4-methoxypiperidin-3-ol:

[0834] A solution of cis-3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (240 mg, 900 μmol, 1 eq) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 3 h and concentrated to give the title compound as a colorless oil (220 mg, crude).

[0835] Analysis of data: LC-MS: (ES, m / z) = 168 [M+1].

[0836] 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:

[0837] Dissolve 220 mg of cis-5,5-difluoro-4-methoxypiperidin-3-ol in IPA (2 mL). Add 2-chloropyrimidin-4-amine (116 mg, 900 μmol, 1 equiv), and then add TEA (454 mg, 4.50 mmol, 5 equiv). React at 100 °C for 18 h. After cooling to room temperature, concentrate the mixture. Purify the residue by preparative TLC (DCM / MeOH = 20:1) to obtain (3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol as a white solid (50 mg, 21.36%). Separate the compound by preparative chiral HPLC using the following conditions: CHIRAL Cellulose-SB 4.6*100 mm 3 μm; 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 as a light yellow solid (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 as a light yellow solid (20 mg).

[0838] Analysis of data: LC-MS: (ES, m / z) = 261 [M+1]; 1 1H-NMR (300 MHz, CD3Cl) δ ppm 7.95 (d, 1H, J = 5.6 Hz), 5.82 (d, 1H, J = 5.6 Hz), 4.87 - 4.70 (m, 1H), 4.67 - 4.48 (m, 3H), 3.91 (s, 1H), 3.67 (d, 3H, J = 1.0 Hz), 3.67 - 3.60 (m, 1H), 3.51 (ddd, 1H, J = 29.0, 14.0, 1.8 Hz), 3.12 (dd, 1H, J = 12.9, 10.1 Hz), 2.41 (s, 1H).

[0839] Example B55: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

[0840]

[0841] Step 1: Synthesis of racemic-cis-3,4-dihydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0842] At room temperature, K2OsO4·2H2O (50.4 mg, 152 μmol) and NMO (533 mg, 4.56 mmol) were added 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 H2O (1 mL), and the mixture was stirred for 12 h. The reaction mixture was diluted with saturated aqueous Na2S2SO3 and extracted with EA and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound as a yellow solid (350 mg, crude).

[0843] Analytical data: LC-MS: (ES, m / z) = 254 [M+23].

[0844] Step 2: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol:

[0845] TFA (2 mL) was added to a solution of racemic-cis-3,4-dihydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (350 mg, crude) in DCM (6 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated and the residue was dissolved in IPA (3 mL). 2-Chloropyrimidin-4-amine (160 mg, 1.23 mmol) and TEA (621 mg, 6.15 mmol) were added, and the mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with water, extracted with EA and washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give the title compound as a yellow solid (200 mg, 72.7%).

[0846] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0847] Example B56: Synthesis of racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

[0848]

[0849] Step 1: Synthesis of tert-butyl 6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate:

[0850] 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 h. The mixture was extracted with EA and water. The organic layer was concentrated and purified by FLASH (30% EA / PE) to afford 460 mg of the title compound as a colorless oil.

[0851] Analytical data: LC-MS: (ES, m / z) = 214 [M+1].

[0852] Step 2: Synthesis of racemic-trans-3,4-dihydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester:

[0853] To a solution of racemic-6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (100 mg, 468 μmol) in H2O (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 afford 180 mg of the title compound as a yellow oil.

[0854] Analytical data: LC-MS: (ES, m / z) = 232 [M+1].

[0855] Step 2: Synthesis of racemic-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol:

[0856] To a solution of racemic-trans-3,4-dihydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.29 mmol) in DCM (10 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure. The residue was dissolved in IPA (2 mL), 2-chloropyrimidin-4-amine (88.8 mg, 686 μmol) and DIEA (441 mg, 3.42 mmol) were added, and the solution was heated to 120 °C for 10 h. The mixture was extracted with EA and water. The organic matter was concentrated and purified by FLASH (50% MeOH / DCM) to afford 80 mg of the title compound as a light yellow solid.

[0857] Analytical data: LC-MS: (ES, m / z) = 225 [M+1].

[0858] Example B57: Synthesis of racemic - tert - butyl 1-(4 - aminopyrimidin - 2 - yl)-3,3 - difluoropiperidin - 4 - ylcarbamate

[0859]

[0860] A mixture of racemic - tert - butyl N-(3,3 - difluoropiperidin - 4 - yl)carbamate (200 mg, 0.85 mmol, 1 equiv), 2 - chloropyrimidin - 4 - amine (109.67 mg, 0.847 mmol, 1 equiv) and TEA (256.98 mg, 2.540 mmol, 3 equiv) in IPA (3 mL) was stirred at 100 °C for 3 h. 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 pale yellow solid.

[0861] Analytical data: LC - MS: (ES, m / z) = 330 [M + 1].

[0862] Example B58: Synthesis of racemic - cis - 1-(5 - amino - 1,2,4 - triazin - 3 - yl)-3 - fluoro - 4 - methylpiperidin - 4 - ol

[0863]

[0864] A mixture of 3 - chloro - 1,2,4 - triazin - 5 - amine (200 mg, 1.53 mmol), cis - 3 - fluoro - 4 - methylpiperidin - 4 - ol (243 mg, 1.83 mmol) and TEA (309 mg, 3.06 mmol) in IPA (5 mL) was stirred at 100 °C for 2 h. Water was added and the reaction was extracted with EA. The organic layer was purified by preparative TLC (DCM:MeOH = 10:1). This gave 300 mg (34.4%) of the title compound as a grey solid.

[0865] Analytical data: LC - MS: (ES, m / z) = 228 [M + 1].

[0866] 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

[0867]

[0868] Step 1: Synthesis of racemic tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate:

[0869] Dissolve racemic tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (Step 3, Example B1; 4 g, 17 mmol) in DMF (40 mL), and add sodium hydride (820 mg, 34.2 mmol) at 0 °C. Stir the mixture at room temperature for 1 hour. Add methyl iodide (4.82 g, 34.2 mmol) and stir the reaction at room temperature for another 2 hours. Quench the reaction with water / ice, extract with EA, wash with brine, dry over anhydrous sodium sulfate and concentrate in vacuo to obtain 5.1 g of tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate as a colorless oil.

[0870] Step 2: Synthesis of racemic 2-(3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine:

[0871] Dissolve racemic tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate (5.1 g) in HCl / dioxane (4 M, 50 mL). Stir the reaction at room temperature for 2 hours. Concentrate the mixture in vacuo. Mix the residue with IPA (30 mL) containing 2-chloropyrimidine-4- (4.21 g, 32.5 mmol) and TEA (5.47 g, 54.2 mmol). Stir the mixture at 100 °C and stir for 16 hours. Concentrate the reaction in vacuo and purify the residue by FLASH (DCM:MeOH = 10:1). This gives 1.6 g of the title compound as a white solid, which is further separated into four isomers using the following conditions:

[0872] Analytical data: LC-MS: (ES, m / z) = 241 [M+1].

[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, hold 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.

[0874] Column name: CHIRAL ND(2) 4.6 * 100 mm, 3 μm; Cosolvent: MeOH(0.1% DEA); Gradient (B%): 10% to 50% in 4.0 minutes, hold 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.

[0875] Example B60: Synthesis of tert-butyl (2-(azetidin-3-yl)-2-(methylsulfonyl)ethyl)carbamate

[0876]

[0877] Step 1: Synthesis of benzyl (3-(1-(methylsulfonyl)prop-2-yn-1-yl)azetidin-1-yl)carbamate:

[0878] At room temperature, Cs2CO3 (544 mg, 1.67 mmol) was added to a solution of 2-methylsulfonylacetonitrile (1 g, 8.39 mmol) and benzyl 3-iodoazetidine-1-carboxylate (3.96 g, 12.5 mmol) in DMF (5 mL). The resulting mixture was stirred at 80 °C for 8 hours. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using PE:EA = 5:1 to give 1.2 g of the title compound as a colorless oil.

[0879] Analytical data: LC-MS: (ES, m / z) = 308 [M+1].

[0880] Step 2: Synthesis of benzyl (3-(2-amino-1-(methylsulfonyl)ethyl)azetidin-1-yl)carbamate:

[0881] At room temperature, benzyl (3-(cyano(methylsulfonyl)methyl)azetidin-1-yl)carbamate (1.2 g, 3.89 mmol) and Raney nickel (10 mg) in EtOH (4 mL) were stirred under a H2 atmosphere for 8 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure to give 600 mg of the title compound as a colorless oil.

[0882] Analytical data: LC-MS: (ES, m / z) = 313 [M+1].

[0883] Step 3: Synthesis of racemic - benzyl 3-(2-(tert - butoxycarbonylamino)-1-(methylsulfonyl)ethyl)azetidine - 1 - carboxylate:

[0884] At 0 °C, (Boc)2O (829 mg, 3.84 mmol) was added to a mixture of Na2CO3 (407 mg, 3.84 mmol) and racemic - benzyl 3-(2 - amino - 1 - methylsulfonylethyl)azetidine - 1 - carboxylate (600 mg, 1.92 mmol) in dioxane / H2O (10 mL / 3 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column using PE:EA = 5:1 to give 650 mg of the title compound as a colorless oil.

[0885] Analytical data: LC - MS: (ES, m / z) = 413 [M + 1].

[0886] Step 4: Synthesis of racemic - tert - butyl 2-(azetidin - 3 - yl)-2-(methylsulfonyl)ethylcarbamate:

[0887] A mixture of racemic - benzyl 3-(2 - amino - 1 - methylsulfonylethyl)azetidine - 1 - carboxylate (600 mg, 1.92 mmol) and Pd(OH)2 / C (300 mg, 2.14 mmol) in MeOH (50 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (300 mg) as a colorless oil.

[0888] Analytical data: LC - MS: (ES, m / z) = 279 [M + 1].

[0889] Example B61: Synthesis of racemic - cis - 2-(hexahydrofuro[3,4 - b]pyrrol - 1 - yl)pyrimidin - 4 - amine

[0890]

[0891] 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 h. The reaction mixture was diluted with water, extracted with EA, and washed with brine. The organic layer was dried over Na2SO4, filtered, evaporated, and purified by column chromatography (DCM:MeOH = 20:1) to afford the title compound as a yellow solid (410 mg, 69.8%).

[0892] Analytical data: LC-MS: (ES, m / z) = 207 [M+1].

[0893] Example B62: Synthesis of tert-butyl ((1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methyl)carbamate

[0894]

[0895] Step 1: Synthesis of 1-tert-butyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate:

[0896] To a solution of 1-tert-butyl 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate (1.5 g, 5.78 mmol) in THF (40 mL) at 0 °C was added NaH (346 mg, 8.67 mmol). After 10 min, MeI (1.23 g, 8.67 mmol) was added and the mixture was stirred for 2 h. The mixture was quenched with ice water and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified on a silica gel column with 10% EA / PE to afford 1-tert-butyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate as a pale yellow oil (1.3 g).

[0897] Analytical data: LC-MS: (ES, m / z) = 296 [M+23].

[0898] Step 2: Synthesis of 1-benzyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate:

[0899] 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 h. The reaction was concentrated. The residue was dissolved in dioxane (20 mL) and water (10 mL), and K2CO3 (1.94 g, 14.1 mmol) and CbzCl (1.60 g, 9.42 mmol) were added at room temperature and stirred for 2 h. The reaction was extracted with EA, dried over Na2SO4 and concentrated to dryness to give the title compound (1.2 g) as a colorless oil.

[0900] Analytical data: LC-MS: (ES, m / z) = 309 [M+1].

[0901] Step 3: Synthesis of 1-(benzyloxycarbonyl)-4-methoxypiperidine-4-carboxylic acid:

[0902] 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 h. After cooling to room temperature, the pH was adjusted to 5 with 1N HCl and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to dryness to give the title compound (1 g) as a colorless oil.

[0903] Analytical data: LC-MS: (ES, m / z) = 294 [M+1].

[0904] Step 4: Synthesis of benzyl 4-carbamoyl-4-methoxypiperidine-1-carboxylate:

[0905] 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 h. The organic layer was separated and washed with water, dried over Na2SO4, 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.

[0906] Analytical data: LC-MS: (ES, m / z) = 293 [M+1].

[0907] Step 5: Synthesis of benzyl 4-(aminomethyl)-4-methoxypiperidine-1-carboxylate:

[0908] To a solution of benzyl 4-carbamoyl-4-methoxypiperidine-1-carboxylate (600 mg, 2.05 mmol) in THF (20 mL) was added NaBH4 (310 mg, 8.20 mmol), followed by BF3·Et2O (1.16 g, 8.20 mmol). The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound as a colorless oil (1.4 g, crude).

[0909] Analytical data: LC-MS: (ES, m / z) = 279 [M + 1].

[0910] Step 6: Synthesis of benzyl 4-((tert-butoxycarbonylamino)methyl)-4-methoxypiperidine-1-carboxylate:

[0911] A solution of benzyl 4-(aminomethyl)-4-methoxypiperidine-1-carboxylate (1.4 g, crude) and Boc2O (1.21 g, 5.58 mmol) in DCM (20 mL) was stirred at room temperature for 1 h. Water was added and the organic layer was separated and purified on a silica gel column using 60% EA / PE to afford the title compound as a colorless oil (250 mg).

[0912] Analytical data: LC-MS: (ES, m / z) = 401 [M + 23].

[0913] Step 7: Synthesis of tert-butyl ((4-methoxypiperidin-4-yl)methyl)carbamate:

[0914] 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 under H2 atmosphere at room temperature for 1 h. The solid was filtered off. The filtrate was concentrated to dryness to afford the title compound as a colorless oil (130 mg).

[0915] Analytical data: LC-MS: (ES, m / z) = 245 [M + 1].

[0916] Step 8: Synthesis of tert-butyl ((1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methyl)carbamate:

[0917] Stir 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) at 80 °C for 2 h. Concentrate the mixture and purify the residue by preparative TLC (EtOAc:PE = 1:1) to afford the title compound (95 mg) as an off-white solid.

[0918] Analytical data: LC-MS: (ES, m / z) = 338 [M+1].

[0919] Example B63: Synthesis of 2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yloxy)ethanol

[0920]

[0921] Add HCl (6 M, 5 mL) to a 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-disilathiradec-7-yl)pyrimidine (600 mg, 930 μmol, from step 2 of Example B70) in EtOH (5 mL). Stir the mixture at 80 °C for 1 h. Concentrate the mixture in vacuo to afford 200 mg of the title compound as a colorless oil.

[0922] Analytical data: LC-MS: (ES, m / z) = 271 [M+1].

[0923] Example B64: Synthesis of tert-butyl 2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate

[0924]

[0925] Step 1: Synthesis of benzyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate:

[0926] At -78 °C, n-Buli (23.5 mL, 58.9 mmol, 2.5 M) was added to a solution of ACN (1.73 g, 42.1 mmol) in THF (80 mL). The mixture was stirred at -78 °C for 30 minutes. Then a solution of benzyl 4-oxopiperidine-1-carboxylate (10.3 g, 44.2 mmol) in THF (20 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with H2O (30 mL), extracted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash Column Silica-CS (PE:EA = 10:1 to 3:2). This gave 1 g (90.9%) of the title compound as a pale yellow solid.

[0927] Analytical data: LC-MS: (ES, m / z) = 275 [M+1].

[0928] Step 2: Synthesis of benzyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate:

[0929] At 0 °C, NaH (216 mg, 5.45 mmol) was added to a solution of benzyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (250 mg, 911 μmol) and methyl iodide (283 mg, 2 mmol) in DMF (30 mL). Then the mixture was 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 in vacuo. The residue was purified by Flash Column Silica-CS (PE:EA = 1:1). This gave 940 mg of benzyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate as a pale yellow gum.

[0930] Analytical data: LC-MS: (ES, m / z) = 311 [M+23].

[0931] Step 3: Synthesis of benzyl 4-(2-aminoethyl)-4-methoxypiperidine-1-carboxylate:

[0932] At 0 °C, BH3-THF (8.73 mL, 8.73 mmol, 1 M) was added to a solution of benzyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate (840 mg, 2.91 mmol) in THF (30 mL). Then the mixture was 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).

[0933] Analytical data: LC-MS: (ES, m / z) = 293 [M+1].

[0934] Step 4: Synthesis of Benzyl 4-(2-(tert-butoxycarbonylamino)ethyl)-4-methoxypiperidine-1-carboxylate:

[0935] 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 h. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by Flash Column Silica-CS (PE:EA = 10:1 to 3:2). This gave 900 mg (79.6%) of the title compound as a pale yellow gum.

[0936] Analytical data: LC-MS: (ES, m / z) = 415 [M+23].

[0937] Step 5: Synthesis of tert-Butyl 2-(4-methoxypiperidin-4-yl)ethylcarbamate:

[0938] 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 h. The reaction mixture was filtered through a Celite bed, 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.

[0939] Analytical data: LC-MS: (ES, m / z) = 259 [M+1].

[0940] Step 6: Synthesis of tert-Butyl 2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate:

[0941] 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 h. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH = 10:1). This gave 280 mg (79.7%) of the title compound as a pale yellow solid.

[0942] Analytical data: LC-MS: (ES, m / z) = 352 [M+1].

[0943] Example B65: Synthesis of 1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0944]

[0945] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate:

[0946] At 0 °C, NaH (175.12 mg, 7.297 mmol, 8 equiv) was added to a mixture of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (200 mg, 0.912 mmol, 1 equiv) and 2,2-dimethyloxirane (526.19 mg, 7.297 mmol, 8 equiv) in DMF (5 mL). The resulting solution was stirred overnight at room temperature. 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 pale yellow oil.

[0947] Analytical data: LC-MS: (ES, m / z) = 292 [M+1].

[0948] Step 2: Synthesis of 1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0949] tert-Butyl (3R,4S)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate (100.00 mg, 0.343 mmol) was added to a solution of TFA (1 mL) in DCM (3 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated in vacuo and the residue was mixed with IPA (2 mL) containing 2-chloropyrimidin-4-amine (50 mg, 0.386 mmol, 1 equiv) and TEA (117.16 mg, 1.158 mmol, 3 equiv). The resulting solution was stirred at 100 °C for 12 h. The mixture was concentrated in vacuo and the residue was applied to a silica gel column with DCM / MeOH (15:1). This gave 20 mg (18.22%) of the title compound as a pale yellow oil.

[0950] Analytical data: LC-MS: (ES, m / z) = 285 [M+1].

[0951] Example B66: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0952]

[0953] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate:

[0954] NaH (262.68 mg, 10.946 mmol, 6 eq) was added to a solution of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (400.00 mg, 1.824 mmol, 1 eq) and 2,2-dimethyloxirane (1315.49 mg, 18.244 mmol, 10 eq) in DMF (20.00 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding 3 mL of water. The resulting solution was extracted with EA and concentrated in vacuo. This gave 200 mg (37.63%) of the title compound as a yellow oil.

[0955] Analytical data: LC-MS: (ES, m / z) = 292 [M+1].

[0956] Step 2: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

[0957] tert-Butyl (3S,4R)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate (200.00 mg, 0.686 mmol, 1 eq) was added to DCM / TFA (8.00 mL / 4.00 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated in vacuo. At 100 °C, the residue was mixed with IPA (3 mL) containing 2-chloropyrimidin-4-amine (67.74 mg, 0.523 mmol, 1 eq) and TEA (158.73 mg, 1.569 mmol, 3.0 eq) and stirred for 3 h. The solvent was removed and the residue was applied to a silica gel column with DCM / MeOH (15:1). This gave 55 mg (37%) of the title compound as a pale yellow oil.

[0958] Analytical data: LC-MS: (ES, m / z) = 285 [M+1].

[0959] Example B67: Synthesis of 2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine

[0960]

[0961] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate:

[0962] At 0 °C, NaH (218 mg, 9.08 mmol) was added to DMF (20 mL, 22.6 mmol) containing (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1000 mg, 4.56 mmol). After stirring for 20 minutes, CD3I (3.30 g, 22.8 mmol) was added and the solution was stirred at room temperature for 16 hours. The reaction was quenched by adding 5 mL of water. The solid was filtered off. The resulting solution was extracted with EA, washed with brine and concentrated. This gave 1140 mg of the title compound as a pale yellow oil.

[0963] Step 2: Synthesis of 2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine:

[0964] TFA (2 mL) was added to DCM (6 mL) containing (3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylic acid tert-butyl ester (1140 mg, 4.82 mmol) and the solution was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was dissolved in IPA (20 mL), then dissolved in 2-chloropyrimidin-4-amine (496 mg, 3.83 mmol) and TEA (0.6 mL). The mixture was stirred at 100 °C overnight. The mixture was concentrated and the residue was purified by FLASH (5% MeOH / EA) to give 425 mg of the title compound as a pale yellow solid.

[0965] Analytical data: LC-MS: (ES, m / z) = 230 [M+1].

[0966] Example B68: Synthesis of 2-((3R,4S)-4-cyclopropyloxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

[0967]

[0968] Step 1: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(vinyloxy)piperidine-1-carboxylate:

[0969] A mixture of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1 equiv), vinyl acetate (515 mg, 5.99 mmol, 5 equiv), Ir(COD)2Cl2 (80.3 mg, 120 μmol, 0.1 equiv) and Na2CO3 (127 mg, 1.20 mmol, 1 equiv) in toluene (1.5 mL) was heated at 100 °C for 3 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated. The residue was purified by preparative TLC (PE / EA = 4:1) to give the title compound as a colorless syrup (200 mg, 68%).

[0970] Step 2: Synthesis of 2-((3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine:

[0971] At 0 °C, diethylzinc (3.59 mL, 3.59 mmol, 4.5 equiv, 1 M in heptane) was added to a solution of diiodomethane (1.17 g, 4.39 mmol, 5.5 equiv) in DCM (2 mL). The mixture was stirred at 0 °C for 1 h. 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 h and then concentrated. The residue was suspended in TFA (1 mL) and DCM (3 mL) and stirred at room temperature for 2 h. The mixture was concentrated. TEA (404 mg, 4.00 mmol, 5 equiv), 2-chloropyrimidin-4-amine (72.5 mg, 560 μmol, 0.7 equiv) and IPA (2 mL) were added to the residue. The mixture was heated at 100 °C for 18 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (DCM / MeOH = 25:1) to give 2-[(3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl]pyrimidin-4-amine as a white solid (80 mg, 40%).

[0972] Analytical data: 1H-NMR (400 MHz, 3d-CD3Cl) δ ppm 7.94 (d, 1H, J = 5.6 Hz), 5.78 (d, 1H, J = 5.6 Hz), 4.83 (ddt, 1H, J = 48.3, 5.7, 2.7 Hz), 4.68 - 4.59 (m, 1H), 4.58 (s, 2H), 4.32 (dddd, 1H, J = 13.4, 5.7, 4.0, 1.5 Hz), 3.84 - 3.71 (m, 1H), 3.61 - 3.42 (m, 2H), 3.35 (dddd, 1H, J = 13.2, 9.3, 3.6, 1.7 Hz), 2.05 - 1.91 (m, 1H), 1.89 - 1.74 (m, 1H), 0.72 - 0.63 (m, 2H), 0.58 - 0.49 (m, 2H).

[0973] Example B69: Synthesis of racemic-2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol

[0974]

[0975] Step 1: Synthesis of racemic-tert-butyl 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,3-difluoropiperidine-1-carboxylate:

[0976] At 0 °C, NaH (1.25 g, 31.5 mmol, 60%) was added to a solution of racemic-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (3 g, 2.6 mmol) in DMF (20 mL). The mixture was stirred at 0 °C for 0.5 h. Then (2-bromoethoxy)(tert-butyl)dimethylsilane (9.04 g, 37.8 mmol) was added. The mixture was stirred at room temperature for 13 h. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by Flash Column Silica-CS (PE:EA = 1:0 to 10:1). This gave 3.8 g (76.3%) of the title compound as a yellow oil.

[0977] Step 2: Synthesis of racemic-2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol:

[0978] At 0 °C, HCl / dioxane (20 mL) was added to a solution of racemic tert-butyl 4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3,3-difluoropiperidine-1-carboxylate (3.7 g, 9.35 mmol) in DCM (10 mL). The mixture was then stirred at room temperature for 2 h. The reaction was concentrated and the residue was dissolved in IPA (4 mL), followed by dissolution in TEA (278 mg, 2.75 mmol) and 2-chloropyrimidin-4-amine (84.7 mg, 654 μmol). The mixture was stirred at 120 °C for 13 h. The mixture was extracted with EA and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by Flash Column Silica-CS (DCM:MeOH = 10:1). This gave 2 g (79.6%) of the title compound as a pale yellow solid.

[0979] Analytical data: LC-MS: (ES, m / z) = 275 [M+1].

[0980] Example B70: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine

[0981]

[0982] Step 1: Synthesis of 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine:

[0983] At 0 °C, tert-butyl(chloro)dimethylsilane (5.98 g, 39.7 mmol) was added portionwise to DMF containing 1H-imidazole (3.60 g, 53.0 mmol) and chiral 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). The mixture was stirred at room temperature for 16 h. The mixture was diluted with EA (500 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash with PE:EA = 2:1 to give 7.5 g of the title compound as a colorless oil.

[0984] Analytical data: LC-MS: (ES, m / z) = 341 [M+1].

[0985] 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:

[0986] Stir 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) under reflux for 3 hours. Dilute the mixture with EA (100 mL) and wash with brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify the residue by flash with PE:EA = 5:1 to afford 10.0 g of the title compound as a colorless oil.

[0987] Analytical data: LC-MS: (ES, m / z) = 601 [M+1].

[0988] Step 3: Synthesis of (3S,4R)-1-(4-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol:

[0989] Add TBAF (83 mL, 83 mmol) to a solution of 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-disilathiradec-7-yl)pyrimidine (10.0 g, 16.6 mmol) in THF. Stir the mixture at room temperature for 2 hours. Concentrate the mixture in vacuo. Purify the residue by preparative TLC with PE:EA = 4:1 to afford 6.5 g of the title compound as a colorless oil.

[0990] Analytical data: LC-MS: (ES, m / z) = 487 [M+1].

[0991] 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:

[0992] 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-disilatetradecan-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 in vacuo. The residue was purified by a silica gel column with PE:EA = 5:1 to give 2.1 g of the title compound as a colorless oil.

[0993] Analytical data: LC-MS: (ES, m / z) = 645 [M+1].

[0994] 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:

[0995] At room temperature, TBAF (10 mL, 10 mmol) was added to THF (10 mL) 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-disilatetradecan-7-yl)pyrimidine (600 mg, 930 μmol). The mixture was stirred at reflux for 1 hour. The mixture was concentrated in vacuo. The residue was purified by a silica gel column with PE:EA = 2:1. This gave 200 mg of the title compound as a colorless oil.

[0996] Analytical data: LC-MS: (ES, m / z) = 531 [M+1].

[0997] 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:

[0998] At 0 °C, (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (456 mg, 2.26 mmol) was added dropwise to a mixture of PPh3 (885 mg, 3.38 mmol), {[azido(phenoxy)phosphoryl]oxy}benzene (930 mg, 3.38 mmol) and 2-{[(3S,4R)-3-fluoro-3-methyl-1-[4-(2,2,12,12-tetramethyl-5,9-dioxo-7-aza-2,12-disilathiradec-7-yl)pyrimidin-2-yl]piperidin-4-yl]oxy}ethan-1-ol (600 mg, 1.13 mmol) in THF. The mixture was stirred at room temperature for 16 h. The mixture was diluted with EA (100 mL) and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative TLC with PE:EA = 5:1 to give 280 mg of the title compound as a yellow solid.

[0999] Analytical data: LC-MS: (ES, m / z) = 556 [M+1].

[1000] Step 7: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine:

[1001] At room temperature, HCl (6 M, 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-dioxo-7-aza-2,12-disilathiradec-7-yl)pyrimidine (260 mg, 467 μmol) in EtOH. The mixture was stirred at reflux for 1 h. The mixture was concentrated in vacuo to give 120 mg of 2-[(3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl]pyrimidin-4-amine as a colorless oil.

[1002] Analytical data: LC-MS: (ES, m / z) = 296 [M+1].

[1003] Example B71: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol

[1004]

[1005] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(oxiran-2-ylmethoxy)piperidine-1-carboxylate:

[1006] 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 was used to obtain 600 mg (95%) of the title compound as a brown solid.

[1007] Analytical data: LC-MS: (ES, m / z) = 220 [M+1-56].

[1008] Step 2: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylate:

[1009] At 0 °C, under a N2 atmosphere, LiBHEt3 (1 M in THF solution) was added to a solution of tert-butyl (3S,4R)-3-fluoro-4-[(oxiran-2-yl)methoxy]piperidine-1-carboxylate (750 mg, 2.72 mmol) in THF. 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 Na2SO4. The organic layer was concentrated to obtain 600 mg (80%) of the title compound as a yellow solid.

[1010] Analytical data: LC-MS: (ES, m / z) = 222 [M+1-56].

[1011] Step 3: Synthesis of 1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol:

[1012] At room temperature, HCl (4 M in dioxane solution) was added to a solution of tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylate (600 mg, 2.16 mmol) in DCM. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was dissolved in DMSO (3 mL), then dissolved in 2-chloropyrimidin-4-amine (380 mg, 2.93 mmol) and DIEA (1.13 g, 8.79 mmol). The mixture was stirred at 120 °C for 2 hours. The mixture was extracted with EA and water. The organic layers were combined and dried over Na2SO4. The organic layer was concentrated and the residue was purified by preparative TLC with DCM / MeOH (15:1). This gave 210 mg of the title compound as a yellow solid.

[1013] Analytical data: LC-MS: (ES, m / z) = 271 [M+1].

[1014] Example B72: Synthesis of 2-((3S,4R)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

[1015]

[1016] Step 1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(vinyloxy)piperidine-1-carboxylate:

[1017] A mixture of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1 equiv), ethyl acetate (515 mg, 5.99 mmol, 5 equiv), Ir(COD)2Cl2 (80.3 mg, 120 μmol, 0.1 equiv) and Na2CO3 (127 mg, 1.20 mmol, 1 equiv) in toluene (1.5 mL) was heated to 100 °C for 3 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated. The residue was purified by preparative TLC (PE / EA = 4:1) to give the title compound as a colorless syrup (200 mg, 68%).

[1018] Step 2: Synthesis of 2-((3S,4R)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine:

[1019] At 0 °C, diethylzinc (3.59 mL, 3.59 mmol, 4.5 equiv, 1 M in heptane) was added to a solution of diiodomethane (1.17 g, 4.39 mmol, 5.5 equiv) in DCM (2 mL). The mixture was stirred at 0 °C for 1 h. 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 carried out at room temperature for 2 h and then concentrated. The residue was suspended in TFA (1 mL) and DCM (3 mL) and stirred at room temperature for 2 h. The mixture was concentrated. Triethylamine (404 mg, 4.00 mmol, 5 equiv), 2-chloropyrimidin-4-amine (72.5 mg, 560 μmol, 0.7 equiv) and IPA (2 mL) were added to the residue. The mixture was heated to 100 °C for 18 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (DCM / MeOH = 25:1) to give the title compound as a white solid (80 mg, 40%).

[1020] Analytical data: 1H-NMR (400 MHz, 3d-CD3Cl) δ ppm 7.94 (d, 1H, J = 5.6 Hz), 5.78 (d, 1H, J = 5.6 Hz), 4.84 (ddd, 1H, J = 48.1, 5.8, 2.8 Hz), 4.66 - 4.59 (m, 1H), 4.57 (s, 2H), 4.39 - 4.27 (m, 1H), 3.85–3.69 (m, 1H), 3.62 - 3.43 (m, 2H), 3.35 (dddd, 1H, J = 13.3, 9.4, 3.6, 1.7 Hz), 1.98 (dddd, 1H, J = 13.4, 6.8, 5.4, 3.2 Hz), 1.83 (ddd, 1H, J = 9.6, 7.8, 4.6 Hz), 0.72 - 0.64 (m, 2H), 0.57 - 0.47 (m, 2H).

[1021] Example B73: Synthesis of 3 - ((3S,4R)-3 - fluoro - 4 - methoxypiperidin - 1 - yl)-1,2,4 - triazin - 5 - amine

[1022]

[1023] 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 h. 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 gave 40 mg (39%) of the title compound as a yellow solid.

[1024] Analytical data: LC - MS: (ES, m / z) = 228 [M + 1].

[1025] Example B74: Synthesis of racemic - (all - cis)-1 - (4 - aminopyrimidin - 2 - yl)-5 - fluoro - 4 - methoxypiperidin - 3 - ol

[1026]

[1027] Step 1: Synthesis of racemic - trans - 6 - (hydroxymethyl)-cis - 2,2 - dimethyldihydrofuran[3,4 - d][1,3]dioxol - 4(3aH)-one:

[1028] Place (±)-cis-3,4-dihydroxy-trans-5-(hydroxymethyl)tetrahydrofuran-2-one (3 g, 20.2 mmol, 1 equiv), TsOH·H2O (385 mg, 2.03 mmol, 0.100 equiv) and anhydrous acetone (60 mL) into a 100 mL round-bottom flask, and then add 2,2-dimethoxypropane (2.53 g, 24.3 mmol, 1.20 equiv) at 0 °C over 5 minutes. Stir the resulting solution at 25 °C for 2 h. Then add solid sodium bicarbonate (255 mg, 3.04 mmol, 0.150 equiv) to the mixture and stir for 5 minutes. Filter the reaction mixture and concentrate it in vacuo. This gives 3.8 g (100%) of the title compound as a white solid.

[1029] Step 2: Synthesis of (±)-((cis)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol- trans-4-yl)methyl methanesulfonate:

[1030] Place (±)-trans-6-(hydroxymethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (3.81 g, 20.3 mmol, 1 equiv), TEA (4.10 g, 40.5 mmol, 2 equiv) and THF (70 mL) into a 100 mL round-bottom flask, and then add MsCl (2.78 g, 24.3 mmol, 1.20 equiv) dropwise at 0 °C. Stir the resulting solution at 25 °C for 1 h. Dilute the mixture with DCM (20 mL) and wash with saturated aqueous NH4Cl (20 mL × 3). Dry the organic layer over MgSO4, filter and concentrate in vacuo. This gives 5.0 g (93%) of the title compound as an orange oil, which is used directly in the next step without further purification.

[1031] Analytical data: LC-MS: (ES, m / z): RT = 0.274 min, LCMS: m / z = 267 [M+1], 1 1H NMR (400 MHz, CDCl3) δ 4.89 - 4.73 (m, 3H), 4.54 - 4.41 (m, 2H), 3.06 (s, 3H), 1.49 (s, 3H), 1.41 (s, 3H).

[1032] Step 3: Synthesis of (±)-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one:

[1033] Place methyl (rac)-((cis)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol- trans-4-yl)methanesulfonate (5.00 g, 18.8 mmol, 1 equiv), NaN3 (3.66 g, 56.3 mmol, 3 equiv) and DMF (60 mL) into a 100 mL round-bottom flask. Stir the resulting solution in an oil bath at 75 °C for 3 h. Dilute the reaction mixture with EA (150 mL) and wash with brine (50 mL×3). Dry the collected organic phase over Na2SO4, filter and concentrate in vacuo. This gives 3.2 g (80%) of the title compound as a red oil.

[1034] Analysis data: 1 1H NMR (400 MHz, CDCl3) δ 4.85 (d, J = 5.6 Hz, 1H), 4.71 - 4.58 (m, 2H), 3.83 - 3.74 (m, 1H), 3.70 - 3.62 (m, 1H), 1.48 (s, 3H), 1.39 (s, 3H).

[1035] Step 4: Synthesis of (rac)-(all-cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridin-4(3aH)-one:

[1036] Under N2 atmosphere, place (rac)-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (3.20 g, 15.0 mmol, 1 equiv), Pd / C (300 mg, 10% purity) and MeOH (30 mL) into a 100 mL round-bottom flask. Stir the resulting solution under H2 (50 psi) atmosphere at 25 °C for 3 h. Filter the mixture and concentrate in vacuo. This gives 2.7 g (93%) of the title compound as a colorless oil.

[1037] Analysis data: 1 1H NMR (400 MHz, CDCl3) δ 7.03 - 6.83 (m, 1H), 4.58 - 4.47 (m, 2H), 4.12 - 4.04 (m, 1H), 3.49 - 3.40 (m, 1H), 3.28 - 3.20 (m, 1H), 1.54 (s, 3H), 1.42 (s, 3H).

[1038] Step 5: Synthesis of (rac)-(all-cis)-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-7-ol:

[1039] Place (±)-(all-cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridin-4(3aH)-one (2.55 g, 13.6 mmol, 1 equiv), LiAlH4 (2.58 g, 68.1 mmol, 5.00 equiv) in THF (50 mL) in a 100 mL round-bottom flask. Stir the mixture at 70 °C under N2 atmosphere for 6 h. Quench the reaction mixture with H2O (3 mL). Dilute the reaction mixture with EA / MeOH (100 mL, v / v = 20 / 1), dry over Na2SO4, filter and concentrate in vacuo. This gives 2.4 g (crude) of the title compound as a white solid.

[1040] Analytical data: LC-MS: (ES, m / z): RT = 0.086 min, LCMS: m / z = 174 [M+1].

[1041] Step 6: Synthesis of (±)-(all-cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester

[1042] Place (±)-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-7-ol (2.36 g, 13.6 mmol, 1 equiv), NaHCO3 (3.43 g, 40.9 mmol, 3 equiv), CbzCl (2.56 g, 15.0 mmol, 1.10 equiv) and THF (50 mL) in a 100 mL round-bottom flask. Stir the resulting solution in an oil bath at 50 °C for 2 h. Filter the mixture and concentrate in vacuo. Purify the residue by column chromatography (SiO2, PE / EA = 3 / 1 and DCM / MeOH = 20 / 1). This gives 2.3 g (53%) of the title compound as a white solid.

[1043] Analytical data: LC-MS: (ES, m / z): RT = 0.665 min, LCMS: m / z = 308 [M+1], 1 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.30 (m, 5H), 5.15 (s, 2H), 4.45 - 4.35 (m, 2H), 4.04 - 3.82 (m, 1H), 3.76 - 3.62 (m, 2H), 3.58 - 3.49 (m, 1H), 3.30 - 3.20 (m, 1H), 2.30 (s, 1H), 1.49 (s, 3H), 1.38 (s, 3H).

[1044] Step 7: Synthesis of racemic-(all-cis)-7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester:

[1045] Place racemic-(all-cis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester (500 mg, 1.63 mmol, 1 equiv) and anhydrous DCM (8 mL) in a 50 mL round-bottom flask. Add DAST (786 mg, 4.88 mmol, 3 equiv) at 0 to 10 °C. Stir the resulting solution at 0 to 10 °C for 1 h. Quench the reaction mixture with saturated aqueous NaHCO3 until pH ~8 and extract with DCM (20 mL × 3). Dry the combined organic layers over Na2SO4 and concentrate in vacuo. Purify the residue by column chromatography (SiO2, PE / EA = 3 / 1 and EA / MeOH = 20 / 1). This gives 0.38 g (75%) of the title compound as a colorless oil.

[1046] Analytical data: LC-MS: (ES, m / z): RT = 0.741 min, LCMS: m / z = 310 [M+1]. 1 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.32 (m, 5H), 5.16 (s, 2H), 4.92 - 4.64 (m, 1H), 4.48 - 4.30 (m, 2H), 3.80 - 3.58 (m, 4H), 1.51 (s, 3H), 1.39 (s, 3H).

[1047] Step 8: Synthesis of racemic-(all-cis)-3-fluoro-4,5-dihydroxypiperidine-1-carboxylic acid benzyl ester:

[1048] Place racemic-(all-cis)-7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylic acid benzyl ester (383 mg, 1.24 mmol, 1 equiv) and HCl / MeOH (10.1 mL, 32.6 equiv, 4 mol / L) in a 50 mL round-bottom flask. Stir the resulting solution at 25 °C for 2 h. Concentrate the mixture in vacuo. This gives 0.28 g (84%) of the title compound as a white solid.

[1049] Analytical data: 1 1H NMR (400 MHz, CDCl3) δ 7.42 - 7.31 (m, 5H), 5.16 (s, 2H), 4.73 - 4.52 (m, 1H), 4.02 - 3.51 (m, 6H).

[1050] 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:

[1051] Place racemic-(all-cis)-3-fluoro-4,5-dihydroxypiperidine-1-carboxylic acid benzyl ester (110 mg, 409 μmol, 1 equiv), Ag2O (94.7 mg, 409 μmol, 1 equiv), MeI (145 mg, 1.02 mmol, 2.50 equiv) and DMF (3 mL) into a 25 mL round-bottom flask. Stir the resulting solution at 25 °C for 24 h. Filter the mixture, dilute with EA (30 mL) and wash with brine (30 mL × 3). Dry the collected organic phase over Na2SO4, filter and concentrate in vacuo. Purify the residue by preparative HPLC; mobile phase: water (10 mmol / L NH4HCO3) and ACN (from 18.0% ACN to 38.0% in 10 min); detector, UV 254 / 220 nm. This gives 20 mg (17%) of the title compound as a colorless oil.

[1052] Analytical data: LC-MS: (ES, m / z): RT = 0.689 min, LCMS: m / z = 284 [M+1], 1 1H 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 as a colorless oil.

[27] LC-MS: (ES, m / z): RT = 0.705 min, LCMS: m / z = 284 [M+1]. 1 1H NMR (400 MHz, CDCl3) δ = 7.43 - 7.29 (m, 5H), 5.20 - 5.09 (m, 2H), 4.76 - 4.51 (m, 1H), 3.89 - 3.61 (m, 5H), 3.59 (s, 3H), 3.40 - 3.30 (m, 1H), 2.50 (s, 1H).

[1053] Step 10: Synthesis of racemic-(all-cis)-5-fluoro-4-methoxypiperidin-3-ol:

[1054] To a 25 mL round-bottom flask were added racemic-(all-cis)-3-fluoro-5-hydroxy-4-methoxypiperidine-1-carboxylic acid benzyl ester and racemic-(all-cis)-3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylic acid benzyl ester (5.00 mg, 17.7 μmol, 1 equiv), Pd / C (5 mg, 10% purity), and THF (1 mL). The resulting solution was stirred at 25 °C under H2 (15 psi) for 2 h. The mixture was filtered and concentrated in vacuo. This gave 2.6 mg (100%) of the title compound as a yellow solid.

[1055] Step 11: Synthesis of racemic-(all-cis)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxypiperidin-3-ol:

[1056] To a 250 mL round-bottom flask were added 2-chloropyrimidin-4-amine (2.28 mg, 17.6 μmol, 1 equiv), racemic-(all-cis)-5-fluoro-4-methoxypiperidin-3-ol (2.63 mg, 17.6 μmol, 1 equiv), DIEA (4.56 mg, 35.3 μmol, 2 equiv), and DMSO (1 mL). The resulting solution was stirred at 100 °C for 12 h. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel preparative TLC (PE:EA = 1:2). This gave 3.5 mg (81%) of the title compound.

[1057] Analytical data: LC-MS: (ES, m / z): RT = 0.077 min, LCMS: m / z = 243 [M+1].

[1058] Example B75: Synthesis of racemic-(all-cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol:

[1059]

[1060] Step 1: Synthesis of racemic-(all-cis)-3-fluoro-5-methoxypiperidin-4-ol:

[1061] To a 25 mL round-bottom flask were added racemic-(all-cis)-3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylic acid benzyl ester (50.0 mg, 176 μmol, 1 equiv), Pd / C (15.0 mg, 10% purity), and THF (3 mL). The resulting solution was stirred at 25 °C under H2 (15 psi) for 2 h. The reaction was filtered and concentrated in vacuo to give the title compound. This gave 28 mg (100%) of the title compound as a colorless oil.

[1062] Analytical data: 11H NMR (400 MHz, CDCl3) δ 7.03 - 6.83 (m, 1H), 4.58 - 4.47 (m, 2H), 4.12 - 4.04 (m, 1H), 3.49 - 3.40 (m, 1H), 3.28 - 3.20 (m, 1H), 1.54 (s, 3H), 1.42 (s, 3H).

[1063] Step 2: Synthesis of racemic-(all-cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol:

[1064] Place racemic-(all-cis)-3-fluoro-5-methoxypiperidin-4-ol (28.0 mg, 188 μmol, 1 equiv), 2-chloropyrimidin-4-amine (36.5 mg, 282 μmol, 1.50 equiv), DIEA (60.6 mg, 469 μmol, 2.50 equiv), CsF (28.5 mg, 188 μmol, 1 equiv) and DMSO (1 mL) into a 25 mL round-bottom flask. Stir the resulting solution at 100 °C for 36 h. Filter the reaction mixture and concentrate it under vacuum. Purify the residue by preparative HPLC; mobile phase: water (10 mmol / L NH4HCO3) and ACN (0% ACN to 20.0% over 10 min); detector: UV 254 / 220 nm. This gives 15 mg (33%) of the title compound as a yellow solid.

[1065] Analytical data: 1 1H NMR (400 MHz, CDCl3) 7.93 (d, J = 5.6 Hz, 1H), 5.79 (d, J = 5.6 Hz, 1H), 4.73 (s, 1H), 4.60 (s, 2H), 4.33 - 4.14 (m, 3H), 3.89 - 3.83 (m, 1H), 3.70 - 3.60 (m, 1H), 3.49 (s, 3H), 3.40 - 3.30 (m, 1H).

[1066] Example B76: Synthesis of racemic-2-((all-cis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine

[1067]

[1068] Step I: Synthesis of racemic-(3S,4R,5R)-3-fluoro-4,5-dimethoxypiperidine:

[1069] To a 25 mL round-bottom flask was added racemic-(all-cis)-3-fluoro-4,5-dimethoxy-piperidine-1-carboxylic acid benzyl ester (produced from the overalkylation in Step 9 of Example B74; 30.0 mg, 101 μmol, 1 equivalent), Pd / C (10.0 mg, 101 μmol, 10% purity), and THF (2 mL). The resulting solution was stirred under a H2 (15 psi) atmosphere at 25 °C for 2 hours. The mixture was filtered and concentrated in vacuo. This gave 16 mg (100%) of the title compound as a colorless oil.

[1070] Step 2: Synthesis of racemic-2-((all-cis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine:

[1071] To a 25 mL round-bottom flask was added racemic-(all-cis)-3-fluoro-4,5-dimethoxy-piperidine (16 mg, 98.1 μmol, 1 equivalent), 2-chloropyrimidin-4-amine (25.4 mg, 196 μmol, 2 equivalents), DIEA (38.0 mg, 294 μmol, 51.2 μL, 3 equivalents), CsF (29.8 mg, 196 μmol, 2 equivalents), and DMSO (1 mL). The resulting solution was stirred at 120 °C for 72 hours. The mixture was diluted with EA (20 mL) and washed with H2O (5 mL × 3). The collected aqueous phase was concentrated in vacuo. The residue was purified by preparative HPLC; water (10 mmol / L NH4HCO3) and ACN (0% ACN to 30.0% in 10 minutes); detector: UV 254 / 220 nm. This gave 8.0 mg (32%) of the title compound as a colorless oil.

[1072] Analytical data: LC-MS: (ES, m / z): RT = 1.141 min, LCMS: m / z = 257 [M+1].

[1073] Example B77: Synthesis of racemic-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol:

[1074]

[1075] Step 1: Synthesis of racemic-3,3-difluoro-5-hydroxy-4-methoxy-piperidine-1-carboxylic acid benzyl ester:

[1076] To a solution of racemic - benzyl 3,3 - difluoro - 4,5 - dihydroxypiperidine - 1 - carboxylate (prepared as in step 2 of Example 54 (Boc - protected), 170 mg, 591 μmol, 1 equiv) and Ag2O (137 mg, 591 μmol, 1 equiv) in DMF (5 mL) was added dropwise MeI (210 mg, 1.48 mmol, 92.1 μL, 2.50 equiv). 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 Na2SO4, filtered and concentrated in vacuo. The crude product 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 min]. This gave 110 mg (61%) of the title compound as a colorless oil.

[1077] Analysis data: 1 1H NMR (400 MHz, CDCl3) δ 7.44 - 7.30 (m, 5H), 5.17 (s, 2H), 4.32 - 3.99 (m, 2H), 3.91 - 3.81 (m, 1H), 3.65 (s, 3H), 3.63 (d, J = 3.6 Hz, 1H), 3.53 - 3.27 (m, 1H), 3.07 - 2.88 (m, 1H), 2.37 (s, 1H).

[1078] Step 2: Synthesis of racemic - 5,5 - difluoro - 4 - methoxypiperidin - 3 - ol:

[1079] Under N2, Pd / C (10 mg, 10% purity) was added to a solution of racemic - benzyl 3,3 - difluoro - 5 - hydroxy - 4 - methoxypiperidine - 1 - carboxylate (100 mg, 331 μmol, 1 equiv) in THF (5 mL). The mixture was stirred at 25 °C under H2 (15 psi) for 1 h. The mixture was filtered and the filtrate was concentrated. The reaction mixture was filtered and the filtrate was concentrated. This gave 50 mg (90%) of the title compound as a colorless oil, which was used directly in the next step.

[1080] Step 3: Synthesis of racemic - 1 - (4 - aminopyrimidin - 2 - yl) - 5,5 - difluoro - 4 - methoxypiperidin - 3 - ol:

[1081] To a solution of racemic-5,5-difluoro-4-methoxypiperidin-3-ol (50.0 mg, 299 μmol, 1 equiv) and DIEA (77.3 mg, 598 μmol, 2 equiv) in DMSO (1 mL) was added 2-chloropyrimidin-4-amine (50.3 mg, 388 μmol, 1.30 equiv), and the mixture was stirred at 120 °C for 16 h. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5% to 38%, 10 min]. This gave 25 mg (32%) of the title compound as a colorless oil.

[1082] Analytical data: 1H NMR (400 MHz, CD3OD) δ 7.72 (d, J = 6.0 Hz, 1H), 5.85 (d, J = 6.0 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.58 (s, 1H), 4.47 (dd, J = 4.8, 12.8, Hz, 1H), 3.75 (dd, J = 10.4, 4.4 Hz, 1H), 3.60 (s, 4H), 3.36 (d, J = 13.6 Hz, 1H), 3.03 (dd, J = 12.4, 11.2 Hz, 1H).

[1083] Example B78: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[1084]

[1085] Step 1: Synthesis of racemic-cis-1-(4-methylthiopyrimidin-2-yl)piperidine-3,4-diol:

[1086] To a solution of racemic-cis-piperidine-3,4-diol (0.500 g, 3.26 mmol, 1 equiv, HCl salt) and DIEA (1.68 g, 13.0 mmol, 2.27 mL, 4.00 equiv) in DMSO (5 mL) was added 2-chloro-4-methylthiopyrimidine (784 mg, 4.88 mmol, 1.50 equiv), and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (120 mL) and extracted with EA (70 mL × 2), and 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 gave 0.68 g (96%) of the title compound as an off-white solid.

[1087] Analytical data: 11H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 5.2 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.24 - 4.17 (m, 1H), 4.16 - 4.07 (m, 1H), 3.96 - 3.86 (m, 2H), 3.73 (dd, J = 13.6, 3.2 Hz, 1H), 3.64 - 3.52 (m, 1H), 2.50 (s, 3H), 1.94 - 1.73 (m, 2H).

[1088] Step 2: Synthesis of racemic-cis-4-(2-methoxyethoxy)-1-(4-methylthio-pyrimidin-2-yl)piperidin-3-ol:

[1089] To a solution of racemic-cis-1-(4-methylthio-pyrimidin-2-yl)piperidine-3,4-diol (470 mg, 1.95 mmol, 1 equiv) and NaI (29.2 mg, 194 μmol, 0.100 equiv) in ACN (10 mL) was added 2-methoxyethyl 4-methylbenzenesulfonate (897 mg, 3.90 mmol, 2 equiv) and Cs2CO3 (1.90 g, 5.84 mmol, 3 equiv). 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%, 9 min]. This gave 0.18 g (30%) of the title compound as a yellow solid.

[1090] Analytical data: 1 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 5.2 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 4.07 - 4.02 (m, 1H), 3.97 - 3.79 (m, 4H), 3.71 - 3.65 (m, 1H), 3.61 - 3.47 (m, 3H), 3.42 - 3.38 (m, 3H), 2.50 (s, 3H), 2.01 - 1.89 (m, 1H), 1.78 - 1.66 (m, 1H).

[1091] Step 3: Synthesis of racemic-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonyl-pyrimidin-2-yl)piperidin-3-ol:

[1092] [8] To a solution of racemic-cis-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-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 h. 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 gave 85 mg (48%) of the title compound as a colorless oil.

[1093] Analytical data: 1 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 4.08 - 3.94 (m, 3H), 3.93 - 3.85 (m, 2H), 3.84 - 3.80 (m, 1H), 3.75 - 3.63 (m, 2H), 3.60 - 3.49 (m, 3H), 3.42 - 3.38 (m, 3H), 3.18 (s, 3H), 2.01 - 1.90 (m, 1H), 1.79 - 1.69 (m, 1H).

[1094] Step 4: Synthesis of racemic-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[1095] A solution of racemic-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol (80.0 mg, 241 μmol, 1 eq) in NH3 / THF (8 mL) was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC [column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 1% to 30%, 10 min]. This gave 5.0 mg (7%) of the title compound as a mixture of enantiomers as a colorless oil.

[1096] Analytical data: 11H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 5.6 Hz, 1H), 5.73 (d, J = 5.6 Hz, 1H), 4.57 (s, 2H), 4.00 - 3.93 (m, 1H), 3.91 - 3.82 (m, 2H), 3.82 - 3.72 (m, 3H), 3.71 - 3.60 (m, 3H), 3.59 - 3.56 (m, 1H), 3.40 (s, 3H), 2 - 1.90 (m, 1H), 1.73 - 1.67 (m, 1H).

[1097] Example B79: Synthesis of trans-racemic (3S,4S)-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol:

[1098]

[1099] Step 1: Synthesis of racemic-trans-3,4-dihydroxypiperidine-1-carboxylic acid tert-butyl ester:

[1100] A solution of KOH (1.13 g, 20.0 mmol, 2 equiv) in water (15 mL) was added to a solution of racemic tert-butyl 7-oxa-4-azabicyclo[4.1.0]heptane-4-carboxylate (2 g, 10.0 mmol, 1 equiv) in dioxane (30 mL). The mixture was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was diluted with water (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (80 mL), dried and concentrated in vacuo. This gave 2 g (90%) of the title compound as a colorless oil, which was used directly in the next step.

[1101] Step 2: Synthesis of (3S,4S)-piperidine-3,4-diol:

[1102] A solution of racemic-trans-3,4-dihydroxypiperidine-1-carboxylic acid tert-butyl ester (2 g, 9.21 mmol, 1 equiv) in HCl / dioxane (5 mL, 4 mol / L) was stirred at 25 °C for 30 min. 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.

[1103] Step 3: Synthesis of racemic-trans-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol:

[1104] To a solution of racemic-trans-piperidine-3,4-diol (1.20 g, 7.81 mmol, 1 equiv., HCl salt) and DIEA (5.05 g, 39.1 mmol, 6.80 mL, 5.00 equiv.) in DMSO (12 mL) was added 2-chloro-4-methylthio-pyrimidine (1.25 g, 7.81 mmol, 1 equiv.). The mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (150 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA = 2:1). This gave 1.30 g (69%) of the title compound as an off-white solid, which was used directly in the next step.

[1105] Step 4: Synthesis of racemic-trans-4-(2-methoxyethoxy)-1-(4-methylthiopyrimidin-2-yl)piperidin-3-ol:

[1106] To a solution of racemic-trans-1-(4-methylthiopyrimidin-2-yl)piperidine-3,4-diol (700 mg, 2.90 mmol, 1 equiv.) and NaI (43.4 mg, 290 μmol, 0.100 equiv.) in ACN (10 mL) was added 2-methoxyethyl 4-methylbenzenesulfonate (1.34 g, 5.80 mmol, 2 equiv.) and Cs2CO3 (2.84 g, 8.70 mmol, 3 equiv.). The mixture was stirred at 80 °C for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC [column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20% to 50%, 11.5 min]. This gave 300 mg (34%) of the title compound as a yellow solid.

[1107] Analytical data: 1 H NMR (400 MHz, CDCl3) δ 8.00 - 7.93 (m, 1H), 6.46 - 6.39 (m, 1H), 5.03 - 4.83 (m, 1H), 4.81 - 4.62 (m, 1H), 4.02 - 3.88 (m, 1H), 3.74 - 3.57 (m, 5H), 3.42 (s, 3H), 3.38 - 3.14 (m, 1H), 3.03 - 2.65 (m, 2H), 2.50 (s, 3H), 2.08 - 2.01 (m, 1H), 1.56 - 1.46 (m, 1H).

[1108] Step 5: Synthesis of racemic - trans - 4-(2 - methoxyethoxy)-1-(4 - methylsulfonylpyrimidin - 2 - yl)piperidin - 3 - ol:

[1109] To a solution of racemic - trans - 4-(2 - methoxyethoxy)-1-(4 - methylthiopyrimidin - 2 - yl)piperidin - 3 - ol (300 mg, 1 mmol, 1 equiv) in THF (10 mL) and H2O (3 mL) was added potassium peroxymonosulfate (1.85 g, 3.01 mmol, 3 equiv), and the mixture was stirred at 25 °C for 3 h. The mixture was washed with saturated aqueous 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 gave 120 mg (36%) of the title compound as a colorless oil.

[1110] Step 6: Synthesis of racemic - trans - 1-(4 - aminopyrimidin - 2 - yl)-4-(2 - methoxyethoxy)piperidin - 3 - ol:

[1111] A solution of racemic - trans - 4-(2 - methoxyethoxy)-1-(4 - methylsulfonylpyrimidin - 2 - yl)piperidin - 3 - ol (120 mg, 362 μmol, 1 equiv) in NH3 / THF (8 mL) was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC [column: Xtimate C18 150*40mm*10μm; mobile phase: [water (0.05% ammonium hydroxide v / v) - ACN]; B%: 10% to 20%, 10 min]. This gave 10.0 mg (10%) of the title compound as a mixture of enantiomers as a colorless oil.

[1112] Analytical data: 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 5.6 Hz, 1H), 5.74 (d, J = 5.6 Hz, 1H), 4.74 - 4.64 (m, 3H), 4.57 - 4.49 (m, 1H), 3.90 - 3.84 (m, 1H), 3.70 - 3.65 (m, 1H), 3.60 - 3.55 (m, 3H), 3.40 (s, 3H), 3.39 - 3.29 (m, 1H), 3.01 - 2.94 (m, 1H), 2.88 (dd, J = 13.2, 9.6 Hz, 1H), 2.03 - 2 (m, 1H), 1.53 - 1.43 (m, 1H).

[1113] Example C1: Synthesis of 1,6 - dichloro - 4 - isopropyl - 2,7 - naphthyridine

[1114]

[1115] Step 1: Synthesis of 6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one:

[1116] At 0 °C, NIS (74 g, 0.33 mol) was added to a solution of 6-chloro-1,2-dihydro-2,7-naphthyridin-1-one (50 g, 0.276 mol) in DMF (300 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, the filter cake was washed with water and dried under vacuum to give the title compound as a pale yellow solid (60 g, 70%).

[1117] 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).

[1118] Step 2: Synthesis of 1,6-dichloro-4-iodo-2,7-naphthyridine:

[1119] A mixture of 6-chloro-4-iodo-1,2-dihydro-2,7-naphthyridin-1-one (60 g, 0.196 mol) in POCl3 (320 mL) was stirred at 100 °C for 1.5 h. LCMS showed consumption of the starting material. The mixture was concentrated and neutralized with cooled saturated aqueous NaHCO3. The mixture was extracted with EA 3×300 mL. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 1,6-dichloro-4-iodo-2,7-naphthyridine as a yellow solid, 53 g (84%).

[1120] Analytical data: LC-MS: (ES, m / z) = 325 [M+1].

[1121] Step 3: Synthesis of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine:

[1122] To a solution of 1,6-dichloro-4-iodo-2,7-naphthyridine (30 g, 92.5 mmol) in 1,4-dioxane / H2O (300 / 70 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15 g, 93 mmol), K2CO3 (37.8 g, 276 mmol), and PdAMPhosCl2 / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (3 g, 4.2 mmol). The resulting solution was stirred at 50 °C for 0.5 h. LCMS showed 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 x 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 in vacuo. The product was purified by chromatography using EA:PE (1:10). This gave 15 g (68.1%) of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine as a white solid.

[1123] Analytical data: LC-MS: (ES, m / z) = 239 [M+1].

[1124] Step 4: Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine:

[1125] 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 a H2 atmosphere for 24 h. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography (EA:PE = 1:8) to give 3 g (75%) of 1,6-dichloro-4-(propan-2-yl)-2,7-naphthyridine as a white solid.

[1126] 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).

[1127] Example C2: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine

[1128]

[1129] Step 1: Synthesis of 5-bromo-N-tert-butyl-2-chloroisonicotinamide:

[1130] Into a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, add DMF (30 mL) containing 5-bromo-2-chloropyridine-4-carboxylic acid (4 g, 16.9 mmol), 2-methylpropan-2-amine (1.47 g, 20.2 mmol), EDC HCl (4.85 g, 25.3 mmol), and HOBT (3.41 g, 25.3 mmol). Stir the resulting solution at room temperature overnight. Add water to the resulting solution and extract the suspension with EA. Then combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under vacuum. Purify the residue by FLASH using PE / EA (2:1). This yields 3 g (60.9%) of 5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide as a white solid.

[1131] 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).

[1132] Step 2: Synthesis of (E)-N-tert-butyl-2-chloro-5-(2-ethoxyvinyl)isonicotinamide:

[1133] Into a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, add dioxane (30 mL) and H2O (6 mL) containing 5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide (2 g, 6.85 mmol), 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). Stir the resulting solution at 80 °C for 2 hours. Dilute the resulting solution with water and extract with EA. Then combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under vacuum. Purify the residue by FLASH using PE / EA (2:1). This yields 1.2 g (62.1%) of N-tert-butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyridine-4-carboxamide as a yellow solid.

[1134] 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).

[1135] Step 3: Synthesis of 7-chloro-2,6-naphthyridin-1(2H)-one:

[1136] Place N-tert-butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyridine-4-carboxamide (1.2 g, 4.24 mmol) in TFA (20 mL) in a 20 mL vial. Stir the resulting solution at 100 °C overnight. Concentrate the resulting mixture in vacuo. This gives 600 mg (91.5%) of 7-chloro-1,2-dihydro-2,6-naphthyridin-1-one as a red solid. The crude product is used directly in the next step without any further purification.

[1137] Analytical data: LC-MS: (ES, m / z) = 181 [M+1].

[1138] Step 4: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1(2H)-one:

[1139] Place 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) in a 250 mL round-bottom flask. Stir the resulting solution at room temperature for 1 h. Collect the solid by filtration. This gives 3 g (69.7%) of the title compound as a white solid.

[1140] Analytical data: LC-MS: (ES, m / z) = 261 [M+1]; 1H 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).

[1141] Step 5: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate:

[1142] To a 50 mL three-necked flask, add DCM (15 mL) and TEA (777 mg, 7.70 mmol) containing 4-bromo-7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (1 g, 3.85 mmol). Cool the resulting mixture to -78 °C, and then add dropwise Tf2O (4.34 g, 15.4 mmol) over 10 minutes. Stir the resulting solution at -78 °C for 0.5 hour. Then warm the mixture to room temperature and stir at this temperature for 0.5 hour. Then quench the reaction by adding 2 mL of water / ice, extract with DCM, then combine the organic layers, dry over anhydrous sodium sulfate and concentrate in vacuo. Apply the residue to a silica gel column with EA / PE (0 to 10%). This gives 1 g (66.6%) of the title compound as a white solid.

[1143] Analytical data: LC-MS: (ES, m / z) = 393 [M+1]; 1 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.78 (s, 1H), 8.14 (d, 1H, J = 0.9 Hz).

[1144] Step 6: Synthesis of 4-bromo-7-chloro-1-iodo-2,6-naphthyridine:

[1145] To a 50 mL three-necked flask, add ACN (9 mL) and NaI (952 mg, 6.35 mmol) containing 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate (500 mg, 1.27 mmol). Cool the resulting mixture to 0 °C and add dropwise ACN (1 mL) containing trifluoromethanesulfonic acid (381 mg, 2.54 mmol) over 10 minutes. Then stir the mixture at room temperature for 1.5 hours. After that, extract the resulting solution with EA, then combine the organic layers, wash with brine, dry over anhydrous sodium sulfate and concentrate in vacuo. This gives 500 mg of the title compound as a black solid. Use the crude compound directly in the next step without further purification.

[1146] Analytical data: LC-MS: (ES, m / z) = 369 [M+1].

[1147] Step 7: Synthesis of 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine:

[1148] To a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere was added 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), K2CO3 (372 mg, 2.7 mmol), and Pd(dppf)Cl2 (0.99 mg, 0.135 mmol) in dioxane (5 mL) and H2O (1 mL). The resulting solution was stirred at 80 °C for 2 h. The resulting solution was extracted with EA, and then the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC with PE / EA (8:1). This gave 200 mg (52.3%) of the title compound as a pale yellow oil.

[1149] Analytical data: LC-MS: (ES, m / z) = 285 [M+1].

[1150] Step 8: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine:

[1151] To a 25 mL round-bottom flask purged and maintained under an inert hydrogen atmosphere was added 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 h. The solid was filtered off. The resulting mixture was concentrated in vacuo. This gave 100 mg (62.1%) of the title compound as a yellow solid.

[1152] Analytical data: LC-MS: (ES, m / z) = 287 [M+1].

[1153] Example C3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine

[1154]

[1155] Step 1: Synthesis of 6-chloro-4-isobutyrylnicotinic acid:

[1156] 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, then cooled back to -78 °C. Then a solution of 6-chloropyridine-3-carboxylic acid (15 g, 95.2 mmol) in THF was added dropwise and the reaction was stirred for 1.5 hours. Then N-methoxy-N,2-dimethylpropanamide (37.3 g, 285 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was quenched with aqueous NH4Cl and the pH was adjusted to 5 - 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 give the desired product as a yellow oil without further purification.

[1157] Analytical data: LC-MS: (ES, m / z) = 228 [M+1].

[1158] Step 2: Synthesis of 7-chloro-1-isopropylpyrido[3,4-d]pyridazin-4(3H)-one:

[1159] NH2NH2·H2O (3.62 g, 72.4 mmol) was added to a solution of 6-chloro-4-(2-methylpropanoyl)pyridine-3-carboxylic acid (11 g, 48.3 mmol) in IPA, 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 as a yellow solid (6 g, crude).

[1160] Analytical data: LC-MS: (ES, m / z) = 224 [M+1].

[1161] Step 3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine:

[1162] 7-Chloro-1-(propan-2-yl)-3H,4H-pyrido[3,4-d]pyridazin-4-one (100 mg, 447 μmol) was added to a solution of POCl3 (5 mL). The mixture was stirred at 100 °C overnight. The mixture was concentrated and the product was used directly without further purification.

[1163] Analytical data: LC-MS: (ES, m / z) = 242 [M+1].

[1164] Example C4: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline

[1165]

[1166] Step 1: Synthesis of 8-bromo-3-chloroisoquinoline-5-yl trifluoromethanesulfonate:

[1167] At -60 °C, trifluoromethanesulfonic anhydride (45.7 g, 162 mmol) was added dropwise to a solution of 8-bromo-3-chloroisoquinolin-5-ol (14 g, 54.1 mmol) and TEA (21.8 g, 216 mmol) in DCM (400 mL). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was concentrated in vacuo. 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.

[1168] Analytical data: LC-MS: (ES, m / z) = 392 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (d, 1H, J = 0.8 Hz), 8.20 (d, 1H, J = 8.3 Hz), 8.02 (d, 1H, J = 8.4 Hz), 7.93 (d, 1H, J = 0.7 Hz).

[1169] Step 2: Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline:

[1170] A mixture of K2CO3 (6 g, 43.5 mmol), 8-bromo-3-chloroisoquinoline-5-yl trifluoromethanesulfonate (17 g, 43.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.30 g, 43.5 mmol) and Pd(dppf)Cl2·CH2Cl2 (2.83 g, 3.48 mmol) in dioxane / H2O (200 / 20 mL) was stirred at 45 °C for 3 h. 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 in vacuo. 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.

[1171] Analytical data: LC-MS: (ES, m / z) = 282 [M+1].

[1172] Step 3: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline:

[1173] Under an H2 balloon atmosphere, a solution of 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) was stirred at room temperature for 1 hour. The solid was filtered off. The mother solvent was concentrated in vacuo. The crude product was purified by silica gel column with PE:EA = 10:1 to afford 6.7 g (93%) of the title compound as a brown solid.

[1174] Analytical data: LC-MS: (ES, m / z) = 284 [M+1].

[1175] Example C5: Synthesis of racemic-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol

[1176]

[1177] Step 1: Synthesis of 2-(8-bromo-3-chloroisoquinolin-5-yl)prop-2-en-1-ol:

[1178] 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 / H2O 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), K2CO3 (1.76 g, 12.8 mmol) and Pd(dPPf)Cl2 (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 with PE:EA (1:1). This gave 2.1 g (54.9%) of the title compound as a white solid.

[1179] Analytical data: LC-MS: (ES, m / z) = 298 [M+1].

[1180] Step 2: Synthesis of racemic-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol:

[1181] A mixture of 2-(8-bromo-3-chloroisoquinolin-5-yl)prop-2-en-1-ol (2 g, 6.69 mmol) and PtO2 (454 mg, 0.05 mmol) in EA (50 mL) was stirred under an H2 atmosphere at room temperature for 2 hours. The resulting mixture was filtered. The filtrate was concentrated in vacuo. The product was purified by Flash with PE:EA (10:1). This gave 1.8 g (90%) of the title compound as a yellow solid.

[1182] Analysis data: LC-MS: (ES, m / z) = 300 [M+1].

[1183] Example C6: Synthesis of 8-bromo-3-chloro-5-methylisoquinoline

[1184]

[1185] A mixture of 8-bromo-3-chloroisoquinoline-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)Cl2 (46.9 mg, 64.0 μmol), and K2CO3 (176 mg, 1.28 mmol) in a mixed solvent (dioxane: H2O = 5:1, 4.8 mL) was stirred at 40 °C under a N2 atmosphere for 16 h. The resulting solution was concentrated in vacuo. The residue was purified by preparative TLC with DCM / MeOH (20 / 1) to afford 100 mg of the title compound as an off-white solid.

[1186] Analysis data: LC-MS: (ES, m / z) = 258 [M+1].

[1187] Example C7: Synthesis of 8-bromo-3-chloroisoquinoline

[1188]

[1189] A mixture of 8-bromo-3-chloroisoquinoline-5-yl trifluoromethanesulfonate (100.00 mg, 0.256 mmol, 1 equiv, from Step 1 of Example C4), [3-(diphenylphosphino)propyl]diphenylphosphine (2.11 mg, 0.005 mmol, 0.02 equiv), palladium(II) acetate (1.15 mg, 0.005 mmol, 0.02 equiv), and triethylsilane (74.43 mg, 0.640 mmol, 2.5 equiv) in DMF (3 mL) was stirred at 60 °C under a N2 atmosphere for 1 h. Water was added, and the mixture was extracted with EA and concentrated. The residue was applied to preparative TLC with DCM / MeOH (10:1). This gave 50 mg (80.5%) of the title compound as a pale yellow solid.

[1190] Analysis data: LC-MS: (ES, m / z) = 242 [M+1].

[1191] Example C8: Synthesis of racemic-3-chloro-5-(1-fluoropropan-2-yl)-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[1192]

[1193] Step 1: Synthesis of racemic - 2 - {3 - chloro - 8 - [3 - (methylsulfonylmethyl)azetidin - 1 - yl]isoquinolin - 5 - yl}propan - 1 - ol:

[1194] 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 h. The resulting solution was diluted with 20 mL of water and extracted with 2 x 20 mL of EA. The organic phase was washed with brine, dried and concentrated in vacuo. The crude product was purified by preparative TLC (DCM:MeOH = 10:1). This gave 100 mg (54.3%) of the title compound as a yellow solid.

[1195] Analytical data: LC - MS: (ES, m / z) = 369 [M + 1].

[1196] Step 2: Synthesis of racemic - 3 - chloro - 5 - (1 - fluoropropan - 2 - yl)-8 - (3 - (methylsulfonylmethyl)azetidin - 1 - yl)isoquinoline:

[1197] At 0 °C, 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). The mixture was stirred at 0 °C for 3 h. 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 in vacuo. The crude product was purified by preparative TLC (DCM:MeOH = 15:1). This gave 80 mg (79.9%) of the title compound as a yellow solid.

[1198] Analytical data: LC - MS: (ES, m / z) = 371 [M + 1].

[1199] Example C9: Synthesis of 8 - bromo - 3 - chloro - 5 - ethoxyisoquinoline

[1200]

[1201] Step 1: Synthesis of 8 - bromo - 3 - chloro - 5 - methoxyisoquinoline:

[1202] Over a period of 10 minutes, a solution of dibromo (1.80 g, 11.3 mmol) dissolved in 10 mL of AcOH was added to a mixture of 3-chloro-5-methoxyisoquinoline (2 g, 10.3 mmol) contained in AcOH (20 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was slowly poured into a solution of K2CO3 (5 g in 100 mL of H2O) while stirring rapidly. 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.

[1203] Analytical data: LC-MS: (ES, m / z) = 272 [M+1]. 1 1H-NMR (300 MHz, 6d-DMSO) δ ppm 9.21 (s, 1H), 8.09 - 7.81 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H).

[1204] Step 2: Synthesis of 8-bromo-3-chloroisoquinolin-5-ol:

[1205] Borane tribromide (5.48 g, 21.9 mmol) was added to a solution of 8-bromo-3-chloro-5-methoxyisoquinoline (2 g, 7.33 mmol) contained in DCM. 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 gave 1.8 g (89%) of the title compound as a yellow solid.

[1206] Analytical data: LC-MS: (ES, m / z) = 258 [M+1].

[1207] Step 3: Synthesis of 8-bromo-3-chloro-5-ethoxyisoquinoline:

[1208] Iodoethane (1.08 g, 6.96 mmol) and Cs2CO3 (3.39 g, 10.4 mmol) were added to a solution of 8-bromo-3-chloroisoquinolin-5-ol (900 mg, 3.48 mmol) contained in DMF (20 mL). 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 in vacuo and purified by chromatography with PE:EA (1:1). This gave 800 mg (80.2%) of the title compound as a yellow solid.

[1209] Analytical data: LC-MS: (ES, m / z) = 286 [M+1]; 1H-NMR (400 MHz, 6d-DMSO) δ ppm 9.23 (d, 1H, J = 0.8 Hz), 8.03 (d, 1H, J = 0.8 Hz), 7.91 (d, 1H, J = 8.3 Hz), 7.20 (d, 1H, J = 8.4 Hz), 4.25 (q, 2H, J = 7.0 Hz), 1.47 (t, 3H, J = 6.9 Hz).

[1210] Example C10: Synthesis of 3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline

[1211]

[1212] Step 1: Synthesis of (1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanol:

[1213] 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 Cs2CO3 (684 mg, 2.10 mmol) in dioxane (25 mL) was stirred at 100 °C for 16 h. The reaction was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound as a yellow solid (230 mg, 76%).

[1214] Analytical data: LC-MS: (ES, m / z) = 291 [M+1].

[1215] Step 2: Synthesis of 3-chloro-8-(3-(iodomethyl)azetidin-1-yl)-5-isopropylisoquinoline:

[1216] 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 h. The solvent was removed and the residue was purified by preparative TLC (PE:EA = 20:1) to give the title compound as a yellow solid (190 mg, 62%).

[1217] Analytical data: LC-MS: (ES, m / z) = 401 [M+1].

[1218] Step 3: Synthesis of 3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline:

[1219] 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 afford the title compound as a yellow solid (100 mg, 94.5%).

[1220] Analytical data: LC-MS: (ES, m / z) = 379 [M+1].

[1221] Example C11: Synthesis of 8-bromo-3-chloro-5-cyclopropylisoquinoline

[1222]

[1223] To a solution of 8-bromo-3-chloroisoquinoline-5-yl trifluoromethanesulfonate (240 mg, 614 μmol) in dioxane / H2O (10 mL / 2 mL) was added 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (123 mg, 736 μmol), K2CO3 (168 mg, 1.22 mmol) and Pd(dppf)Cl2 (50.1 mg, 61.4 μmol). The mixture was stirred at 80 °C under N2 atmosphere for 16 h. Water was added to the mixture and the mixture was extracted with EA. The organic phase was concentrated and purified by FLASH (50% EA / PE) to afford the title compound as a yellow solid 90 mg (52%).

[1224] Analytical data: LC-MS: (ES, m / z) = 284 [M+1].

[1225] Example C12: Synthesis of 3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[1226]

[1227] Step 1: Synthesis of 7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1228] 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 h. The solvent was removed and the residue was purified by preparative TLC (5% MeOH / DCM) to afford 170 mg (81.7%) of the title compound as a yellow solid.

[1229] Analytical data: LC-MS: (ES, m / z) = 431 [M+1].

[1230] Step 2: Synthesis of 3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1231] 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), K2CO3 (23.8 mg, 173 μmol) and Pd(dppf)Cl2 (14.1 mg, 17.3 μmol) in dioxane / H2O (7 mL / 2 mL) was stirred at 80 °C for 3 h. The mixture was extracted with EA. The organic matter was concentrated and purified by FLASH (5% MeOH / DCM) to afford 55 mg (87%) of the title compound as a yellow solid.

[1232] Analytical data: LC-MS: (ES, m / z) = 367 [M+1].

[1233] Example C13: Synthesis of 3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[1234]

[1235] Step 1: Synthesis of 7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1236] At room temperature, NBS (163 mg, 918 μmol) was added portionwise to DMF (20 mL) containing 3-chloro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline (360 mg, 1.02 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC with PE:EA = 1:1 to afford 350 mg of the title compound as a yellow solid.

[1237] Analytical data: LC-MS: (ES, m / z) = 431 [M+1].

[1238] Step 2: Synthesis of 3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

[1239] At -78 °C under a N2 atmosphere, n-BuLi (2.5 M, 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 h. The mixture was quenched with H2O, diluted with EA and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC with DCM:MeOH = 30:1 to afford 80 mg of the title compound as a yellow solid.

[1240] Analytical data: LC-MS: (ES, m / z) = 371 [M+1].

[1241] Example C14: Synthesis of 3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline

[1242]

[1243] Step 1: Synthesis of 3-chloro-5-iodo-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

[1244] 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 iodosulfanilamide (58.6 mg, 337 μmol), and the mixture was stirred at room temperature for 1 h. 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.

[1245] Analytical data: LC-MS: (ES, m / z) = 451 [M+1].

[1246] Step 2: Synthesis of 3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline:

[1247] Under a 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 h. 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 pale yellow solid.

[1248] Analytical data: LC-MS: (ES, m / z) = 393 [M+1].

[1249] 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

[1250]

[1251] Step 1: Synthesis of 6-chloro-4-iodo-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridine

[1252] Stir 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) at 100 °C for 3 h. Dilute the mixture with EA and wash with brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify the residue by TLC (PE:EA = 1:1). This gives 300 mg (72.1%) of the title compound as a pale yellow solid.

[1253] Analytical data: LC-MS: (ES, m / z) = 452 [M+1].

[1254] 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:

[1255] Under an N2 atmosphere, place 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-1,3,2-dioxaborolan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (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) in a 50 mL sealed tube. Stir the resulting solution at 85 °C for 6 h. Dilute the mixture with EA and wash with brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify the residue by Flash Column Silica-CS (DCM:MeOH = 10:1). This gives 150 mg (89.2%) of the title compound as a white solid.

[1256] Analytical data: LC-MS: (ES, m / z) = 382 [M+1].

[1257] 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:

[1258] 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 PtO2 (29.5 mg, 130 μmol). The mixture was then hydrogenated under a hydrogen balloon at room temperature for 1 h. The mixture was filtered and concentrated. The residue was purified by TLC (DCM:MeOH = 10:1). This gave 110 mg of the title compound as a yellow solid.

[1259] Analytical data: LC-MS: (ES, m / z) = 384 [M+1].

[1260] Example C16: Synthesis of 3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline:

[1261]

[1262] Step 1: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-ol:

[1263] At -78 °C, to a solution of 3-chloro-5,7-difluoro-8-methoxy-isoquinoline (300 mg, 1.31 mmol, 1 equiv) in DCM (5 mL) was added BBr3 (982 mg, 3.92 mmol, 3 equiv), and the mixture was then stirred at 25 °C for 2 h. The mixture was quenched with 10 mL of water and some solid precipitated out. The solid was collected by filtration and washed with 10 mL of water. This gave 0.22 g (77%) of the title compound as a brown solid.

[1264] Analytical data: LC-MS: (ES, m / z): RT = 0.645 min, LCMS: m / z = 215.8 [M+1].

[1265] Step 2: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-yl trifluoromethanesulfonate:

[1266] A mixture of 3-chloro-5,7-difluoro-isoquinolin-8-ol (200 mg, 923 μmol, 1 equiv), 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (994 mg, 2.78 mmol, 3 equiv) and TEA (282 mg, 2.78 mmol, 3 equiv) 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 (from PE to PE / EA = 50 / 1). This gave 0.26 g (76%) of the title compound as a white solid.

[1267] Analytical data: LC-MS: (ES, m / z): RT = 0.966 min, LCMS: m / z = 348.0 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.33 (dd, J = 9.6, 10.4 Hz, 1H), 8.28 (s, 1H).

[1268] Step 3: Synthesis of 3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline:

[1269] To a mixture of trifluoromethanesulfonic acid (3-chloro-5,7-difluoro-8-isoquinolinyl ester) (140 mg, 403 μmol, 1 equiv), 3-(methylsulfonylmethyl)azetidine (159 mg, 604 μmol, 1.50 equiv, TFA salt), and Cs2CO3 (393 mg, 1.21 mmol, 3 equiv) in toluene (1 mL) was added (1E,4E)-1,5-diphenylpent-1,4-dien-3-one; palladium (23.2 mg, 40.3 μmol, 0.1 equiv), BINAP (201 mg, 322 μmol, 0.8 equiv), and Pd(OAc)2 (18.1 mg, 80.5 μmol, 0.2 equiv). The mixture was degassed with N2 and purged three times, 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 gave 10 mg (7%) of the title compound as a yellow solid.

[1270] Analytical data: LC-MS: (ES, m / z): RT = 0.900 min, LC...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein: Z is O or NH; Each A 1 , A 2 and A 3 independently is N or CR; where each R is independently H, halogen or CH3; Ring A is a 4- to 12-membered heterocyclic group; Each R 1 is independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or -O-C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl in the group represented by R 1 or the group represented by R 1 is optionally substituted by 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy; 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 the alkyl, alkoxy or cycloalkyl represented by R 2 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 a 4- to 6-membered monocyclic heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group represented by R 5 is optionally substituted with 1 to 3 groups selected from halogen, CN, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy; R 6 is H or optionally a C1-C4 alkyl group substituted with 1 to 3 groups selected from halogen, CN, OH, NR a R b and C1-C2 alkoxy; and Each R a and R b is independently H or C1-C4 alkyl.

2. The compound or a 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 or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by structural formula (II-A):

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Z is O.

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluorine, C1-C4 alkyl, C1-C4 alkoxy or C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl represented by R 2 is optionally substituted with 1-3 groups selected from halogen and OH.

6. The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R 6 is H, methyl, ethyl, C1-C2 haloalkyl or C1-C2 aminoalkyl.

7. The compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R 5 is H; C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen, CN and NR a R b ; 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 are each independently selected from H, methyl and ethyl.

8. The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein ring A is a 4- to 7-membered monocyclic heterocyclic group optionally substituted with 1 to 6 Rs 1 substituted.

9. The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally 1-6 R-substituted 7-12 membered bicyclic heterocyclic group. 1 substituted.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein m is 1, 2, 3, 4 or 5; and Each R 1 is independently halogen, CN, OH, NR a R b , C1-C4 alkyl, C1-C4 alkoxy, -O-C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl in the group represented by R 1 or represented by R 1 is optionally substituted by 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy.

11. The compound according to any one of claims 1-10 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.

12. The compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R 6 is H, CH3 or CH2NH2.

13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 and 10-12, wherein ring A is optionally substituted by 1 to 6 Rs 1 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]non-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl.

14. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein at least one R 1 is OH, C1-C4 alkoxy or -O-C3-C6 cycloalkyl, wherein the alkoxy or cycloalkyl in the group represented by R 1 or in the group represented by R 1 is optionally substituted by 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C1-C2 alkyl and C1-C2 alkoxy.

15. A compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently 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 any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein is 17. The compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R 2 is H or isopropyl.

18. The compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally 1-6 R 1 substituted piperidinyl.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18.

20. A method for treating cancer, which comprises administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-18, or the pharmaceutical composition according to claim 19.

21. The method according to claim 20, wherein the cancer is non-small cell lung cancer.

22. The method according to claim 20 or 21, wherein the cancer in the subject in need thereof has metastasized.

23. The method according to any one of claims 20-22, 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 method according to claim 23, wherein the cancer is further characterized by epidermal growth factor receptor (EGFR) C797S mutation.

25. The method according to any one of claims 20-24, which further comprises administering to a subject in need thereof an effective amount of afatinib, osimertinib, erlotinib or gefitinib.

26. A method for inhibiting epidermal growth factor receptor (EGFR), which comprises administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-18, or the pharmaceutical composition according to claim 19.

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