Methods for preparing EGFR inhibitors

Abstract

The present disclosure relates to a compound of structural formula (I) A method for producing JPEG2024524246000081.jpg4593 or a pharma- ceutically acceptable salt thereof is provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 214,069, filed June 23, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] EGFR (epidermal growth factor receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. Upon binding to its ligand (e.g., epidermal growth factor (EGF)), EGFR can form homodimers on the cell membrane or heterodimers with other receptors in the family (e.g., erbB2, erbB3, and erbB4). The formation of these dimers leads to phosphorylation of key tyrosine residues in the EGFR cell, which activates multiple downstream signaling pathways in the cell. These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis. Disturbances in the EGFR signaling pathway, including increased expression of ligands and receptors, amplification and alterations (e.g., mutations, deletions, etc.) of the EGFR gene, promote malignant transformation of cells and play important roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. For example, alterations such as mutations and deletions in the EGFR gene are found in non-small cell lung cancer (NSCLC) tumors. The two most frequent EGFR alterations in NSCLC tumors are a short in-frame deletion (del19) in exon 19 and a single missense mutation L858R in exon 21 (Cancer Discovery 2016 6(6)601). These two mutations lead to ligand-independent EGFR activation and are referred to as primary or activating mutations in EGFR-mutated NSCLC (EGFR M+).Clinical experience has demonstrated that the objective response rate (ORR) in patients with EGFR M+ NSCLC treated with first-line (1L) EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib is approximately 60-85% (Lancet Oncol.2010 Vol.11,121; Lancet Oncol.2016 Vol.17,577; N.Engl. J.Med.2017 Nov 18 Doi:10.1056 / NEJMoa1713137; Lancet Oncol.2011 Vol.12,735), thus demonstrating that EGFR mutant NSCLC tumors are dependent on oncogenic EGFR activity for survival and growth, and establishing del19 and L858R mutant EGFR as tumorigenic drivers of the disease, thus validating drug targets and biomarkers for the treatment of NSCLC.

[0003] However, after a mean of 10-12 months of treatment with first-generation (erlotinib, gefitinib) and second-generation (afatinib) EGFR TKIs, resistance to these small molecule inhibitors has been observed in almost all NSCLC patients (Lancet Oncol.2010 Feb;11(2):121-8.; Lancet Oncol.2016 May;17(5):577-89; Lancet Oncol.2011 Aug;12(8):735-42). The most prominent resistance mechanism to first- and second-generation EGFR TKIs is due to a secondary EGFR mutation, T790M, which progresses to first- and second-generation EGFR inhibitors in 50%-70% of patients (Cancer Discov;2(10);872-5,2012; Cancer Res.,65:(16),2005). This secondary mutation reduces the affinity of the drug to the target, thereby creating drug resistance, leading to tumor recurrence or disease progression.

[0004] Given the prevalence of this mutation in drug resistance arising from EGFR-targeted treatments in lung cancer, several companies have attempted to develop new small molecule EGFR inhibitors to treat these drug-resistant lung cancer patients by inhibiting the resistant mutant EGFR-T790M. For example, the third-generation EGFR TKI osimertinib (Tagrisso®) was developed to treat NSCLC patients whose cancer cells harbor primary EGFR mutation del19 or L858R-positive (with or without T790M mutation in the gene encoding EGFR).

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

[0006] The compound of formula (I) is a highly selective EGFR TKI inhibitor that can inhibit triple mutant variants.In addition, the compound represented by this formula can inhibit the EGFR mutant del19 / L858R T790M C797S with triple mutation with high selectivity, and at the same time has little or no activity against wild-type EGFR. [ka] Summary of the Invention

[0007] Provided herein are new methods for making and purifying compounds of formula (I). Additionally, novel intermediates are also disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Disclosed herein is a method for preparing a compound of formula (I). The method comprises reacting a first starting material of formula (Ic): [ka] or a salt thereof, with a second starting material of formula (Id): [ka] or a salt thereof. Also disclosed herein are i) methods for preparing compounds of formula (Ic) from readily available starting materials, and ii) intermediates obtained from the preparation of compounds of formula (Ic).

[0009] The reaction of the starting material of formula (Ic) with the starting material of formula (Id) is in one embodiment carried out in the presence of a palladium catalyst and a phosphine ligand. The palladium catalyst and the phosphine ligand are separate compounds. Alternatively, one complex contains both the palladium catalyst and the phosphine ligand.

[0010] A non-limiting list of palladium catalysts includes Pd(dppe)2 (bis[1,2-bis(diphenylphosphino)ethane]palladium(0)), CX-11 (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), CX-12 (1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), Pd(t-Bu3P)2 (bis(tri-tert-butylphosphine)palladium(0 )), Pd(PCy3)2 (bis(tricyclohexylphosphine)palladium(0)), Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)), Pd2(dba)3 (tris(dibenzylideneacetone)-dipalladium(0)), Pd(OAc)2 (palladium(II) acetate), PdCl2(PPh3)2 (dichlorobis-(triphenylphosphine)palladium(II)), PdCl2(Amphos)2 (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropa radium(II)), Pd(MeCN)2Cl2 (bis(acetonitrile)-dichloropalladium(II)), PdCl2(P(o-Tol)3)2 (dichlorobis(tri-o-tolylphosphine)palladium(II)), Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), Pd(MeCN)4(BF4)2 (tetrakis(acetonitrile)palladium(II) tetrafluoroborate), Pd-PEPPSI-IPent (dichloro[1,3-bis(2,6-di-3 Pd-PEPPSI-IPr ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride), Pd-PEPPSI-SIPr ((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride), and bis(dibenzylideneacetone)palladium(0) (Pd(dba)2).

[0011] A non-limiting list of phosphine ligands and complexes containing both palladium catalysts and phosphine ligands includes triphenylphosphine (PPh3); bis(tri-o-tolylphosphine) (P(o-Tol)3)2; tri-tert-butoxyphosphine (Pt-Bu3); tri-tert-butylphosphonium tetrafluoroborate (Pt-Bu3HBF4); bis(tricyclohexylphosphine (PCy3); bis(1-adamanyl)butylphosphane (n-BuP(AD)2); 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), bis[(2-diphenylphosphino)phenyl]ether (DPEPhos); 1,1'-bis(diphenylphosphino)ferrocene (dppf);1,1'-Bis(di-tert-butylphosphino)ferrocene (dcypf), 1,3-bis(diphenylphosphino)propane (DPPP), (2-biphenylyl)di-tert-butylphosphine (JohnPhos), chloro(2-dicyclohexylphosphino-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] (CyJohnPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (Da vePhos), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] (RuPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] (Brett Phos), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] (t-BuBrettPhos), 2-di-tert-butylphosphino No-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (Me4-tBuXPhos), 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'bipyrazole (BippyPhos), di(1-adamantyl)-2-morpholinophenylphosphine (MorDalPhos), palladium / 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride (IPr; .HCL), [2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (AdBrettPhos), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2 ',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos), [(2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (JackiePhos), [(2-di-tert-butylphosphino-3,6-dimethoxy Mesyl(2-(di-tert-butylphosphino)-1,1'-binaphthyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos), (2-biphenyl)di-tert-butylphosphine, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (t-BuDav ePhos), 2-di-tert-butylphosphino-2'-methylbiphenyl (t-BuMePhos), chloro(2-dicyclohexylphosphino-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) (CyJohnPhos), 2-dicyclohexylphosphino-2'-methylbiphenyl (MePhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (PhDavePhos), 2-dicyclohexylphosphino-2'-methoxy-4',6'-Di-tert-butylbiphenyl (VPhos), 2-[(tert-butyl)phenylphosphino]-2',6'-bis(N,N-dimethylamino)biphenyl (PhCPhos), [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CPhos), methanesulfonato[2-diethylphosphino-2',6'-bis(dimethylamino)-1,1-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (EtCPhos), 2-di(tert-butyl)phosphino-2',4' ,6'-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos), di-1-adamantyl(4"-butyl-2",3",5",6"-tetrafluoro-2',4',6'-triisopropyl-2-methoxy-meta-terphenyl)phosphine (AlPhos), 2-(t-butylphenylphosphino)-2',6'-dimethylamino-1,1'-biphenyl, ((t-Bu)PhCPhos), and dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (XPhos). The above list also includes examples where a palladium catalyst and a phosphine ligand are part of the complex.

[0012] In one embodiment, the palladium catalyst and phosphine ligand used in the preparation of compounds of formula (I) are other than the complex methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos-Pd-G4).

[0013] In another embodiment, the palladium catalyst used in the preparation of the compound of formula (I) is bis(dibenzylideneacetone)palladium(0) (Pd(dba)2). In another embodiment, the phosphine ligand is dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (XPhos). In yet another embodiment, the palladium catalyst used in the preparation of the compound of formula (I) is bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) and the phosphine ligand is dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (XPhos).

[0014] In another embodiment, the reaction mixture further comprises a base. Suitable bases include potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), potassium hydroxide (KOH), and sodium tert-butoxide (NaOtBu). In another embodiment, the base is cesium carbonate (Cs2CO3) or sodium tert-butoxide (NaOtBu).

[0015] In another embodiment, the reaction is carried out in a solvent such as toluene, 1,4-dioxane, tetrahydrofuran (THF), methyltetrahydrofuran, anisole, water (H2O), or a mixture thereof. In some examples, the reaction is carried out in 1,4-dioxane, tetrahydrofuran (THF), water (H2O), or a mixture thereof. In some examples, the reaction is carried out in 1,4-dioxane, toluene, or a mixture thereof.

[0016] In one embodiment, the compound of formula (I) can be purified by recrystallization in a solvent system such as, for example, dimethylsulfoxide (DMSO) and ethanol. For example, the compound of formula (I) can be dissolved in dimethylsulfoxide (DMSO) (optionally with heating) and then ethanol (or water) can be added (optionally with cooling). In another embodiment, seed crystal(s) of the compound of formula (I) can be added to promote crystallization. In one embodiment, the compound of formula (I) is obtained from the method described above or in the Examples and is isolated from the reaction, for example as a wet cake.

[0017] Specific conditions for preparing compounds of formula (I) from compounds of formula (Ic) and (Id) are shown in Example 4.

[0018] Also disclosed herein is the preparation of compounds of formula (Ic). [ka]

[0019] As mentioned above, the compound of formula (Ic) is the starting material used to prepare the compound of formula (I). The method for preparing the compound of formula (Ic) comprises reacting a first starting material of formula (Ia) [ka] or a salt thereof, with a second starting material of formula (Ib) [ka] or a salt thereof in the presence of a base, a palladium catalyst, and a phosphine ligand to form a compound of formula (Ic). Suitable palladium catalysts and phosphine ligands are as described above for the preparation of compounds of formula (I).

[0020] Suitable bases are as described above for the preparation of compounds of formula (I).

[0021] In one embodiment, the base in the reaction between starting materials (Ia) and (Ib) is cesium carbonate (Cs2CO3), the palladium catalyst is bis(dibenzylideneacetone)palladium(0) (Pd(dba)2), and the phosphine ligand is (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos). In some examples, the reaction is carried out in a polar solvent (e.g., dioxane). The reaction can also be carried out with heating (e.g., with heating at 90°C to 110°C, or 92°C to 108°C, or 95°C to 105°C).

[0022] In one embodiment, the base in the reaction between starting materials (Ia) and (Ib) is potassium hydroxide (KOH), the palladium catalyst is bis(dibenzylideneacetone)palladium(0) (Pd(dba)2), and the phosphine ligand is (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos). In some examples, the reaction is carried out in a non-polar solvent (e.g., toluene). The reaction can also be carried out with heating (e.g., with heating at 70°C to 110°C, or 80°C to 100°C, or 85°C to 95°C).

[0023] In one embodiment, compound (Ic), prepared by the method described above, is reacted with a compound of formula (Id) without isolating the compound of formula (Ic).

[0024] Specific conditions for preparing compound (Ic) are shown in Example 4.

[0025] Also disclosed herein is a method for preparing a compound of formula (Ia). As mentioned above, the compound of formula (Ia) is the starting material used to prepare the compound of formula (Ic). The preparation of the compound of formula (Ia) is a five-step process, each of which is described below. Each reaction step is considered a separate embodiment. Also, combinations of these reaction steps, including combinations of the five-step process that produce the compound of formula (Ia), are considered separate embodiments.

[0026] The first step in the preparation of a compound of formula (Ia) is a method for preparing a compound of formula (III). [ka]

[0027] This method comprises reacting a starting material of formula (II) [ka] and hydrogenating in the presence of a platinum hydrogenolysis catalyst or a palladium hydrogenolysis catalyst to form a compound of formula (III). Suitable hydrogenolysis catalysts include 20% palladium hydroxide on carbon (Pearlman's catalyst), palladium chloride, palladium, wet palladium on carbon, and platinum oxide (PtO2). In one embodiment, the platinum hydrogenolysis catalyst is PtO2 and the palladium hydrogenolysis catalyst is wet palladium on carbon. In another embodiment, the reaction is carried out in ethyl acetate (EtOAc) at 20°C to 30°C or 22°C to 28°C.

[0028] Compounds of formula (II) can be prepared from 4-bromo-indanone (see Example 1.1), which is a known compound (CAS 15115-60-3) and is commercially available from Sigma Aldrich (catalog number 644366).

[0029] The second step in the preparation of a compound of formula (Ia) is the process for preparing a compound of formula (IV). [ka]

[0030] This method comprises reacting a starting material of formula (III) [ka] with tert-butyl nitrite (t-BuONO) and hydrogen chloride to form a compound of formula (IV). In one embodiment, the reaction is carried out in tetrahydrofuran (THF) at 0-10° C. and the hydrogen chloride is methanolic hydrogen chloride. In another embodiment, the starting material of structural formula (III) is prepared as described in the first step.

[0031] The third step in the preparation of a compound of formula (Ia) is the reaction of a compound of formula (V) [ka] or a salt thereof.

[0032] The method comprises the step of: [ka] or a salt thereof with phosphoryl chloride (POCl3), phosphorus pentachloride (PCl5), and hydrogen chloride to form a compound of formula (V).

[0033] In one embodiment, the starting material of formula (IV) is combined with POCl3 and PCl5 at 0° C.-25° C., or 5° C.-20° C., or 10° C.-15° C., then hydrogen chloride is added and warmed to 50° C.-70° C., or 55° C.-65° C. In one embodiment, the reaction is carried out in dioxane. In another embodiment, the starting material of structural formula (IV) is prepared as described in the second step.

[0034] The fourth step in the preparation of a compound of formula (Ia) is the method of preparing a compound of formula (VI). [ka]

[0035] The method comprises the step of: [ka] or a salt thereof in the presence of an amine base, a hydride reducing agent, and a palladium catalyst to form a compound of formula (VI).

[0036] Amine bases are nitrogen-containing compounds capable of accepting a proton. Examples include methylamine (CH3NH2), dimethylamine ((CH3)2NH), triethylamine ((CH3)3N) and their C2-C6 alkylamine analogs, aniline (PhNH2) and its derivatives, N,N-diisopropylethylamine, dimethylaminopyridine (DMAP), tetramethylethylenediamine (TMEDA), and pyridine.

[0037] Hydride reducing agents produce negatively charged hydrogen ions (H - A hydrogen peroxide (H2O2) is a chemical compound that can reduce a compound of interest by adding an alkali metal ion to it. Examples include sodium hydride (NaH), lithium hydride (LiH), lithium aluminum hydride (LiAlH4), sodium triethylborohydride, and sodium borohydride (NaBH4).

[0038] Suitable palladium catalysts are as described above for the first embodiment. In one aspect, the palladium catalyst is 1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (Pd(dba)2), the hydride reducing agent is sodium borohydride, and the amine base is tetramethylethylenediamine (TMEDA). In one aspect, the reaction is carried out in tetrahydrofuran at 20°C to 30°C. In another aspect, the starting material of formula (V) is prepared as described in the third step.

[0039] The fifth step in the preparation of a compound of formula (Ia) is the reaction of a starting material of formula (VI) [ka] with a brominating agent in acid to form a compound of formula (Ia).

[0040] Suitable acids include, but are not limited to, sulfuric acid, methanesulfonic acid, triflic acid, and the like.

[0041] Brominating agents are electrophilic bromine atoms (Br + ) to the compound of interest. Suitable brominating agents are cyanogen bromide (CNBr), bromine (Br2), and N-bromosuccinimide (NBS). In one embodiment, the brominating agent is N-bromosuccinimide (NBS) and the acid is sulfuric acid (H2SO4). In another embodiment, the starting material of formula (VI) is prepared as described in the fourth step.

[0042] A five-step procedure for preparing compounds of formula (Ia) is outlined in Example 1. Specific conditions for each of these reaction steps are provided in Example 1.

[0043] Also disclosed herein are methods for preparing compounds of formula (Ib). [ka]

[0044] As mentioned above, the compound of formula (Ib) is the starting material used in the preparation of the compound of formula (Ic). The preparation of the compound of formula (Ib) is a five-step procedure, each of which is described below.

[0045] Each reaction step is considered to be a separate embodiment, and any combination of these reaction steps, including the combination of the five-step procedure to produce the compound of Formula (Ib), is also considered to be a separate embodiment.

[0046] The first step in the preparation of a compound of formula (Ib) is a process for preparing a compound of formula (VII). [ka]

[0047] The definition of R is given below. This method comprises reacting a starting material of formula (VIIa) [ka] with a sulfonyl chloride (e.g., ethanesulfonyl chloride (also known as ethyl chloride or EsCl)) and an amine base (e.g., triethylamine (TEA)) to form a compound of formula (VII).

[0048] Sulfonyl chlorides have the general formula RSO2Cl, where R is a C1-C4 linear or branched alkyl group, or a phenyl group optionally substituted with halogen, a C1-C4 alkyl group, and / or a nitro group. Examples include benzenesulfonyl chloride, tosyl chloride (para-toluenesulfonyl chloride), brosyl chloride (para-bromophenylsulfonyl chloride), nosyl chloride (nitrophenylsulfonyl chloride), mesyl chloride (methylsulfonyl chloride), and esyl chloride (ethylsulfonyl chloride). The sulfonyl group is represented by RSO2-. In one embodiment, the reaction is carried out in dichloromethane at 5°C to 20°C or 10°C to 15°C.

[0049] Suitable amine bases are as described above for the preparation of compounds of formula (VI).

[0050] The starting material of formula (VIIa) can be obtained according to the procedures described in Frigola et al., J. Med. Chem., 38:1203 (1995), the entire teachings of which are incorporated herein by reference.

[0051] The second step in the preparation of a compound of formula (Ib) is a method for preparing a compound of formula (VIII). [ka]

[0052] The method comprises the steps of: [ka] (for example, [ka] or a salt thereof, with a second starting material of formula (VIIIb) [ka] and a base (e.g., potassium carbonate (K2CO3)) to form a compound of formula (VIII). R is as described above for compounds of formula (VII). In another embodiment, the starting material of formula (VII) is prepared as described in the first step.

[0053] The third step in the preparation of the compound of formula (Ib) is the preparation of the second starting material of formula (VIIIb). This method comprises the reaction of 2-bromoacetate methyl [ka] This includes reacting with

[0054] The fourth step in the preparation of a compound of formula (Ib) is the process for preparing a compound of formula (IX). [ka]

[0055] This method comprises the step of reacting a starting material of formula (VIII) [ka] or a salt thereof with lithium chloride (LiCl) in the presence of water to form a compound of formula (IX). For example, 0.4-0.6 mol equivalents of water can be used. In one embodiment, the reaction is carried out in dimethylacetamide (DMAc) at 160° C.-170° C. In another embodiment, the starting material of formula (VIII) is prepared as described in the third step.

[0056] The fifth step in the preparation of a compound of formula (Ib) or a salt thereof comprises reacting a starting material of formula (IX) [ka] or a salt thereof in the presence of a palladium hydrogenolysis catalyst to form a compound of formula (Ib). In one embodiment, the palladium hydrogenolysis catalyst is palladium hydroxide 20 wt.% on a dry basis on carbon (20% Pd(OH)2 / C) and the reaction is carried out in methanol (MeOH) at 30° C.-50° C. or 35° C.-45° C. In another embodiment, the starting material of formula (IX) is prepared as described in the fourth step.

[0057] A five-step procedure for preparing compounds of formula (Ib) is outlined in Example 2. Specific conditions for each of these reaction steps are provided in Example 2.

[0058] Another embodiment of the present disclosure is a compound selected from: [ka] where R is as defined herein, for example: [ka] (Es is ethylsulfonyl), [ka] Or a salt of any of the foregoing.

[0059] These compounds have basic groups and can react with inorganic and organic acids to form salts. Examples of such salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1, Examples of suitable salts include 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate. EXAMPLES

[0060] Preparation of Exemplary Compounds definition ACN: Acetonitrile C: Celsius Cs2CO3: Cesium carbonate DCM: dichloromethane DMAc: Dimethylacetamide DMSO: Dimethyl sulfoxide EsCl: Ethanesulfonyl chloride EtOAc: ethyl acetate EtOH: Ethanol g: grams h: time H2: Hydrogen H2O: Water H2SO4: Sulfuric acid HCl: Hydrogen chloride HPLC: High-performance liquid chromatography I C 50 :50% inhibitory concentration LC-MS: Liquid chromatography-mass spectrometry LiCl: Lithium chloride K2CO3: Potassium carbonate kg: kilogram mbar: millibar MeOH: Methanol min:minutes MTBE: Methyl tert-butyl ether N2: Nitrogen NaBH4: Sodium borohydride NaHSO3: Sodium bisulfite Na2SO4: Sodium sulfate NLT:~ or above NMT: ~ or less PtO2: Platinum oxide R1: First reactor R2: Second reactor RT: retention time rt: room temperature SiO2: Silicon dioxide t-BuONO: tert-butyl nitrite TEA: Triethylamine TLC: Thin Layer Chromography TMEDA: Tetramethylethylenediamine THF: tetrahydrofuran *3: Number of repetitions (e.g. 3 times) LC-MS: Liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were obtained on an Agilent model-1260 LC system using an Agilent model 6120 mass spectrometer with ES-API ionization and equipped with an Agilent Poroshel 120 (EC-C18, 2.7 um particle size, 3.0 x 50 mm dimensions) reversed phase column at 22.4 degrees Celsius. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of 95% water / 5% organic to 5% water / 95% organic mobile phase over 4 minutes was used. The flow rate was constant at 1 mL / min.

[0061] Alternatively, liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were obtained on a Shimadzu LCMS system (Shimadzu LCMS mass spectrometer using ESI ionization equipped with an Agilent (Poroshel HPH-C18, 2.7 um particle size, 3.0 x 50 mm dimensions) reversed phase column) at 22.4 degrees Celsius. The mobile phase consisted of a solvent mixture of 5 mM NH4HCO3 (or 0.05% TFA) in water and acetonitrile. A constant gradient of 90% water / 5% organic to 10% water / 95% organic mobile phase over 2 minutes was used. The flow rate was constant at 1.5 mL / min.

[0062] Silica gel chromatography: Silica gel chromatography was performed on a Teledyne Isco CombiFlash® Rf unit, a Biotage® Isolera Four unit, or a Biotage® Isolera Prime unit.

[0063] Proton NMR: 1 H NMR spectra were obtained on a Varian 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.5 seconds, delay 1 second; 16-64 scans), or an Avance 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.99 seconds, delay 1 second; 4-64 scans), or an Avance 300MHz Unity Inova 300MHz NMR instrument (acquisition time = 5.45 seconds, delay 1 second; 4-64 scans). All protons are reported as parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent unless otherwise indicated.

[0064] GC: Gas chromatographs were obtained on an Agilent 7890C gas chromatograph or similar (injector temperature 250°C, detector temperature 325°C, constant flow rate of 1.6 mL / min of nitrogen carrier gas) equipped with a DB-1 15 m × 0.25 mm × 1.0 μm or equivalent column.

[0065] Synthesis Examples: Example 1: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline (Ia) [ka]

[0066] 1.1 Preparation of 4-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-1-one (II) [ka] To a solution of compound (IIa) (500 g, 2.37 mol, 1.00 equiv.) in dioxane (2500 mL) and H2O (500 mL), compound (IIb) (398 g, 2.37 mol, 1.00 equiv.), Pd(dppf)Cl2 (17.3 g, 23.6 mmol, 0.01 equiv.), and TEA (719 g, 7.11 mol, 989 mL, 3.00 equiv.) were added at 25° C. The reaction mixture was stirred at 80° C. for 12 h. LCMS showed that compound (IIa) was completely consumed and the desired mass was detected (RT=0.885 min). The three batches were combined. The mixture was filtered through Celite and the filter cake was washed with ethyl acetate (500 mL*3). H2O (4000 mL) was added to the filtrate and extracted with ethyl acetate (1000 mL*3). The organic phase was washed with brine (2000 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 → 10 / 1, Rf = 0.4). Compound (II) (1.05 kg, 6.05 mol, yield 85.1%, purity 99.0%) was obtained as a light yellow solid. 1 Confirmed by 1 H NMR and LCMS. LC-MS: Product: RT=0.885 min, m / z = 173.0 (M+H) + . 1HNMR: (400 MHz, CDCl3) [ppm] δ 7.68 (dd, J = 7.6, 0.8 Hz, 1H), 7.49 (dd, J = 8.0, 1.2 Hz, 1H), 7.34 - 7.38 (m, 1H), 5.30 - 5.31 (m, 1H), 5.10 (d, J = 1.2, 0.8 Hz, 1H), 3.15 - 3.18 (m, 2H), 2.67 - 2.71 (m, 2H), 2.14 - 2.15 (m, 3H).

[0067] 1.2 Preparation of 4-isopropyl-2,3-dihydro-1H-inden-1-one (III) [ka] To a solution of compound (II) (1.05 kg, 6.04 mol, 1.00 equiv) in EtOAc (10.5 L) was added wet Pd / C (210 g, 10% Pd content) under N2 at 25°C. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (20 psi) at 25°C for 12 h. LCMS showed that compound (II) was completely consumed and the desired mass (RT=0.802 min) was detected. The mixture was filtered through Celite and washed with ethyl acetate (2000 mL*3). The filtrate was concentrated to give a residue. This residue was used in the next step without further purification. Compound (III) (1.08 kg, crude) was obtained as a white solid, confirmed by LCMS. LC-MS: Product: RT=0.858 min, m / z = 175.1 (M+H) + .

[0068] 1.3 Preparation of (E)-2-(hydroxyimino)-4-isopropyl-2,3-dihydro-1H-inden-1-one (IV) [ka] To a solution of compound (III) (295 g, 1.69 mol, 1.00 equiv.) in THF (750 mL) was added t-BuONO (262 g, 2.54 mol, 302 mL, 1.50 equiv.) under N2 atmosphere at 0-10 °C. HCl / MeOH (4 M, 110 mL, 0.26 equiv.) was then added dropwise to the mixture at 0-10 °C. After this addition, the reaction mixture was stirred at 0 °C for 2 h. LCMS showed that compound (III) was consumed and the desired mass (RT = 0.774 min) was detected. The reaction mixture was concentrated to give a residue. The residue was slurried with petroleum ether / ethyl acetate = 7 / 1 (800 mL), filtered, and the filter cake was collected to give a light yellow solid. Compound (IV) (205 g, 1.00 mol, 59.2% yield, 99.4% purity) was obtained as a light yellow solid, which was determined by LCMS and HPLC. 1 Confirmed by 1 H NMR. LC-MS: Product: RT=0.773 min, m / z = 204.1 (M+H) + . 1 H NMR: (400 MHz, DMSO) δ [ppm] 12.65 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 3.77 (s, 2H), 3.06 - 3.36 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H).

[0069] 1.4 Preparation of 1,3-dichloro-5-isopropylisoquinoline (V) [ka] To a solution of compound (IV) (133 g, 650 mmol, 1.00 equiv) in dioxane (650 mL) was added POCl3 (151 g, 984 mmol, 91.5 mL, 1.51 equiv) at 25 °C. Then PCl5 (203 g, 976 mmol, 1.50 equiv) was added to the mixture in portions at 0-20 °C. The mixture was stirred at 0-20 °C for 0.5 h. Then HCl / dioxane (4 M, 16.3 mL, 0.10 equiv) was added to the mixture at 0-20 °C and the mixture was stirred at 60 °C for 11 h. LCMS showed that compound (IV) was completely consumed and the desired mass (RT = 1.074 min) was detected. The mixture was quenched with H2O (1500 mL) and extracted with dichloromethane (300 mL * 3). The organic phase was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to give a residue. The combined residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 → 100 / 1, R f =0.35). The residue was purified by TLC (petroleum ether / ethyl acetate = 1 / 0, R f =0.35). Compound (V) (138 g, 575 mmol, 64.5% yield) was obtained as a yellow oil and was identified by LCMS. LC-MS: Product: RT=1.074 min, m / z = 239.9 (M+H) + .

[0070] 1.5 Preparation of 3-chloro-5-isopropylisoquinoline (VI) [ka] To a solution of compound (V) (170 g, 581 mmol, 1.00 equiv.) in THF (850 mL) was added Pd(dppf)Cl2 (4.25 g, 5.81 mmol, 0.01 equiv.) under nitrogen at 25° C. Then TMEDA (101 g, 872 mmol, 132 mL, 1.50 equiv.) and NaBH4 (81.6 g, 2.16 mol, 3.71 equiv.) were added to the mixture. The reaction mixture was stirred at 25° C. for 1 h. TLC (petroleum ether / ethyl acetate=10 / 1) showed that compound (V) (R f =0.8) was completely consumed, and the main spot (R f=0.6) was detected. The mixture was poured into cooled 1N HCl aqueous solution (1000 mL) and extracted with ethyl acetate (500 mL*3). The organic phase was filtered through Celite, and the filtrate was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0→100 / 1, R f =0.6) to give compound (VI) (137 g, crude) as a yellow oil. 1 Confirmed by 1 H NMR and LCMS. LC-MS: Product: RT=0.901 min, m / z = 206.1 (M+H) + . 1 H NMR: (400 MHz, CDCl3) δ [ppm] 9.06 (s, 1H), 7.94 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 6.8 Hz, 1H), 7.55 - 7.58 (m, 1H), 3.55 - 3.65 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H).

[0071] 1.6 Preparation of 3-chloro-5-isopropylisoquinoline (Ia) [ka] Compound (VI) (93.8 g, 392 mmol, 1.00 equiv.) was added to a solution of H2SO4 (500 mL) at -10 to 0 °C. After this addition, the mixture was cooled to -10 to -20 °C and NBS (90.7 g, 510 mmol, 1.30 equiv.) was added to the mixture at -10 to -20 °C. The reaction mixture was then stirred at 25 °C for 2 h. TLC (petroleum ether / ethyl acetate = 20 / 1) confirmed that compound (VI) (R f =0.6) remains, and the main spot (R f=0.9) was formed. The mixture was poured onto ice (1500g) at 0~10℃, adjusted to pH=9 with ammonium hydroxide (1800mL), and then extracted with ethyl acetate (500mL*2). The organic phase was washed with brine (1000mL), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0→50 / 1, R f =0.9), Compound (VI) (70.03 g, 230 mmol, 58.7% yield, 93.6% purity) was obtained as an off-white solid. 1 The product was confirmed by 1 H NMR, LCMS, and HPLC. LC-MS: Product: RT=1.149 min, m / z = 283.9 (M+H) + . HPLC: Product: RT=2.863 min, purity 93.6% (under 220 nm). 1 HNMR: (400 (MHz, CDCl3) δ [ppm] 9.43 (s, 1H), 7.91 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 3.51 - 3.62 (m, 1H), 1.38 (d, J = 7.2 Hz, 6H).

[0072] Example 2: Synthesis of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (Ib) [ka]

[0073] 2.1 Preparation of methyl 2-(methylsulfonyl)acetate (VIIIb): [ka] A 3000 L reactor was charged with sodium methylsulfinate (153.19 kg, 1500 mol, 1.2 equiv.) and acetone (760.00 kg) and 2-bromomethyl acetate (BMA) (190.00 kg, 1250 mol, 1.0 equiv.) was added in one portion. The reaction mixture was heated to 55-60°C and stirred at 55-60°C for 12-16 hours. Upon completion of the reaction (GC monitoring), the reaction mixture was cooled to 15-20°C. The reaction mixture was filtered and the filter cake was washed once with acetone (50 L). The combined filtrate was concentrated under vacuum to a volume of 300-350 L. n-Heptane (200 L) was added and the mixture was subsequently concentrated to a volume of 300-350 L. This operation was repeated twice to remove residual acetone.

[0074] n-Heptane (400 L) was charged and the mixture was stirred at 20-30° C. for 1-2 h. The mixture was filtered and the filter cake was washed once with n-heptane (60 L). The wet cake was dried at 35-40° C. for 6-10 h to give compound (VIIIb) as a white solid (167.60 kg, 88.2% yield). GCAP: 100%. GC purity: 100% (a / a), RT=3.79 min. 1 H NMR: (400 MHz, CDCl3) δ [ppm] 4.02 (s, 2H), 3.85 (s, 3H), 3.16 (s, 2H).

[0075] 2.2 Preparation of (((2R,3S)-1-benzhydryl-methylazetidin-3-yl)oxy)esylate (VIIc) [ka] A 2000 L reactor was charged with compound (VIIa) (215.00 kg, 848.7 mol, 1.0 equiv) and DCM (1144.00 kg). After stirring for 5 minutes, TEA (111.64 kg, 1103.3 mol, 1.3 equiv) was added. The reaction mixture was cooled to 0-10° C. under nitrogen protection. EsCl (120.03 kg, 933.5 mol, 1.1 equiv) was added slowly to the reaction over 2-3 hours while maintaining the temperature below 10° C. A white solid formed during the addition. After the addition, the reaction was stirred for an additional 1-2 hours.

[0076] The reaction mixture was quenched with HO (645 L) and stirred for 15 min. The organic layer was separated and the aqueous phase was extracted once with DCM (215 L). The combined organic phase was washed with 10% brine (215 L). The organic portion was concentrated under vacuum at 40-45 °C to a volume of 450-500 L. n-Heptane (645 L) was added and the mixture was distilled to a volume of 450-500 L. This operation was repeated twice to remove residual DCM. n-Heptane (645 L) was charged and the mixture was stirred at 20-30 °C for 1-2 h. The mixture was filtered, the filter cake was washed once with n-heptane (88 L) and the wet cake was dried under vacuum at 45-55 °C for 6-10 h to give compound (VIIc) as a yellow solid (284.20 kg, 96.9% yield). HPLC purity: 99.7% (a / a), RT=6.70 min. 1 H NMR: (400 MHz, CDCl3) δ [ppm] 7.45-7.33 (m, 4H), 7.30-7.21 (m, 6H), 4.66-4.61 (ddd, 1H), 4.43 (s, 1H), 3.77-3.73 (dd, 1H), 3.43-3.36 (dq, 1H), 3.43-3.37 (q, 2H), 2.91-2.87 (dd, 1H), 1.43-1.40 (t, 3H), 0.84-0.83 (d, 3H).

[0077] 2.3 Preparation of methyl (S) 2-(2R,3S)-1-benzyhydryl-2-methylazetidin-3-yl)-2-((methylsulfonyl)acetate) (VIII) [ka] To a 2000 L reactor was added compound (VIIc) (142.2 kg, 411.6 mol, 1.0 equiv.) and acetonitrile (665.50 kg). After stirring for 5 minutes, methyl 2-(methylsulfonyl)acetate compound (VIIIb) (75.16 kg, 494.0 mol, 1.2 equiv.) and K2CO3 (113.78 kg, 823.3 mol, 2.0 equiv.) were added separately. The reaction mixture was heated to 68-72 °C and stirred at 68-72 °C for 16 h. K2CO3 (28.45 kg, 205.8 mol, 0.5 equiv.) was added to the reaction mixture, which was then stirred at 68-72 °C for 24 h. Upon completion of the reaction (HPLC monitoring), the reaction mixture was cooled to 15-20 °C. The reaction mixture was centrifuged, the filtrate was concentrated to a volume of 150-200 L, and the filtrate was combined with the filtrate from the next step.

[0078] The centrifugal filter cake was suspended in ethyl acetate (570 L) and stirred for 1-2 h. The slurry was centrifuged. The filtrate was combined with the filtrate from the previous step. Prepared 10% aqueous NaCl solution (156 L) was added to the combined liquid and stirred for 15 min. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (142 L). The combined organic phase was washed twice with 10% brine (142 L x 2). The organic phase was concentrated under reduced pressure at 45-55 °C.

[0079] MTBE (284 L) was added to the residue and stirred for 1-2 h, then n-heptane (383 L) was added slowly for 2-3 h at 15-20 °C. The resulting slurry was filtered and the filter cake was washed once with n-heptane (50 L). The wet cake was dried under vacuum at 45-55 °C for 6-10 h to give compound (VIII) as a yellow solid (125.70 kg, 78.9% yield). HPLC purity: 97.7% (a / a), RT=6.30 min. 1H NMR: (400 MHz, DMSO-d6) δ [ppm] 7.43-7.27 (m, 4H), 7.25-7.18 (m, 6H), 4.69-4.59 (dd, 1H), 4.50 (s, 1H), 3.74 (s, 3H), 3.45-3.40 (ddd, 1H), 3.35-3.15 (m, 1H), 3.05 (d, 3H), 2.73-2.55 (m, 2H), 0.76-0.58 (dd, 3H).

[0080] 2.4 Preparation of (2R,3S)-1-benzhydryl-2-methyl-3-((methylsulfonyl)methyl)azetidine (IX) [ka] A reactor was charged with compound (VIII) (120.8 kg, 311.7 mol, 1.0 equiv.) and DMAc (849.00 kg), followed by LiCl (19.82 kg, 467.6 mol, 1.5 equiv.) and HO (3.00 kg, 166.7 mol, 0.53 equiv.), and the mixture was stirred until dissolved. The above mixture was reacted in a flow reactor at 170-175°C. The reaction time is 17 min. The reaction mixture was monitored by HPLC every 1-2 h. Water (725 L) and ethyl acetate (966 L) were added to the reaction mixture, stirred for 15 min, the organic layer was separated, and the aqueous phase was extracted once with ethyl acetate (725 L).

[0081] The combined organic phase was washed twice with 10% brine (725 L x 1, 483 L x 1) and the organic phase was concentrated under reduced pressure at 45-55 °C. MTBE (242 L) was added to the residue and stirred for 1-2 h, then n-heptane (121 L) was added slowly over 2-3 h at 15-25 °C. The resulting slurry was filtered and the filter cake was washed once with MTBE (30 L). The wet cake was dried under vacuum at 45-55 °C for 6-10 h to obtain compound (IX) as a yellow solid (74.70 kg, 72.7% yield). HPLC purity: 98.8% (a / a), RT=8.81 min. 1H NMR: (400 MHz, CDCl3) δ [ppm] 7.45-7.40 (m, 4H), 7.32-7.19 (m, 6H), 4.35 (s, 1H), 3.70-3.65 (m, 1H), 3.26-3.10 (m, 3H), 2.85 (s, 3H), 2.65-2.57 (m, 2H), 0.85-0.82 (d, 3H).

[0082] 2.5 Preparation of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (Ib) [ka] A 1000 L reactor was charged with compound (IX) (143.9 kg, 436.8 mol, 1.0 equiv.) and MeOH (447.50 kg), followed by separate addition of 20% Pd(OH)2 / C (28.78 kg, 20% w / w%) and AcOH (26.21 kg, 436.8 mol, 1.0 equiv.). The mixture was hydrogenolyzed under 0.5-1.0 MPa H2 pressure at 25-35 °C for 8-12 h. Upon completion of the reaction (HPLC monitoring), the reaction mixture was filtered and the filter cake was washed once with MeOH (144 L). 4M HCl / MeOH was added to the filtrate to adjust the pH to a target range of 1-2. The mixture was concentrated under vacuum at 45-55 °C to a volume of 400 L. The residue was washed twice with n-heptane (288 L x 2) and the n-heptane phase was discarded. The residue was then concentrated under reduced pressure at 45-55 °C. MeOH (144 L) was added to the residue and stirred at 45-55 °C for 0.5-1 h, then THF (864 L) was added slowly over 2-3 h at 45-55 °C. The mixture was cooled to 20-30 °C over 5 h and stirred for an additional 4-5 h. The resulting slurry was filtered and the filter cake was washed once with THF (32 L). The wet cake was dried under vacuum at 45-55 °C for 6-10 h to give compound (Ib) as a white solid (76.20 kg, 87.7% yield). GC purity: 98.9% (a / a), RT=18.98 min. 1H NMR: (400 MHz, DMSO-d6) δ [ppm] 9.22-9.13 (m, 2H), 4.32-4.25 (m, 1H), 3.90 (m, 1H), 3.75 (m, 1H), 3.55 (m, 2H), 2.95 (m, 4H), 1.48-1.46 (d, 3H).

[0083] Example 3a: Synthesis of 2-((3s,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (Id) [ka]

[0084] 3.1: Synthesis of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (i) Compound (i) (tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate) was synthesized according to the method described in J. Org. Chem., 2013, 78, 8892-8897.

[0085] 3.2 Synthesis of S(3S,4R)-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate (ii) Sodium hydride (218.90 mg, 9.122 mmol, 4 equiv.) was added to tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate compound (i) (500 mg, 2.280 mmol, 1 equiv.) in THF (10 mL) at 0° C. After stirring for 20 min, methyl iodide (1294.73 mg, 9.122 mmol, 4 equiv.) was added. The resulting solution was stirred at 0° C. for an additional 1 h. The reaction was then quenched by adding 10 mL of water. The solid was filtered. The resulting solution was extracted with EA and concentrated under vacuum. This resulted in 500 mg (94.1%) of the title compound as a pale yellow oil. LC-MS: (ES, m / z) = 178 [M+1-56].

[0086] 3.3 Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine (iii) A solution of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate compound (ii) (500 mg, 2.143 mmol, 1 equiv.) in TFA / DCM (3 / 10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to give 500 mg (crude) of compound (iii) as a solid.

[0087] 3.4 Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (Id) A mixture of (3S,4R)-3-fluoro-4-methoxypiperidine Compound (iii) (3 g, 22.528 mmol, 1 eq.), 2-chloropyrimidin-4-amine Compound (iv) (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.

[0088] The solvent was removed in vacuum and the residue was purified by flash (5% MeOH in DCM) to give 3.3 g (66%) of compound (Id) as a pale yellow solid. LC-MS: (ES, m / z) = 227 [M+1]. 1 H-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).

[0089] Example 3b: Synthesis of 2-((3s,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (Id) [ka]

[0090] Steps 1 and 2: Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine (iii) Exactly 75 mL of tetrahydrofuran and 30.0 g (0.1368 mol) of N-Boc-(3S,4R)-3-fluoro-4-hydroxypiperidine compound (i) were added to a 250 mL three-neck round bottom flask equipped with an overhead stirrer and nitrogen inlet / outlet. 5 g (6.4 mL) of tert-butyl alcohol were then added and the glass funnel was rinsed with 2.5 g (2.8 mL) of tetrahydrofuran (note: toluene / THF can also be used). To this was added 26 g (0.20 mol, 1.5 mol equiv.) of dimethyl sulfate (note: CH3I can also be used) and the resulting mixture was stirred for 5 minutes. Potassium-tert-butylate 20% in THF (26.5 g, 0.24 mol, 1.75 mol equiv.) was added via the addition funnel over 1 hour while maintaining the internal temperature between 20-30°C. This addition was exothermic and the temperature was controlled by the rate of addition. The reaction mixture initially thickened and then thinned as the addition proceeded. After the addition was complete, the addition funnel was rinsed with 3 mL of THF. The reaction mixture was stirred at 20-30°C for 30 minutes and then sampled to confirm completion of the reaction. The reaction was deemed complete when less than 2.0%-a / a of compound (i) remained. The reaction can be held at 20-40°C for 24 hours without adversely affecting yield or quality. 30 mL of water was then added to the reaction mixture with stirring.

[0091] A 2 L Erlenmeyer flask was charged with 850 mL of deionized water and 100 g of 25% ammonia solution, and the resulting solution was stirred for 5 minutes. 32 mL of this solution was then added to the reaction mixture, followed by 15 mL of water, and the temperature was maintained at 20-30°C. The resulting mixture was stirred at this temperature for 2 hours, then sampled to confirm complete consumption of dimethyl sulfate. Complete quenching was determined when less than 5 ppm of dimethyl sulfate remained. The mixture was transferred to a 250 mL separatory funnel and the layers were allowed to separate for 30 minutes. Remove and discard the lower spent aqueous phase. Combine any rag layer with the organic layer. Allow the upper product-rich organic layer to settle for 5 minutes, then remove and discard any additional spent aqueous layer. Return the product-rich organic layer to the three-neck round bottom flask. 4.5 g of acetic acid was then added to the mixture, followed by 45 mL of water. The resulting biphasic mixture was stirred at 20-30°C for 30 minutes. Stirring was stopped and the biphasic mixture was transferred back to the 250 mL separatory funnel. The layers were allowed to separate for 30 minutes, then the bottom spent aqueous layer was removed and discarded. The organic layer was allowed to settle for an additional 5 minutes, then any aqueous layer was removed and discarded. The organic layer was transferred back to the 250 mL three-neck flask and the mixture was warmed to 40-50 °C under slight scale vacuum until a gentle reflux was achieved, distilling off approximately 20 mL of the THF / water azeotrope. 75 mL of toluene was then added and the mixture was warmed to 40-50 °C under slight scale vacuum until a gentle reflux was achieved, distilling off approximately 20 mL of the THF / toluene / water azeotrope. The step 1 mixture was sampled for Karl-Fischer analysis (KF). The KF endpoint is reached at <0.25%-w / w. The step 1 mixture can be held at 20-30 °C for 72 hours without adverse effects on yield or quality. The step 1 mixture was transferred to a glass bottle and 20 mL of toluene was added.

[0092] Exactly 80 g (100 mL) of isopropyl alcohol was charged to a 500 mL three-neck flask fitted with an overhead stirrer and nitrogen inlet / outlet. With gentle stirring via the gas inlet tube, 25 g of hydrogen chloride (100%) was charged to the reactor ensuring that the gas inlet tube was below the surface of the isopropyl alcohol. This addition was highly exothermic. The solution of hydrochloric acid in toluene was stirred under nitrogen at 0-15°C for 1 hour. The temperature of the solution of hydrochloric acid in isopropyl alcohol was adjusted to 20-30°C and the mixture from step 1 was added dropwise via the addition funnel over 90 minutes. CO2 gas evolution was observed and controlled by the rate of addition. After the addition was complete, the addition funnel was rinsed with 10 mL of toluene and the resulting slurry was stirred at 20-30°C for 3-4 hours. The reaction was deemed complete when less than 0.5%-a / a of the mixture from step 1 remained. The slurry can be held at 20-30°C for 24 hours without adversely affecting yield or quality. The slurry was heated under slight vacuum to 40-50°C until a gentle reflux was obtained and approximately 70-80 mL of isopropyl alcohol / toluene was distilled off. An additional 100 mL of toluene was charged with distillation to maintain a constant volume in the three-neck flask, and approximately 100 mL of solvent was removed (repeated twice). The slurry was cooled to 20-30°C and sampled to assess solvent exchange. The endpoint was reached when less than 2%-a / a of isopropyl alcohol remained. 9 mL of isopropyl alcohol was charged to the slurry and stirred for an additional hour. The crystals were collected by filtration and the cake was washed with 2 cake volumes (approximately 50 mL) of toluene. The cake was deliquored under nitrogen for 1 hour and then dried under vacuum at 45-50°C for 24 hours.

[0093] Step 3. Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (Id) Exactly 80 g (78 mL) of dioxane, 31.0 g (0.183 mol, 1.09 mol equiv.) of compound (iii), 21.6 g (0.167 mol, 1.0 mol equiv.) of 4-amino-2-chloropyrimidine, 14.5 g (0.027 mol, 0.16 mol equiv.) of 25% ZnCl2 in 2-methyltetrahydrofuran, and 44.0 g (60.0 mL, 0.43 mol) of triethylamine were charged to a 500 mL three-neck flask equipped with an overhead stirrer and nitrogen inlet and outlet. The resulting mixture was heated to reflux (90-100 °C) and stirred at this temperature for 16 h. The reaction mixture was cooled to 50-60 °C and sampled to confirm completion of the reaction. The reaction was considered complete when less than 1.0%-a / a of 4-amino-2-chloropyrimidine remained. The reaction was cooled to 20-30°C and then 43 mL of water and 110 g of 30% NaOH were added. The resulting biphasic mixture was stirred at 20-30°C for 20 minutes. Agitation was stopped and the layers were allowed to separate for 30 minutes. The lower, spent aqueous phase was removed and discarded. Any rag layer was removed along with the lower, spent aqueous phase which was then sampled for pH determination. The pH of the spent aqueous layer was greater than 12. The upper, rich organic stream was allowed to settle for an additional 5 minutes. The spent aqueous layer was removed and discarded. To the product-rich organic layer was added 40 g of 30% NaOH and 16 g of water. The resulting biphasic mixture was stirred at 20-30°C for 20 minutes. Agitation was stopped and the layers were allowed to separate for 30 minutes. The lower, spent aqueous layer was removed and discarded. Any rag layer was removed and discarded. The upper, product-rich organic layer was allowed to settle for an additional 5 minutes. The spent aqueous layer was removed and discarded. The product-rich organic phase was polish filtered into a second 500 mL three-neck flask equipped with an overhead stirrer and nitrogen inlet / outlet. The first flask was rinsed with 1,4-dioxane (28 mL) and the rinse was transferred to the second flask. The solution was heated to 40-60 °C under mini vacuum until a gentle reflux was achieved and 100-120 mL of 1,4-dioxane was distilled off. 130 mL of toluene was then charged to the mixture and the resulting solution was warmed to 40-60 °C under mini vacuum until a gentle reflux was achieved. The 1,4-dioxane / toluene solvent mixture was removed by distillation.An additional 200 mL of toluene was added during the distillation to maintain a constant volume. A total of 180-220 mL of 1,4-dioxane / toluene distillate was removed. The solvent exchange was deemed complete when less than 5%-a / a 1,4-dioxane remained. The resulting slurry was warmed to 65-75°C, stirred at this temperature for 30 minutes, cooled to 20-30°C, and then cooled to 0-10°C. The slurry was held at this temperature for 30 minutes. The crystals were collected by filtration, washed with 30 mL of toluene, and then drained under nitrogen for 30 minutes. LC-MS: (ES, m / z) = 227 [M+1]. 1 H-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).

[0094] Example 4a: Synthesis of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (I) [ka] A glass jacketed reactor (R1) at 20-30 °C was charged with 1,4-dioxane (18.0 L, 4.0 vol), compound (Ia) (6.0 kg, 1.0 equiv), compound (Ib) (4.5 kg, 1.05 equiv), and Cs2CO3 (23.6 kg, 3.4 equiv). R1 ​​was inerted with N2 and vacuum (2 cycles) and then charged with Pd(dba)2 (364 g, 0.03 equiv) and XantPhos (366 g, 0.03 equiv). R1 ​​was again inerted with N2 and vacuum (2 cycles) and the batch was heated to 100 °C for 4-8 h and then cooled to 40-50 °C. The reaction mixture containing compound (Ic) was then cooled to 20-30 °C and used directly in the next step. 1 HNMR(CDCl3): δ [ppm] = 9.43 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H, 7.8 Hz), 7.45 (d, 1H, 7.8 Hz), 3.56 (hept, 1H, 6.9 Hz), 1.38 (d, 6H, 6.9 Hz).

[0095] To the reaction mixture containing compound (Ic) is added compound (Id) (4.2 kg, 1.05 equiv), Pd(dba)2 (352 g, 0.04 equiv), XPhos (501 g, 0.06 equiv), and 1,4-dioxane (5 L, 0.83 vol) as a rinse. The batch is heated to 100° C. for 4 hours, then cooled to 50° C. and additional Pd(dba)2 (241 g, 0.024 equiv) is added along with 1,4-dioxane (1 L, 0.15 vol) as a rinse. The reaction is stirred at 100° C. for an additional 4 hours.

[0096] The batch was cooled to 50-60°C, diluted with water (12 L, 2 vol), stirred at 55-65°C for 30 minutes, and the aqueous layer removed (kept at 50°C while separating layers). Water (9 L, 1.50 vol) and 38% (w / w) NaHSO3 (10.4 kg, 2.2 eq) were added, the batch was stirred at 55-65°C for 2 hours, then diluted with 1,4-dioxane (72 L, 12 vol). The batch was azeotropically dried by distillation (40-50°C, 200 mbar) removing 14 vol of distillate. The azeotropic distillation was continued by adding more 1,4-dioxane (72 L, 12 vol) and then distilling to remove another 12 vol of distillate. The water content of the batch was checked (should be less than or equal to 1.0% water) and if higher the charge of more 1,4-dioxane and distillation were repeated. After the water reached 1.0% or less, the batch was diluted with 1,4-dioxane (84 L, 14 vol) and stirred at 65-75 °C for ≥ 1 h. The batch was cooled to 25 °C and filtered (R1 → R2) to remove the Pd-bisulfite precipitate. R1 was rinsed with 1,4-dioxane (5 L, 0.80 vol) and filtered into R2. The filtrate was concentrated (50-60 °C, 150 mbar) to remove 16.3 vol (~98 L) of distillate.

[0097] Seed crystals (0.15% w / w) of previously synthesized compound (I) were added at 50-60°C, then anti-solvent of EtOH (60 L, 10 vol) was added slowly over 1 h at 50-60°C. The ratio of 1,4-dioxane to EtOH was confirmed (1,4-dioxane: 15% or less), then the reaction was cooled slowly over 3 h to 15-25°C and stirred for an additional 3 h. The resulting compound (I) solid was isolated by filtration and displacement washed with EtOH (9 L, 1.4 vol), then reslurry washed twice with water (2 x 18 L, 2 x 2.8 vol), followed by three more EtOH displacement washes (3 x 6 L, 3 x 0.9 vol). Compound (I) was then dried under vacuum (50 mbar, 65-75° C.) to give crude compound (I) (5.6 kg, 37% yield, 94% a / a purity by HPLC). HPLC: 93.7%(a / a). 1HNMR(DMSO-d6): δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J=5.67), 7.42 (1H, d, J=8.08), 6.56 (1H, d, J=8.08), 6.49 (1H, d, J=5.67), 4.94 (1H, dddd, J=50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J=14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J=7.25, 7.25), 4.49 (1H, bd, J=12.46), 4.20 (1H, dq, J=6.25, 6.25), 3.64 (1H, dd, J=7.25, 7.25), 3.59 (1H, dddd, J=24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J=14.34, 6.33), 3.53-3.48 (1H, bm), 3.52-3.44 (1H, m), 3.51 (1H, dd, J=14.34, 8.33), 3.37 (3H, s), 3.29 (1H, ddd, J=12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1H, dddd, J=7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J=12.95, 4.27, 4.27, 3.99), 1.75 (1H, dddd, J=10.56, 10.56, 10.56, 4.22, 1.64), 1.43 (3H, d, J=6.09), 1.31 (3H, d, J=6.95), 1.30 (3H, d, J=6.92).

[0098] Example 4b: Synthesis of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (I) [ka]

[0099] Exactly 44 g (45 mL) of toluene, 12.3 g (43.2 mmol, 1.0 equiv.) of 8-bromo-3-chloro-5-isoquinoline (compound (Ia)), 9.1 g (45.6 mmol, 1.05 equiv.) of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (compound (Ib)), 110 mg (0.2 mmol, 0.005 equiv.) of bis(dibenzylideneacetone)palladium(0) (Pd(dba)2), and 110 mg (0.2 mmol, 0.005 equiv.) of Xantphos were added to the overhead stirrer. The resulting mixture was placed under nitrogen in a 250 mL three-neck flask fitted with a filter and reflux condenser. The flask was evacuated twice with minivac and then the vacuum was released with nitrogen. 11.8 g (7.7 mL, 105 mmol, 2.65 mol equiv.) of 50% potassium hydroxide and 8.0 mL of deionized water were then added. The flask was again evacuated with minivac and the vacuum was released with nitrogen. The resulting biphasic mixture was warmed to 85-95°C and held at this temperature for 10 hours. The reaction mixture was cooled to 55-65°C. The reaction was considered complete when 1.0%-a / a of compound (Ia) remained. The reaction mixture was cooled to 20-30°C and then charged with 9 mL of deionized water followed by 9 mL of toluene. The biphasic mixture was stirred for an additional 0.5 h. Stirring was stopped and the mixture was transferred to a separatory funnel and the layers were allowed to separate for 0.5 h. The lower spent aqueous stream was discarded along with the rag layer. The upper product-rich organic phase was allowed to settle for 5 min and the aqueous layer was discarded. The product-rich organic stream was returned to the three-neck flask. 9 mL of deionized water and 30 mg (30 uL) of acetic acid were charged to a separate 25 mL Erlenmeyer flask. Aqueous acetic acid was added to the organic layer and the biphasic mixture was stirred for 30 min. The mixture was stirred. The stirring was stopped and the biphasic mixture was transferred to a separatory funnel and the layers were allowed to separate for 0.5 h. The lower spent water stream was discarded along with the rag layer. The product-rich organic layer was allowed to settle for 5 min and any aqueous layer was discarded. The product-rich toluene stream was returned to the three-neck flask and heated to reflux, distilling off 15-25 mL of toluene / water azeotrope. An additional 40 mL of toluene was charged to the three-neck flask and this was warmed to reflux, distilling off an additional 40 mL of toluene / water azeotrope. The product-rich toluene stream was cooled to 20-30 °C and sampled for KF.Once the KF was less than 0.2%-w / w, the mixture (compound Ic) was abrasively filtered through a Celite pad, the pad was rinsed with approximately 2 mL of toluene, and mixed thoroughly.

[0100] [ka] Exactly 42 mL of the compound Ic solution prepared above, containing 15.06 g (0.041 mol, 1.03 eq) (assay 35.95%), was charged to a 250 mL three-neck round bottom flask equipped with an overhead stirrer and nitrogen inlet / outlet. Then 9.0 g (0.0398 mol, 1.00 eq) of compound (Id), 46 mg (0.08 mmol, 0.02 mol eq) of bis(dibenzylideneacetone)palladium, 39 mg (0.08 mmol, 0.02 mol eq) of Xphos, and 7.5 mL of toluene were charged to the flask. The reactor was evacuated twice with a mini vacuum. The vacuum was released with nitrogen. Then 29 g (0.06 mol, 1.5 mol eq) of a 20 wt.% solution of sodium tert-butylate in THF was charged to the flask, followed by 3 mL of toluene. The resulting mixture was warmed to 45°C, held for 15 minutes, and then slowly warmed to 80-95°C. The reaction mixture was held at this temperature for 6 hours. The mixture was cooled to 55-60°C. The reaction was deemed complete when less than 4%-a / a of either compound (Ic) or compound (Id) remained. The reaction was charged with 63 mL of 1,4-dioxane, followed by 3.5 mL (3.67 g, 0.061 mol) of acetic acid.

[0101] A separate 500 mL Erlenmeyer flask was charged with 23 g (0.141 mol) N-acetylcysteine, 284 mL deionized water, and 20 mL 30 wt.% sodium hydroxide. The mixture was stirred at room temperature for 15 min. 25 mL of this solution was charged to the reaction mixture. The mixture was heated to 55-60 °C and stirred at this temperature for 30 min. Stirring was stopped and the mixture was transferred to a 250 mL separatory funnel and the layers were allowed to separate for 30 min. The lower dark brown spent aqueous layer was discarded. The rag layer was combined with the upper product-rich organic phase and the upper organic phase was allowed to settle for 15 min. The additional spent aqueous layer was discarded. The reaction mixture was returned to the three-neck round bottom flask and charged with 25 mL of the N-acetylcysteine ​​solution. The resulting biphasic mixture was warmed to 55-60 °C and stirred at this temperature for 30 min. Stirring was stopped, the mixture was transferred to a 250 mL separatory funnel, and the layers were allowed to separate for 30 min. The lower dark brown spent aqueous layer was discarded. The rag layer was combined with the upper product-rich organic phase, and the upper organic phase was allowed to settle for 15 min. The further spent aqueous layer was discarded. The organic phase was returned to the three-neck round-bottom flask, and 25 mL of N-acetylcysteine ​​solution was charged. The resulting biphasic mixture was warmed to 55-60 °C and stirred at this temperature for 30 min. Stirring was stopped, the mixture was transferred to a 250 mL separatory funnel, and the layers were allowed to separate for 30 min. The lower dark brown spent aqueous layer was discarded. The rag layer was combined with the upper product-rich organic phase, and the upper organic phase was allowed to settle for 15 min. The further spent aqueous layer was discarded. 27 mL of deionized water was charged to the reaction mixture. 10 g of 1,4-dioxane (peroxide free) was charged to the reaction mixture, which was heated to 55-60 °C and held at this temperature for 30 min. Stirring was stopped, the mixture was transferred to a separatory funnel, and the layers were allowed to separate for 30 min. The lower dark brown spent aqueous layer was discarded. The rag layer was combined with the upper product-rich organic phase, and the upper organic phase was allowed to settle for 15 min. An additional spent aqueous layer was discarded. The reaction mixture was returned to the three-neck round bottom flask, and 50 mL of toluene was charged to the mixture. The mixture was heated to reflux (80-120 °C) and 50 mL of the toluene / dioxane / water azeotrope was distilled. An additional 90-110 mL of toluene was added to the mixture to maintain a constant volume during the distillation. The product-rich toluene stream was cooled to 70-90 °C to check for crystallization.The crystal slurry was cooled to 15-25°C over 4 hours while maintaining an inert atmosphere with nitrogen. The crystal slurry was stirred at this temperature for an additional 2 hours. The crystals were collected by filtration. The cake was washed by displacement washing with approximately 30 mL of toluene. The filter cake was washed twice with approximately 30 mL of ethanol denatured with toluene, and the cake was deliquored to obtain crude compound (I). LC-MS: (ES, m / z) = 557 [M+1]. 1HNMR(DMSO-d6): δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J=5.67), 7.42 (1H, d, J=8.08), 6.56 (1H, d, J=8.08), 6.49 (1H, d, J=5.67), 4.94 (1H, dddd, J=50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J=14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J=7.25, 7.25), 4.49 (1H, bd, J=12.46), 4.20 (1H, dq, J=6.25, 6.25), 3.64 (1H, dd, J=7.25, 7.25), 3.59 (1H, dddd, J=24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J=14.34, 6.33), 3.53-3.48 (1H, bm), 3.52-3.44 (1H, m), 3.51 (1H, dd, J=14.34, 8.33), 3.37 (3H, s), 3.29 (1H, ddd, J=12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1H, dddd, J=7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J=12.95, 4.27, 4.27, 3.99), 1.75 (1H, dddd, J=10.56, 10.56, 10.56, 4.22, 1.64), 1.43 (3H, d, J=6.09), 1.31 (3H, d, J=6.95), 1.30 (3H, d, J=6.92).

[0102] Example 5a: Recrystallization of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (I) [ka] Crude compound (I) (6.3 kg) from Example 4 was dissolved in DMSO (10 L, 1.5 vol) and treated with Pd scavenger Quadrasil MP (850 g, 14% w / w equivalent based on compound (I)). After stirring at 70° C. for 1.5 h, the scavenger was removed by filtration (50° C.), the silica gel scavenger solids were washed with DMSO (5 L, 0.8 vol) and all filtrates were combined. The batch was heated to 55° C. and EtOH (95 L, 15.0 vol) was added slowly over 3 h (2 vols of EtOH were added to the mixture prior to seeding with previously synthesized compound (I)), then the batch was cooled to 45° C. Cooling was continued slowly to 10° C. with stirring over 2 h. The batch was filtered and the compound (I) solids were washed twice with EtOH displacement washes (3×6.3 L, 3×1.0 vol). The compound (I) solid was dried under vacuum (50° C., 35 mbar) for not less than 16 hours to give recrystallized compound (I) (4.9 kg, 78% yield, 99.3% a / a purity by HPLC). HPLC: 99.3% (a / a) 1HNMR(DMSO-d6): δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J=5.67), 7.42 (1H, d, J=8.08), 6.56 (1H, d, J=8.08), 6.49 (1H, d, J=5.67), 4.94 (1H, dddd, J=50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J=14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J=7.25, 7.25), 4.49 (1H, bd, J=12.46), 4.20 (1H, dq, J=6.25, 6.25), 3.64 (1H, dd, J=7.25, 7.25), 3.59 (1H, dddd, J=24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J=14.34, 6.33), 3.53-3.48 (1H, bm), 3.52-3.44 (1H, m), 3.51 (1H, dd, J=14.34, 8.33), 3.37 (3H, s), 3.29 (1H, ddd, J=12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1H, dddd, J=7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J=12.95, 4.27, 4.27, 3.99), 1.75 (1H, dddd, J=10.56, 10.56, 10.56, 4.22, 1.64), 1.43 (3H, d, J=6.09), 1.31 (3H, d, J=6.95), 1.30 (3H, d, J=6.92).

[0103] Example 5b: Recrystallization of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (I) [ka] A 500 mL jacketed three-neck flask equipped with an overhead stirrer, nitrogen inlet and bottom valve was charged with 65 mL of dimethyl sulfoxide (DMSO), 5.4 g of Quadrasil MP (scavenger), 2.8 g of SiliaMetS diamine, and 23 g (0.0413 mol) of compound I. The resulting suspension was warmed to 85-95°C and held at this temperature for 2 hours. The suspension was cooled to 65-75°C and filtered. The spent Quadrasil / SiliaMetS diamine cake was washed with 25 mL of hot (65-75°C) DMSO. The combined filtrate and washes were heated to 85-95°C. 23 mL of deionized water was then added slowly over 10 minutes, followed by 2 g of seed crystals. Finally, 8 mL of water was added over 20 minutes. The resulting slurry was stirred at 85-95°C for 2 h, then cooled to 15-25°C over 4 h and held at this temperature for at least 3 h. The crystals were collected by filtration, washed with 60 mL of absolute ethanol, deliquored under nitrogen for 1 h, and dried under vacuum at 50-55°C for 24 h. LC-MS: (ES, m / z) = 557 [M+1]. 1HNMR(DMSO-d6): δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J=5.67), 7.42 (1H, d, J=8.08), 6.56 (1H, d, J=8.08), 6.49 (1H, d, J=5.67), 4.94 (1H, dddd, J=50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J=14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J=7.25, 7.25), 4.49 (1H, bd, J=12.46), 4.20 (1H, dq, J=6.25, 6.25), 3.64 (1H, dd, J=7.25, 7.25), 3.59 (1H, dddd, J=24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J=14.34, 6.33), 3.53-3.48 (1H, bm), 3.52-3.44 (1H, m), 3.51 (1H, dd, J=14.34, 8.33), 3.37 (3H, s), 3.29 (1H, ddd, J=12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1 H, dddd, J=7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J=12.95, 4.27, 4.27, 3.99), 1.75 (1H, ddddd, J=10.56, 10.56, 10.56, 4.22, 1.64), 1.43 (3H, d, J=6.09), 1.31 (3H, d, J=6.95), 1.30 (3H, d, J=6.92).

Claims

1. A method for preparing a compound of formula (Ic), comprising: 【Chemical Formula 1】 reacting a first starting material of formula (Ia) 【Chemical 2】 or a salt thereof with a second starting material of formula (Ib) 【Chemical Formula 3】 or a salt thereof, in the presence of a base, a palladium catalyst, and a phosphine ligand to form the compound of formula (Ic), optionally: (i) the base is cesium carbonate (Cs₂CO₃) or potassium hydroxide (KOH), the palladium catalyst is bis(dibenzylideneacetone)palladium(0) (Pd(dba)₂), and the phosphine ligand is (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), and / or (ii) the reaction is carried out at 90 °C to 110 °C in dioxane, said method.

2. A method for preparing a compound of formula (V) or a salt thereof, comprising reacting a starting material of formula (IV) 【Chemical Formula 4】 optionally, combining the starting material with POCl₃ and PCl₅ at 0 °C to 25 °C, then adding hydrogen chloride and heating to 50 °C to 70 °C, wherein the reaction is carried out in dioxane, 【Chemical Formula 5】 or a salt thereof is reacted with phosphoryl chloride (POCl ３ ), phosphorus pentachloride (PCl ５ ), and hydrogen chloride to form the compound of the formula (V), said method.

3. The method according to claim 2, wherein the compound of formula (IV) is prepared by a method comprising reacting a starting material of formula (III) with tert-butyl nitrite (t-BuONO) and hydrogen chloride to form the compound of formula (IV), [Chemical Formula 6] optionally, the reaction is carried out at 0 °C to 10 °C in tetrahydrofuran (THF) and the hydrogen chloride is methanolic hydrogen chloride, said method.

4. The method according to claim 3, wherein the compound of formula (III) is prepared by a method comprising hydrogenating a starting material of formula (II) in the presence of a platinum hydrocracking catalyst or a palladium hydrocracking catalyst to form the compound of formula (III), 【Chemical Formula 7】 optionally, (i) the platinum hydrocracking catalyst is PtO₂ and the palladium hydrocracking catalyst is wet palladium / carbon, and / or (ii) the reaction is carried out at 20 °C to 30 °C in ethyl acetate (EtOAc), said method.

5. A method for preparing a compound of formula (VI), comprising: reacting a starting material of formula (V) 【Chemical Formula 8】 or a salt thereof, in the presence of an amine base, a hydride reducing agent, and a palladium catalyst to form the compound of formula (VI), 【Chemical Formula 9】 optionally, ​ (i) The palladium catalyst is 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dba)₂), the hydride reducing agent is sodium borohydride (NaBH₄), and the amine base is tetramethylethylenediamine (TMEDA), and / or (ii) The reaction is carried out at 20 °C to 30 °C in tetrahydrofuran (THF), The method.

6. A method for preparing a compound of formula (Ia), comprising 【Chemical Formula 10】 reacting a starting material of formula (VI) with 【Chemical 11】 a brominating agent in an acid to form the compound of formula (Ia), optionally, the brominating agent is N-bromosuccinimide (NBS) and the acid is sulfuric acid (H₂SO₄), The method.

7. A compound selected from the following 【Chemical Formula 12】 or a salt thereof.

8. A method for preparing a compound of formula (VIII), comprising 【Chemical 13】 reacting a first starting material of formula (VIIc) 【Chemical Formula 14】 or a salt thereof with a second starting material of formula (VIIIb) 【Chemical Formula 15】 and potassium carbonate (K ２ CO ３ ), to form a compound of formula (VIII), optionally, the second starting material of formula (VIIIb) is methyl 2-bromoacetate 【Chemical 16】 to prepare by reacting with, The method.

9. A method for preparing a compound of formula (IX), comprising 【Chemical 17】 reacting a starting material of formula (VIII) 【Chemical 18】 or a salt thereof with lithium chloride (LiCl) to form the compound of formula (IX), optionally, the reaction is carried out at 160 °C to 170 °C in dimethylacetamide (DMAc), The method.

10. A method for preparing a compound of formula (Ib) 【Chemical 19】 or a salt thereof, comprising hydrogenating a starting material of formula (IX) 【Chemical 20】 or a salt thereof in the presence of a palladium hydrocracking catalyst to form the compound of formula (Ib), optionally, the palladium hydrocracking catalyst is 20 wt.% palladium hydroxide on carbon (20% Pd(OH)₂ / C) on a dry basis, and the reaction is carried out at 30 °C to 50 °C in methanol (MeOH), The method.

11. A method for preparing a compound of formula (I), comprising 【Chemical 21】 reacting a first starting material of formula (Ic) or a salt thereof with 【Chemical 22】 a second starting material of formula (Id) or a salt thereof in the presence of 【Chemical 23】 a palladium catalyst and a phosphine ligand to form the compound of formula (I), wherein the palladium catalyst and the phosphine ligand are either separate compounds or a complex containing both the palladium catalyst and the phosphine ligand, Optionally, (i) the palladium catalyst and the phosphine ligand are other than complex methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos-Pd-G4); or (ii) The palladium catalyst is Pd(dppe)₂ (bis[1,2-bis(diphenylphosphino)ethane]palladium(0)), CX-11 (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), CX-12 (1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), Pd(t-Bu₃P)₂ (bis(tri-tert-butylphosphine)palladium(0)), Pd(PCy₃)₂ (bis(tricyclohexylphosphine)palladium(0)), Pd(PPh₃)₄ (tetrakis(triphenylphosphine)palladium(0)), Pd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(0)), Pd(OAc)₂ (palladium(II) acetate), PdCl₂(PPh₃)₂ (dichlorobis-(triphenylphosphine)palladium(II)), PdCl₂(Amphos)₂ (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)), Pd(MeCN)₂Cl₂ (bis(acetonitrile)-dichloropalladium(II)), PdCl₂(P(o-Tol)₃)₂ (dichlorobis(tri-o-tolylphosphine)palladium(II)), Pd(dppf)Cl₂ (1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)), Pd(MeCN)₄(BF₄)₂ (tetrakis(acetonitrile)palladium(II) tetrafluoroborate), Pd-PEPPSI-IPent (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)), Pd-PEPPSI-IPr ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride), Pd-PEPPSI-SIPr ((1,3-bis(2,Selected from the group consisting of 6 - diisopropylphenyl)imidazolidene)(3 - chloropyridyl)palladium(II) dichloride), and bis(dibenzylideneacetone)palladium(0) (Pd(dba)₂), and, (iii) The phosphine ligand, or the complex containing the palladium catalyst and the phosphine ligand, is triphenylphosphine (PPh3); bis(tri-o-tolylphosphine) (P(o-Tol)3)2; tri-tert-butoxyphosphine (Pt-Bu3); tri-tert-butylphosphonium tetrafluoroborate (Pt-Bu3HBF4); bis(tricyclohexylphosphine (PCy3); bis(1-adamantyl)butylphosphane (n-BuP(AD)2); 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), bis[(2-diphenylphosphino)phenyl]ether (DPEPhos); 1,1'-bis(diphenylphosphino)ferrocene (dppf); 1,1'-bis(di-tert-butylphosphino)ferrocene (dcypf), 1,3-bis(diphenylphosphino)propane (DPPP), (2-biphenylyl)di-tert-butylphosphine (JohnPhos), chloro(2-dicyclohexylphosphino-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] (CyJohnPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] (RuPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] (BrettPhos), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-Biphenyl)](t-BuBrettPhos), 2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (Me4-tBuXPhos), 5-(Di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'bipyrazole (BippyPhos), Di(1-adamantyl)-2-morpholinophenylphosphine (MorDalPhos), Palladium / 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride (IPr.HCL), [2-(Di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate (AdBrettPhos), (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate (RuPhos), [(2-Dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate (BrettPhos), [(2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate (JackiePhos), [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate (t-BuBrettPhos), Mesyl(2-(di-tert-butylphosphino)-1,1'-binaphthyl)[2-(2'-amino-1,1'-biphenyl)]palladium (TrixiePhos), (2-Biphenyl)di-tert-butylphosphine, 2'-(Di-tert-butylphosphino)-N,Selected from the group consisting of N-dimethylbiphenyl-2-amine (t-BuDavePhos), 2-di-tert-butylphosphino-2'-methylbiphenyl (t-BuMePhos), chloro(2-dicyclohexylphosphino-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (CyJohnPhos), 2-dicyclohexylphosphino-2'-methylbiphenyl (MePhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (PhDavePhos), 2-dicyclohexylphosphino-2'-methoxy-4',6'-di-tert-butylbiphenyl (VPhos), 2-[(tert-butyl)phenylphosphino]-2',6'-bis(N,N-dimethylamino)biphenyl (PhCPhos), [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CPhos), methanesulfonato[2-diethylphosphino-2',6'-bis(dimethylamino)-1,1-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (EtCPhos), 2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos), di-1-adamantyl(4''-butyl-2'',3'',5'',6''-tetrafluoro-2',4',6'-triisopropyl-2-methoxy-metha-terphenyl)phosphine (AlPhos), 2-(t-butylphenylphosphino)-2',6'-dimethylamino-1,1'-biphenyl, ((t-Bu)PhCPhos), and dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (XPhos), the method.

12. The palladium catalyst is bis(dibenzylideneacetone)palladium(0) (Pd(dba) ２ ), and the phosphine ligand is dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (XPhos), the method according to claim 11.

13. The method according to any one of claims 11 and 12, wherein the reaction mixture further comprises a base, and optionally, the base is selected from the group consisting of potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), potassium hydroxide (KOH), and sodium tert-butoxide (NaOtBu), the method.

14. The reaction is carried out in a solvent selected from toluene, 1,4-dioxane, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), anisole, water (H ２ O), or a mixture thereof, according to any one of claims 11 and 12.

15. The method according to claim 11, further comprising a compound of formula (I) 【Chemical 24】 purifying to form a crystallization product, comprising recrystallizing the compound of formula (I) in a solvent system (for example, a solvent system containing dimethyl sulfoxide (DMSO) and ethanol), optionally, the solvent system comprises a solvent system containing dimethyl sulfoxide (DMSO) and ethanol, or the solvent system comprises a solvent system containing dimethyl sulfoxide (DMSO) and water, the method.

Images