Macrocyclic compounds as CFTR regulators

Abstract

The present invention relates to Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 and X are as described in the specification, their preparation, pharma- ceutically acceptable salts and their use as medicaments, pharmaceutical compositions comprising one or more compounds of formula (I), and their use, in particular as modulators of CFTR. [Formula 1] TIFF2024511752000289.tif74156

Description

[Technical Field]

[0001] The present invention relates to novel macrocyclic compounds of formula (I) and, in particular, to their use as pharmaceuticals in the treatment of CFTR-related diseases and disorders such as cystic fibrosis. The present invention also relates to related aspects including methods for producing the above compounds, pharmaceutical compositions having one or more compounds of formula (I), and their use as modifiers of CFTR. [Background technology]

[0002] Cystic fibrosis (CF; sometimes called mucoviscidosis, fibrocystic disease of pancreas, or pancreatic fibrosis) is an autosomal recessive genetic disorder caused by dysfunction of an epithelial chloride / bicarbonate channel called the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR dysfunction leads to impaired regulation of chloride, bicarbonate, and water transport on the surface of secretory epithelium, resulting in the accumulation of viscous mucus in organs including the lungs, pancreas, liver, and intestines, and consequently causing multi-organ failure. Today, the most severe debilitating effect of CF is observed in the lungs, with abnormal hydration of the airway surface fluid. Due to hydration, mucus plugging, impaired mucociliary clearance, chronic inflammation, and infection, the lungs eventually lose their function, leading to death from respiratory failure (Elborn, 2016). Human CFTR is a multi-domain protein with 1480 amino acids. Many different mutations causing CF dysfunction have been found in CF patients, for example, loss of functional CFTR protein (class I mutations), CFTR trafficking defects (class II mutations), CFTR regulation defects (also known as gating defects; class III mutations), CFTR conductance defects (class IV mutations), a decrease in CFTR protein due to splicing defects (class V mutations) or decreased CFTR stability (class VI mutations), and loss of CFTR protein due to mRNA destabilization (class VII mutations) (de Boeck, Acta Paediatr. 2020, 109(5):893-895). The CFTR2 database (http: / / cftr2.org; data as of 06.07.2021) currently has information on 360 disease-causing mutations. The most frequent disease-causing mutation is the deletion of phenylalanine at position 508 (F508del; allele frequency 0.697 in the CFTR2 database), which causes channel misfolding during synthesis in the endoplasmic reticulum, degradation of the misfolded protein, and a significant reduction in its transport to the cell surface (class II mutation). The remaining F508del-CFTR that traffics to the cell surface is functional, but less functional than wild-type CFTR, meaning that F508del-CFTR also includes gating impairment (Dalemans, 1991).Approximately 40% of all CF patients are homozygous for the F508del mutation, while another 40% are heterozygous for the F508del mutation and have another disease-causing mutation from class I, II, III, IV, V, VI, or VII. Such disease-causing mutations are quite rare, with class III G551D mutation (allelic frequency 0.0210), class I G542X mutation (allelic frequency 0.0254), and class II N1303K mutation (allelic frequency 0.0158) being the next most frequent.

[0003] Currently, cholangiocarcinoma (CF) is treated with a wide range of medications for various organ symptoms and disorders. Intestinal and pancreatic disorders are treated by supplementing with pancreatic digestive enzymes, based on the diagnosis. Lung symptoms are mainly treated with hypertonic saline inhalation, mucolytics, anti-inflammatory drugs, bronchodilators, and antibiotics (Elborn, 2016).

[0004] In addition to symptomatic treatment, CFTR modulators have been developed and approved for patients with specific CFTR mutations. These compounds either directly improve CFTR trafficking to the cell surface (CFTR correctors) or improve CFTR function on the cell surface (CFTR potentiators). CFTR modulators can also enhance the function of non-mutant (i.e., wild-type) CFTR, and are therefore being studied in non-CF disorders such as chronic bronchitis / COPD (Le Grand, J Med Chem. 2021, 64(11):7241-7260. Patel, Eur Respir Rev. 2020, 29(156):190068) and dry eye disease (Flores, FASEB J. 2016, 30(5):1789-1797) where increasing wild-type CFTR function has beneficial effects.

[0005] CFTR modulators and their combinations can be identified and optimized by evaluating their ability to promote trafficking and function of mutant CFTRs in in vitro culture recombinants and primary cell lines. Activity in such systems predicts activity in CF patients.

[0006] WO2019 / 161078 discloses macrocyclic compounds as modulators for cystic fibrosis, which are generally 15-membered macrocyclic compounds having a (pyridine-carbonyl)-sulfamoyl moiety bonded to a further aromatic group. Macrocyclic tetrapeptides (12 or 13 members), such as apicidin (CAS: 183506-66-3), have been proposed as potential agents for the treatment of CF (Hutt DM et al., ACS Med Chem Lett. 2011;2(9):703-707. doi:10.1021 / ml200136e). WO2020 / 128925 discloses macrocyclic compounds that can modulate the activity of CFTR, which have an optionally substituted divalent N-(pyridine-2-yl)pyridinyl-sulfonamide moiety. Non-macrocyclic CFTR collectors and / or potentiators for CFTR are disclosed, for example, in WO2011 / 119984, WO2014 / 015841, WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, WO2013 / 130669, WO2014 / 078842 and WO2018 / 227049, WO2010 / 037066, WO2011 / 127241, WO2013 / 112804, WO2014 / 071122 and WO2020 / 128768.Furthermore, specific macrocyclic compounds in which the phenylene group, which is part of the macrocyclic compound, is always unsubstituted can be found as screening compounds (CAS registry numbers: CAS-2213100-89-9, CAS-2213100-96-8, CAS-2213100-99-1, CAS-2213101-02-9, CAS-2213101-04-1, CAS-2213101-06-3, CAS-2213101-08-5, CAS-2213101-09-6, CAS-2213101-19-8, CAS-2213 101-24-5, CAS-2215788-95-5, CAS-2215788-98-8, CAS-2215789-01-6, CAS-2215789-02-7, CAS-2215789-09-4, CAS-2215789-15-2, CAS-221 5789-20-9, CAS-2215789-24-3, CAS-2215789-35-6, CAS-2215789-37-8, CAS-2215946-94-2, CAS-2215947-04-7, CAS-2215947-13-8, CAS-2. 215947-24-1, CAS-2215947-34-3, CAS-2215947-44-5, CAS-2215947-51-4, CAS-2215947-64-9, CAS-2215947-68-3, CAS-2215 947-78-5, CAS-2215947-91-2, CAS-2215954-57-5, CAS-2216342-34-4, CAS-2216342-78-6, CAS-2216342-86-6, CAS-2216343 -03-0, CAS-2216343-09-6, CAS-2216343-14-3, CAS-2216343-18-7, CAS-2216343-24-5, CAS-2216343-32-5, CAS-2216343-38 -1, CAS-2216343-45-0, CAS-2216343-53-0, CAS-2216343-59-6, CAS-2216343-64-3, CAS-2216343-74-5, CAS-2216343-76-7).

[0007] This invention provides macrocyclic compounds that act as regulators of CFTR. Therefore, the compounds of this invention may be useful in the treatment of cystic fibrosis.

Summary of the Invention

[0008] 1) The first aspect of the present invention relates to a compound of formula (I):

Chemical formula

[0009] [ka] A partially aromatic bicyclic ring; The C replaced by 1-3 -alkyl; or, -- -L X2 -Ar X2 (--- L X2 These are independently, directly bonded, C 1-3 -Alkilen, -C 1-3 -Alkilen-O- * or -C 1-3 -Alkilen-OC 1-2 -Alkilen- * It represents; the asterisk is based on the Ar X2 This indicates a bond; --- Ar X2 The group Ar independently represents an aryl (especially phenyl or naphthyl) or a 5-10 membered heteroaryl (especially oxadiazolyl, triazolyl, isoxazolyl, pyridinyl, or quinolinyl); the group Ar X2 These are independently unsubstituted or substituted with one or two substituents, and the substituents are ---- C 1-4 -alkyl; ---- C 1-3 -alkoxy; ---- Halogen; ---- C 3-6 -Cycloalkyl; ---- C 1-3 -fluoroalkyl; and ---- Ar X3 (Ar X3 The group Ar independently represents phenyl or a 5- or 6-membered heteroaryl (especially pyridinyl); the group Ar X3 These are independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkyl, C 3-5 -Cycloalkyl, C 1-3 -Independently selected from fluoroalkyl and halogen groups. It is selected independently from the others. It represents; and, R 1 Independently, - Hydrogen; - -C 1-8-Alkyl (especially methyl); - -C 2-6 - Alkyl, with one hydroxyl or C 1-4 - The C substituted with an alkoxy (particularly methoxy, tert-butoxy) 2-6 -alkyl; - -C 1-6 -alkyl (especially the -C) 1-6 -Alkyl is -(CH2) m -(m represents an integer 1 or 2.) ) and one R 11 Replaced by; R 11 However, independently, -- A 5- or 6-membered saturated heterocycloalkyl having one or two ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen and oxygen, and the 5- or 6-membered heterocycloalkyl is independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -A 5- or 6-membered heterocycloalkyl group independently selected from alkyl (especially methyl), halogen, and benzyl; C 3-6 -Cycloalkyl (especially cyclohexyl), which is unsubstituted or has one C 1-4 - The C substituted with alkoxy (especially methoxy) 3-6 -Cycloalkyl; -- Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl), independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -alkyl, C 1-4 -alkoxy, C 1-3 -Fluoroalkyl, C 1-3 -The phenyl or 5- or 6-membered heteroaryl, independently selected from fluoroalkoxys, halogens, cyanos, and morpholine-4-yl; -- Benzyl oxy;

[0010] [ka] A spiro ring fragment;

[0011] [Chem.] a saturated bicyclic ring; or,

[0012] [Chem.] a partially aromatic bicyclic ring; said C which represents 1-6 -alkyl; represents; ※ or, a fragment

[0013] [Chem.] (R X is - hydrogen; - C 1-4 -alkyl; - C 3-6 -cycloalkyl; - C 1-4 -alkyl which is substituted by one C 3-4 -cycloalkyl of said C 1-4 -alkyl; - C 2-4 -alkyl which is substituted by one hydroxy or C 1-3 -alkoxy of said C 2-4 -alkyl; - phenyl or a 5- or 6-membered heteroaryl (especially pyridinyl), which is independently unsubstituted or substituted by 1 or 2 substituents, and said substituents are independently selected from C 1-4 -alkyl, C 1-3 -alkoxy, C 1-3 -fluoroalkyl, C 1-3 -fluoroalkoxy, cyano or halogen, of said phenyl or 5- or 6-membered heteroaryl [In particular, such a group is phenyl or pyridinyl; said group is independently unsubstituted or substituted as defined above.];

[0014] [Chem.] (R SX1 represents hydrogen or -CO-O-C 1-4 -alkyl.); - -CO-R OX1 or -SO2-R OX1 ;(R OX1 is independently -- C 1-4 -alkyl; -- C 1-3 -alkyl which is substituted by one C 1-3 -alkoxy (especially methoxy), tetrahydropyranyl, morpholin-4-yl, phenyl, 10-membered heteroaryl (especially quinolinyl) or -NR ONX1 R ONX2 (R ONX1 and R ONX2 are independently hydrogen or C 1-3 -alkyl.)-substituted said C 1-3 -alkyl; -- Tetrahydropyranyl; -- Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl or pyrazinyl), which is independently unsubstituted or substituted by 1 or 2 substituents, and the above substituents are C 1-4 -alkyl, C 1-3 -alkoxy, C 1-3 -fluoroalkyl, C 1-3 -fluoroalkoxy, cyano or halogen; or -- Group of structure (R X-A ));

[0015]

Chemical formula

[0016] 2) Further embodiments relate to compounds of formula (I) according to embodiment 1), * X is -CR X1 R X2 It represents; (- R X1 and R X2 along with the carbon atoms to which they bond: C 3-6 -Cycloalkane-1,1-diyl- (especially cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl); -- C condensed on the benzene ring 5-6 -Cycloalkane-1,1-diyl-(especially 1,3-dihydro-2H-indene-2,2-diyl); C 3-6 -Cycloalkane-1,1-diyl-, which has one C 1-3 - The C substituted with an alkoxy or two fluorocarbons 3-6 -Cycloalkane-1,1-diyl group (especially 3-methoxycyclobutane-1,1-diyl, 3,3-difluorocyclobutane-1,1-diyl); It forms a ring; or, - R X1 and R X2 All of them are independently C 1-4 - Represents an alkyl group (in particular, such group X is propane-2,2-diyl); or, - R X1 represents hydrogen, and, R X2 teeth, -- Hydrogen; C 1-6 -alkyl (especially C 1-4 -alkyl); C 1-4 -fluoroalkyl; C 3-6 -Cycloalkyl; C 1-3 -alkyl, one --- Hydroxy; --- C1-4 -alkoxy; --- -L X1 -C 3-6 -Cycloalkyl(the C 3-6 - The cycloalkyl group is either unsubstituted or substituted with two fluorocarbons; L X1 ' / ' independently represents a direct bond or oxygen atom. --- C 4-6 - A heterocycloalkyl having one ring oxygen atom. 4-6 -heterocycloalkyl; --- -NR N1 R N2 (R N1 and R N2 Together with the above nitrogen, it forms a 4-6 membered carbon ring containing this nitrogen atom (i.e., an azetidine-1-yl, pyrrolidine-1-yl, or piperidine-1-yl ring), and the ring is substituted with one or two fluorocarbons. 1-3 -alkyl; Or, -- -L X2 -Ar X2 (--- L X2 These are independently, directly bonded, C 1-3 -Alkilen, -C 1-3 -Alkilen-O- * or -C 1-3 -Alkilen-OC 1-2 -Alkilen- * It represents; the asterisk is based on the Ar X2 It shows a bond that connects to something; --- Ar X2 The group Ar independently represents an aryl (especially phenyl or naphthyl) or a 5-10 membered heteroaryl (especially oxadiazolyl, triazolyl, isoxazolyl, pyridinyl, or quinolinyl); the group Ar X2 These are independently unsubstituted or substituted with one or two substituents, and the substituents are ---- C 1-4 -alkyl; ---- C 1-3 -alkoxy; ---- Halogen; ---- C 3-6 -Cycloalkyl; ---- C 1-3 -fluoroalkyl; and ---- Ar X3 (Ar X3 The group Ar independently represents phenyl or a 5- or 6-membered heteroaryl (especially pyridinyl); the group Ar X3 These are independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkyl, C 3-5 -Cycloalkyl, C 1-3 -Independently selected from fluoroalkyl and halogen groups. It is selected independently from the others. It represents; and, R 1 Independently, - Hydrogen; - -C 1-6 -Alkyl (especially methyl); - -C 2-6 -alkyl, with 1 C 1-4 - The C substituted with an alkoxy (particularly methoxy, tert-butoxy) 2-6 -alkyl; - -C 3-6 - Alkyl, and the C is substituted with one phenyl or benzyloxy molecule. 3-6 -alkyl; - -(CH2) m -R 11 (m represents an integer 1 or 2; R 11 Independently, -- A 5- or 6-membered saturated heterocycloalkyl having 1 or 2 ring oxygen atoms, independently unsubstituted or 1 or 2 C 1-4 -A 5- or 6-membered heterocycloalkyl group substituted with alkyl (especially methyl); C 3-6-Cycloalkyl (especially cyclobutyl, cyclohexyl) which is unsubstituted or has one C 1-4 - The C substituted with alkoxy (especially methoxy) 3-6 -Cycloalkyl; -- Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl), independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -alkyl, C 1-4 -alkoxy, C 1-3 -Fluoroalkyl, C 1-3 -A phenyl or 5- or 6-membered heteroaryl group independently selected from fluoroalkoxy, cyano, or halogen groups [in particular, such group represents phenyl];

[0017] [ka] A spiro ring fragment;

[0018] [ka] A saturated bicyclic ring; or,

[0019] [ka] A partially aromatic bicyclic ring; This represents... Does it represent; * Or, fragment

[0020] [ka] (R X teeth, - Hydrogen; - C 1-4 -alkyl; - C 3-6 -Cycloalkyl; - C 1-4 -alkyl, with 1 C 3-4- The C substituted with cycloalkyl 1-4 -alkyl; - C 2-4 - Alkyl, with one hydroxyl or C 1-3 - The C substituted with alkoxy 2-4 -alkyl; - Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl), independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -alkyl, C 1-3 -alkoxy, C 1-3 -Fluoroalkyl, C 1-3 -A phenyl or 5- or 6-membered heteroaryl group independently selected from fluoroalkoxy, cyano, or halogen [in particular, such group is phenyl];

[0021] [ka] (R SX1 is hydrogen or -CO-OC 1-4 - Represents alkyl groups. - -CO-R OX1 or -SO2-R OX1 ;(R OX1 Independently, C 1-4 -alkyl; C 1-3 -alkyl, with 1 C 1-3 -alkoxy (especially methoxy), tetrahydropyranyl, morpholine-4-yl, phenyl, 10-membered heteroaryl (especially quinolinyl), or -NR ONX1 R ONX2 (R ONX1 and R ONX2 These are independently hydrogen or C 1-3 - Represents alkyl.) The C substituted by 1-3 -alkyl; -- Tetrahydropyranyl; -- Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl or pyrazinyl), independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -alkyl, C 1-3 -alkoxy, C 1-3 -Fluoroalkyl, C 1-3 -The phenyl or 5- or 6-membered heteroaryl, independently selected from fluoroalkoxy, cyano, or halogen; or, -- Structure (R X-A ) base:

[0022] [ka] (wherein (A) represents a 5 or 6-membered non-aromatic ring condensed to the phenyl group, and ring (A) comprises two heteroatoms independently selected from oxygen and nitrogen; ring (A) is independently unsubstituted or substituted with one substituent, the substituent being oxo and C) 1-3 - Selected independently from alkyl groups. It represents; or, - -CO-OR OX2 ;(R OX2 teeth, C 1-4 -alkyl; -- 2,2,2-trichloroethyl; or, -- Tetrahydropyranyl; This represents... (This represents...) This represents a complex algebra; R 2 is C 1-4 - Represents alkyl (especially methyl); R 3 is hydrogen; C 1-6 -Alkyl (especially methyl, isobutyl);-CH2-C 3-6 -Cycloalkyl (especially -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl); C 2-4 - Represents alkynyl (especially -CH2-C≡CH); R 4is the base-CO-NH-R 41 Represents; R 41 teeth, - C 2-6 -alkyl, with 1 C 1-4 -alkoxy (especially methoxy), C 1-4 -Fluoroalkoxy (especially difluoromethoxy) or hydroxylated C 2-6 -alkyl; - C 1-3 -alkoxy-C 2-3 -Alkilen-O-CH2-CH2-; - -CH2-CH2-C 5-6 -A heterocycloalkyl having one ring oxygen atom, and the C 5-6 - Heterocyclyl is unsubstituted or has 1 or 2 C 1-4 - The C substituted with alkyl (especially methyl) 5-6 -heterocycloalkyl; - -L 1 -Aryl;(L 1 -CH2-CH2-, -CH2-CH2-O- * -CH2-CF2- * -CH2-(cyclopropane-1,1-diyl)- * -CH(CH2-OH)-CH2- * or -CH2-CH(OH)- * It represents; the asterisk is L 1 This indicates a bond that connects to the above aryl; the aryl represents phenyl or naphthyl (especially phenyl); the aryl is unsubstituted or substituted with one, two, or three substituents, the substituents independently being C 1-4 -Alkyl (especially methyl, ethyl, tert-butyl), C 1-4 -alkoxy (especially methoxy, ethoxy), C 1-3 -Fluoroalkyl, C 1-3 -Fluoroalkoxy, halogen (especially fluoro, chloro, bromo), cyano, hydroxy-C 1-3 -alkyl, C 2-3 -Alkinyl, Morpholin-4-yl, C 1-3-alkyl-SO2-, 5 or 6-membered heteroaryls (especially pyrazolyl, triazolyl, pyrimidinyl, pyrazinyl) or -NR N41 R N42 (Independently, R N41 is hydrogen or C 1-4 -It is alkyl, R N42 is hydrogen or C 1-4 -It is alkyl. ) It is. ); - -L 2 -HET 1 ;(L 2 -CH2-CH2-, -CH2-CF2- * -CH2-(cyclopropane-1,1-diyl)- * or -CH2-CH(OH)- * It represents; the asterisk is L 2 HET 1 This shows the bond that connects to (especially L 2 represents -CH2-CH2-. );HET 1 represents a 5 or 6-membered heteroaryl (in particular thiophenyl, furanyl, thiazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl), where the 5 or 6-membered heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents, where the substituents are independently C 1-4 -Alkyl (especially methyl); C 1-4 -alkoxy (especially methoxy); C 1-3 -Fluoralkyl;C 1-3 -Fluoroalkoxy; halogen; cyano; C 3-6 -Cycloalkyl (especially cyclopropyl); C 3-6 -Cycloalkyl-methyl;C 1-3 -alkoxy-C 1-3 -alkyl;C 2-3 -Alkynnyl, benzyl; or phenyl, which is unsubstituted or substituted with one or two substituents, wherein the substituents are independently C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy) or C 1-4-It is a phenyl that is a fluoroalkoxy (especially trifluoromethoxy); - -CH2-CH2-HET 2 (HET 2 HET represents a 9 or 10-membered bicyclic heteroaryl (in particular, benzoxazolyl, benzoisoxazolyl, benzofuranil, benzo[d][1,2,3]triazolyl, or [1,2,4]triazolo[1,5-a]pyrimidinil), and the HET 2 is either unsubstituted or has one C 1-4 - Substituted with alkyl. - -CH2-CH2-HCy 1 (HCy 1 This represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a 5-7 member saturated heterocycle having one or two heteroatoms independently selected from oxygen and nitrogen, wherein if nitrogen is present and has a free valence, the nitrogen is either unsubstituted or has one carbon atom. 1-4 -Substituted with alkyl (especially methyl); the phenyl ring of the partially aromatic bicyclic ring system is unsubstituted or substituted with 1, 2, or 3 substituents, the substituents independently being C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy), C 1-3 -Fluoroalkyl, C 1-3 -Fluoroalkoxy, halogen (especially chloro), or cyano; - -CH2-CH2-HCy 2 (HCy 2 This represents a partially aromatic bicyclic ring system consisting of a 5-membered heteroaryl compound fused to a saturated carbon ring of 5-7 members. ); or, - HCy 3 ;(HCy 3 This represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a 5-7 member saturated heterocycle having one oxygen atom; the group HCy 3 This is a partial aroma, where the carbon atom in the 5-7 member saturated heterocycle is bonded to the nitrogen of the -CO-NH- group; The phenyl ring in a bicyclic system is either unsubstituted or has one carbon atom. 1-4 -Alkyl (especially methyl) or C1-4 - Substituted with alkoxy (especially methoxy). It represents; Ar 1 teeth, - 5- or 6-membered heteroarylenes, and unsubstituted such 5- or 6-membered heteroarylenes (especially pyridine-3,4-diyl, thiophene-2,3-diyl); - Phenylene or a 5- or 6-membered heteroarylene, independently substituted with 1, 2, or 3 substituents, wherein the substituents are C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy, ethoxy), C 1-3 -Fluoroalkyl, C 1-3 - Phenylene or 5- or 6-membered heteroarylene independently selected from fluoroalkoxy, cyano, and halogen (especially fluoro and chloro); - Phenylene condensed to a 5- or 6-membered saturated heterocycle having 1 or 2 oxygen atoms, wherein the 5- or 6-membered saturated heterocycle is independently unsubstituted or substituted with 2 fluorocarbons; or, - A bicyclic aromatic ring selected from naphthylene and 8-10 membered bicyclic heteroarylenes; independently, unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -A bicyclic aromatic ring independently selected from alkyl (especially methyl) and halogen (especially fluoro, chloro); or, - Quinoline-diyl, wherein the quinoline-diyl exists in the form of each N-oxide; the quinoline-diyl N-oxide is unsubstituted or the quinoline-diyl N-oxide is substituted with one methyl or fluoro group; It represents; [Based on the above] 1 In this, -CO- group and oxygen (i.e., Ar 1 The group that connects to the rest of the molecule is, as shown in formula (I), Ar 1 It shall be bonded in an ortho configuration to the aromatic ring carbon atom. Ar 2 teeth, - Phenyl or naphthyl (especially phenyl); - 5 or 6-membered heteroaryls (especially pyridinyl); or, - 9 or 10-membered heteroaryls (especially benzothiophenyl); It represents.

[0023] 3) The second aspect is given by equation (I E The following relates to a compound of formula (I) according to embodiment 1) or 2):

[0024] [ka] 4) Another aspect is, * X is -CR X1 R X2 It represents; (- R X1 and R X2 along with the carbon atoms to which they bond: C 3-6 -Cycloalkane-1,1-diyl-(especially cyclopropane-1,1- Diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl); -- C condensed on the benzene ring 5-6 -Cycloalkane-1,1-diyl-(especially 1,3-dihydro-2H-indene-2,2-diyl); or, C 3-6 -Cycloalkane-1,1-diyl-, which has one C 1-3 - The C substituted with an alkoxy or two fluorocarbons 3-6 -Cycloalkane-1,1-diyl group (especially 3-methoxycyclobutane-1,1-diyl, 3,3-difluorocyclobutane-1,1-diyl); Does it form a ring? - R X1 and R X2 All of them are independently C 1-4 - Represents an alkyl group (in particular, such group X is propane-2,2-diyl); or, - R X1represents hydrogen, and, R X2 teeth, -- Hydrogen; C 1-6 -alkyl (especially C 1-4 -alkyl); C 1-4 -fluoroalkyl; C 3-6 -Cycloalkyl; C 1-3 -alkyl, one --- Hydroxy; --- C 1-4 -alkoxy; --- -L X1 -C 3-6 -Cycloalkyl(the C 3-6 - The cycloalkyl group is either unsubstituted or substituted with two fluorocarbons; L X1 ' / ' independently represents a direct bond or oxygen atom. --- C 4-6 - A heterocycloalkyl having one ring oxygen atom. 4-6 -heterocycloalkyl; --- -NR N1 R N2 (R N1 and R N2 Together with the above nitrogen, it forms a 4-6 membered carbon ring containing this nitrogen atom (i.e., an azetidine-1-yl, pyrrolidine-1-yl, or piperidine-1-yl ring), and the ring is substituted with one or two fluorocarbons. 1-3 -alkyl; -- -L X2 -Ar X2 (--- L X2 These are independently, directly bonded, C 1-3 -Alkilen, -C 1-3 -Alkilen-O- * or -C 1-3 -Alkilen-OC 1-2 -Alkilen- * It represents; the asterisk is based on the Ar X2 It shows a bond that connects to something; --- ArX2 The group Ar independently represents an aryl (especially phenyl or naphthyl) or a 5-10 membered heteroaryl (especially oxadiazolyl, triazolyl, isoxazolyl, pyridinyl, or quinolinyl); the group Ar X2 These are independently unsubstituted or substituted with one or two substituents, and the substituents are ---- C 1-4 -alkyl; ---- C 1-3 -alkoxy; ---- Halogen; ---- Cyano; ---- C 3-6 -Cycloalkyl; ---- C 1-3 -fluoroalkyl; and ---- Ar X3 (Ar X3 The group Ar independently represents phenyl or a 5- or 6-membered heteroaryl (especially pyridinyl); the group Ar X3 These are independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkyl, C 3-5 -Cycloalkyl, C 1-3 -Independently selected from fluoroalkyl and halogen groups. It is selected independently from the others. It represents; and, R 1 However, independently, hydrogen or -C 1-3 - Represents alkyl (especially methyl); or, * X is -CR X1 R X2 It represents; (- R X1 represents hydrogen, and, R X2 -CR represents hydrogen or methyl; (i.e., -CR X1 R X2 The base X(R) represents the following X1represents hydrogen. ) is methylene or ethane-1,1-diyl. ); or, - R X1 and R X2 C 3-5 -Forms a ring that is a cycloalkane-1,1-diyl (especially cyclopropane-1,1-diyl); and, R 1 However, independently, - -C 4-6 -alkyl (especially 3,3-dimethylbutyl); - -C 2-6 -alkyl, with 1 C 1-4 - The C substituted with an alkoxy (particularly methoxy, tert-butoxy) 2-6 -Alkyl (in particular, such groups are 2-methoxyethyl, 3-methoxypropyl, 3-methoxy-3-methylbutyl, and 2-(tert-butoxy)ethyl); - -C 3-6 - Alkyl, and the C is substituted with one phenyl or benzyloxy molecule. 3-6 -alkyl; - -(CH2) m -R 11 (m represents an integer 1 or 2; R 11 Independently, -- A 5- or 6-membered saturated heterocycloalkyl (especially tetrahydrofuranyl, tetrahydropyranyl) having one or two ring oxygen atoms, independently unsubstituted or with one or two C atoms. 1-4 -A 5- or 6-membered heterocycloalkyl group substituted with alkyl (especially methyl); C 3-6 -Cycloalkyl (especially cyclobutyl, cyclohexyl) which is unsubstituted or has one C 1-4 - The C substituted with alkoxy (especially methoxy) 3-6 -Cycloalkyl; -- Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl), independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -alkyl, C1-4 -alkoxy, C 1-3 -Fluoroalkyl, C 1-3 -A phenyl or 5- or 6-membered heteroaryl group independently selected from fluoroalkoxy, cyano, or halogen groups [in particular, such group represents phenyl];

[0025] [ka] A spiro ring fragment;

[0026] [ka] A saturated bicyclic ring; or,

[0027] [ka] A partially aromatic bicyclic ring; This represents... Does it represent; * Or, fragment,

[0028] [ka] (R X teeth, - Hydrogen; - C 1-4 -alkyl; - C 3-4 -Cycloalkyl; - C 1-4 -alkyl, with 1 C 3-4 - The C substituted with cycloalkyl 1-4 -alkyl; - C 2-4 - Alkyl, with one hydroxyl or C 1-3 - The C substituted with alkoxy 2-4 -alkyl; - Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl), independently unsubstituted or substituted with one or two substituents, wherein the substituents are C1-4 -alkyl, C 1-3 -alkoxy, C 1-3 -Fluoroalkyl, C 1-3 -A phenyl or 5- or 6-membered heteroaryl group independently selected from fluoroalkoxy, cyano, or halogen [in particular, such group represents phenyl];

[0029] [ka] (R SX1 is hydrogen or -CO-OC 1-4 - Represents alkyl groups. - -CO-R OX1 or -SO2-R OX1 ;(R OX1 Independently, C 1-4 -alkyl; C 1-3 -alkyl, with 1 C 1-3 -alkoxy (especially methoxy), tetrahydropyranyl, morpholine-4-yl, phenyl, 10-membered heteroaryl (especially quinolinyl), or -NR ONX1 R ONX2 (R ONX1 and R ONX2 These are independently hydrogen or C 1-3 - Represents alkyl.) The C substituted by 1-3 -alkyl; -- Tetrahydropyranyl; -- Phenyl or 5- or 6-membered heteroaryl (especially pyridinyl or pyrazinyl), independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -alkyl, C 1-3 -alkoxy, C 1-3 -Fluoroalkyl, C 1-3 -The phenyl or 5- or 6-membered heteroaryl, independently selected from fluoroalkoxy, cyano, or halogen; or, -- Structure (R X-A ) base:

[0030] [ka] (wherein (A) represents a 5 or 6-membered non-aromatic ring condensed to the phenyl group, and ring (A) comprises two heteroatoms independently selected from oxygen and nitrogen; ring (A) is independently unsubstituted or substituted with one substituent, the substituent being oxo and C) 1-3 - Selected independently from alkyl groups. It represents; or, - -CO-OR OX2 ;(R OX2 teeth, C 1-4 -alkyl; -- 2,2,2-trichloroethyl; or, -- Tetrahydropyranyl; This represents... This represents... Represents a complex algebra; This relates to a compound that conforms to any one of embodiments 1) to 3).

[0031] 5) Another aspect is, * X is -CR X1 R X2 It represents; (- R X1 and R X2 along with the carbon atoms to which they bond: C 3-6 -Cycloalkane-1,1-diyl- (especially cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl); -- C condensed on the benzene ring 5-6 -Cycloalkane-1,1-diyl-(especially 1,3-dihydro-2H-indene-2,2-diyl); C 3-6 -Cycloalkane-1,1-diyl-, which has one C 1-3 - The C substituted with an alkoxy or two fluorocarbons 3-6 -Cycloalkane-1,1-diyl group (especially 3-methoxycyclobutane-1,1-diyl, 3,3-difluorocyclobutane-1,1-diyl); Does it form a ring? - R X1 and R X2 All of them are independently C 1-4 - Represents an alkyl group (in particular, such group X is propane-2,2-diyl); or, - R X1 represents hydrogen, and, R X2 teeth, -- Hydrogen; C 1-6 -alkyl (especially C 1-4 -alkyl); C 1-4 -fluoroalkyl; C 3-6 -Cycloalkyl; C 1-3 -alkyl, one --- Hydroxy; --- C 1-4 -alkoxy; --- -L X1 -C 3-6 -Cycloalkyl(the C 3-6 - The cycloalkyl group is either unsubstituted or substituted with two fluorocarbons; L X1 ' / ' independently represents a direct bond or oxygen atom. --- C 4-6 - A heterocycloalkyl having one ring oxygen atom. 4-6 -heterocycloalkyl; --- -NR N1 R N2 (R N1 and R N2 Together with the above nitrogen, it forms a 4-6 membered carbon ring containing this nitrogen atom (i.e., an azetidine-1-yl, pyrrolidine-1-yl, or piperidine-1-yl ring), and this ring is substituted with one or two fluorocarbons.

[0032] [ka] A partially aromatic bicyclic ring; The C replaced by 1-3-alkyl; or, -- -L X2 -Ar X2 (--- L X2 These are independently, directly bonded, C 1-3 -Alkilen, -C 1-3 -Alkilen-O- * or -C 1-3 -Alkilen-OC 1-2 -Alkilen- * It represents; the asterisk is based on the Ar X2 It shows a bond that connects to Ar X2 represents phenyl, which is independently unsubstituted or substituted with one or two substituents, and the substituents are ---- C 1-4 -alkyl; ---- C 1-3 -alkoxy; ---- Halogen; ---- C 3-6 -cycloalkyl; and ---- C 1-3 -fluoroalkyl; Selected independently from; or, --- L X2 These are independently, directly bonded, C 1-3 -Alkilen, -C 1-3 -Alkilen-O- * or -C 1-3 -Alkilen-OC 1-2 -Alkilen- * It represents; the asterisk is based on the Ar X2 It shows a bond that connects to Ar X2 Each independently represents a 5- or 6-membered heteroaryl [in particular, a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen and nitrogen (in particular, oxadiazolyl, triazolyl, or isoxazolyl); or a 6-membered heteroaryl having 1 or 2 nitrogen atoms (in particular, pyridinyl or pyrazinyl)]; the heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents, the substituents being ---- C 1-4 -alkyl; ---- C 1-3 -alkoxy; ---- Halogen; ---- C 3-6 -Cycloalkyl; ---- C 1-3 -fluoroalkyl; and ---- Ar X3 (Ar X3 The group Ar independently represents a phenyl or a 5- or 6-membered heteroaryl (in particular a 6-membered heteroaryl having one or two nitrogen atoms, especially pyridinyl); the group Ar X3 These are independently unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkyl, C 3-5 -Cycloalkyl, C 1-3 -Independently selected from fluoroalkyl and halogen groups. Selected independently from; --- L X2 These are independently, directly bonded, C 1-3 - Alkilen or -C 1-3 -Alkilen-O- * It represents; the asterisk is based on the Ar X2 It shows a bond that connects to Ar X2 This independently represents naphthyl or an 8- to 10-membered heteroaryl (especially a 10-membered heteroaryl having one nitrogen atom, particularly quinolinyl); the group Ar X2 These are independently unsubstituted or substituted with one or two substituents, and the substituents are ---- C 1-4 -alkyl; ---- C 1-3 -alkoxy; ---- Halogen; ---- C 3-6 -cycloalkyl; and ---- C 1-3 -fluoroalkyl; It is selected independently from the others. It represents; and, R 1 However, independently, -C 1-3 - Represents alkyl (especially methyl); or, * X is -CR X1 R X2 (R X1 and R X2 Both represent hydrogen. ) represent; and R 1 However, independently, - -C 4-6 -alkyl; - -C 2-6 -alkyl, with 1 C 1-4 - The C substituted with an alkoxy (particularly methoxy, tert-butoxy) 2-6 -alkyl; - -C 3-6 - Alkyl, and the C is substituted with one phenyl or benzyloxy molecule. 3-6 -alkyl; - -(CH2) m -R 11 (m represents an integer 1 or 2; R 11 Independently, -- A 5- or 6-membered saturated heterocycloalkyl having 1 or 2 ring oxygen atoms, independently unsubstituted or 1 or 2 C 1-4 -A 5- or 6-membered heterocycloalkyl group substituted with alkyl (especially methyl); C 3-6 -Cycloalkyl (especially cyclobutyl, cyclohexyl) which is unsubstituted or has one C 1-4 - The C substituted with alkoxy (especially methoxy) 3-6 -Cycloalkyl; -- Phenyl;

[0033] [ka] A spiro ring fragment;

[0034] [ka] A saturated bicyclic ring; or,

[0035] [ka] A partially aromatic bicyclic ring; This represents... Does it represent; * Or, fragment

[0036] [ka] (R X teeth, - C 1-4 -alkyl; - C 3-4 -Cycloalkyl; - C 1-4 -alkyl, with 1 C 3-4 - The C substituted with cycloalkyl 1-4 -alkyl; - C 2-4 - Alkyl, with one hydroxyl or C 1-3 - The C substituted with alkoxy 2-4 -alkyl; - Phenyl; - A six-membered heteroaryl (especially pyridinyl) which is unsubstituted or substituted with one halogen (especially fluoro);

[0037] [ka] (R SX1 -CO-OC 1-4 - Represents alkyl groups. - -CO-R OX1 or -SO2-R OX1 ;(R OX1 Independently, C 1-4 -alkyl; C 1-3 -alkyl, with 1 C 1-3-alkoxy (especially methoxy), tetrahydropyranyl, morpholine-4-yl, phenyl, 10-membered heteroaryl (especially quinolinyl), or -NR ONX1 R ONX2 (R ONX1 and R ONX2 These are independently hydrogen or C 1-3 - Represents alkyl.) The C substituted by 1-3 -alkyl; -- Tetrahydropyranyl; -- Phenyl, which is unsubstituted or substituted with one or two substituents, wherein the substituents are independently C 1-3 -alkoxy, C 1-3 -Phenyls that are fluoroalkoxy or halogens; -- 5 or 6-membered heteroaryls (especially pyridinyl, pyrazinyl), independently unsubstituted or with one C 1-3 -The 5 or 6-membered heteroaryl substituted with an alkoxy; or, -- Structure (R X-A ) base:

[0038] [ka] (wherein (A) represents a 5 or 6-membered non-aromatic ring condensed to the phenyl group, and ring (A) comprises two heteroatoms independently selected from oxygen and nitrogen; ring (A) is independently unsubstituted or substituted with one substituent, the substituent being oxo and C) 1-3 - Selected independently from alkyl groups. It represents; or, - -CO-OR OX2 ;(R OX2 teeth, C 1-4 -alkyl; -- 2,2,2-trichloroethyl; or, -- Tetrahydropyranyl; This represents... This represents... Represents a complex algebra; This relates to a compound that conforms to any one of embodiments 1) to 3).

[0039] 6) Another aspect is fragment

[0040] [ka] but:

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] [ka] (R X teeth, - C 1-4 -alkyl; - C 3-4 -Cycloalkyl; - C 1-4 -alkyl, with 1 C 3-4 - The C substituted with cycloalkyl 1-4 -alkyl; - C 1-4 - Alkyl, with one hydroxyl or C 1-3 - The C substituted with alkoxy 1-4 -alkyl; - Phenyl; - A six-membered heteroaryl (especially pyridinyl) which is unsubstituted or substituted with one halogen (especially fluoro);

[0045] [ka] (R SX1 -CO-OC 1-4 - Represents alkyl groups. - -CO-R OX1 or -SO2-R OX1 ;(R OX1 Independently, C 1-4 -alkyl; C 1-3 -alkyl, with 1 C 1-3 -alkoxy (especially methoxy), tetrahydropyranyl, morpholine-4-yl, phenyl, 10-membered heteroaryl (especially quinolinyl), or -NR ONX1 R ONX2 (R ONX1 and R ONX2 These are independently hydrogen or C 1-3 - Represents alkyl.) The C substituted by 1-3 -alkyl; -- Tetrahydropyranyl; -- Phenyl, which is unsubstituted or substituted with one or two substituents, wherein the substituents are independently C 1-3 -alkoxy, C 1-3 -Phenyls that are fluoroalkoxy or halogens; -- 5 or 6-membered heteroaryls (especially pyridinyl, pyrazinyl), independently unsubstituted or with one C 1-3 -The 5 or 6-membered heteroaryl substituted with an alkoxy; or, -- Structure (R X-A ) base:

[0046] [ka] (wherein (A) represents a 5 or 6-membered non-aromatic ring condensed to the phenyl group, and ring (A) comprises two heteroatoms independently selected from oxygen and nitrogen; ring (A) is independently unsubstituted or substituted with one substituent, the substituent being oxo and C) 1-3 - Selected independently from alkyl groups. It represents; or, - -CO-OROX2 ;(R OX2 teeth, C 1-4 -alkyl; -- 2,2,2-trichloroethyl; or, -- Tetrahydropyranyl; This represents... This represents...

[0047] [ka] Representing a group selected from; relating to a compound that follows any one of embodiments 1) to 3); The above groups A), B), C), D), E), F), G), and H) each form a specific sub-configuration; in particular, groups A), B), and C) together form another sub-configuration, group D) forms another sub-configuration, and groups E), F), G), and H) together form another sub-configuration. Another specific sub-configuration is formed by groups A), D), E), F), and G).

[0048] 7) Another aspect is R 2 The present invention relates to compounds that follow any one of embodiments 1) to 6) where methyl is represented.

[0049] 8) Another aspect is R 3 This relates to a compound that follows any one of embodiments 1) to 7) where isobutyl is represented.

[0050] 9) Another aspect is R 4 is the base-CO-NH-R 41 Represents; R 41 but, - C 2-6 -alkyl, with 1 C 1-4 -alkoxy (especially methoxy) or C 1-4 -C substituted with fluoroalkoxy (especially difluoromethoxy or trifluoromethoxy) 2-6 -alkyl; - C 1-3 -alkoxy-C 2-3 -Alkilen-O-CH2-CH2-; - -CH2-CH2-C5-6 -A heterocycloalkyl having one ring oxygen atom, and the C 5-6 - Heterocyclyl is unsubstituted or has 1 or 2 C 1-4 - The C substituted with alkyl (especially methyl) 5-6 -heterocycloalkyl; - -L 1 -Aryl;(L 1 -CH2-CH2-, -CH2-CH2-O- * or -CH2-CF2- * -CH2-(cyclopropane-1,1-diyl)- * -CH(CH2-OH)-CH2- * or -CH2-CH(OH)- * It represents; the asterisk is L 1 This indicates a bond that connects to the above aryl; aryl represents phenyl; the aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents, and the substituents are independently C 1-4 -Alkyl (especially methyl, ethyl, tert-butyl), C 1-4 -alkoxy (especially methoxy, ethoxy), C 1-3 -Fluoroalkyl, C 1-3 -Fluoroalkoxy, halogen (especially fluoro, chloro, bromo), cyano, hydroxy-C 1-3 -alkyl, C 2-3 -Alkinyl, Morpholin-4-yl, C 1-3 -alkyl-SO2-, 5 or 6-membered heteroaryl (especially pyrazolyl, triazolyl, pyr) (Midinyl, pyrazinyl) or -NR N41 R N42 (Independently, R N41 is hydrogen or C 1-4 -It is alkyl, R N42 is hydrogen or C 1-4 -It is alkyl. ) It is. ); - -L 2 -HET 1 ;(L 2 -CH2-CH2-, -CH2-CF2- * -CH2-(cyclopropane-1,1-diyl)-* or -CH2-CH(OH)- * It represents; the asterisk is L 2 HET 1 This shows the bond that connects to (especially L 2 represents -CH2-CH2-. );HET 1 is a 5 or 6-membered heteroaryl (in particular thiophenyl, furanyl, thiazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl; or pyridinyl, pyrimidinyl or pyrazinyl), where the 5 or 6-membered heteroaryl is independently unsubstituted or substituted with one or two substituents, where the substituents are independently C 1-4 -Alkyl (especially methyl); C 1-4 -alkoxy (especially methoxy); C 1-3 -Fluoroalkyl;halogen;C 3-6 -Cycloalkyl (especially cyclopropyl); C 3-6 -Cycloalkyl-methyl;C 1-3 -alkoxy-C 1-3 -alkyl;C 2-3 -Alkynnyl, benzyl; or phenyl, which is unsubstituted or substituted with one or two substituents, wherein the substituents are independently C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy) or C 1-4 -It is a phenyl that is a fluoroalkoxy (especially trifluoromethoxy); - -CH2-CH2-HET 2 (HET 2 HET represents a 9 or 10-membered bicyclic heteroaryl (in particular, benzoxazolyl, benzoisoxazolyl, benzofuranil, benzo[d][1,2,3]triazolyl, or [1,2,4]triazolo[1,5-a]pyrimidinil), and the HET 2 It is not substituted. - -CH2-CH2-HCy 1 (HCy 1This represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a 5-7 member saturated heterocycle having one or two heteroatoms independently selected from oxygen and nitrogen, wherein if nitrogen is present and has a free valence, the nitrogen is either unsubstituted or has one carbon atom. 1-4 - Substituted with alkyl (especially methyl); the phenyl ring of the partially aromatic bicyclic ring system is unsubstituted or substituted with one or two substituents, the substituents independently being C 1-4 -Alkyl (especially methyl), C 1-4 -It is an alkoxy (especially methoxy) or halogen (especially chloro, bromo); or, - -CH2-CH2-HCy 2 (HCy 2 This represents a partially aromatic bicyclic ring system consisting of a 5-membered heteroaryl compound fused to a saturated carbon ring of 5-7 members. This relates to a compound that conforms to any one of embodiments 1) to 8).

[0051] 10) Another aspect is R 4 is the base-CO-NH-R 41 Represents; R 41 but, - -L 1 -Aryl;(L 1 is -CH2-CH2- or -CH2-CH2-O- * It represents; the asterisk is L 1 This indicates a bond that connects to the above aryl; aryl represents phenyl; the aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents, and the substituents are independently C 1-4 -Alkyl (especially methyl, ethyl, tert-butyl), C 1-4 -alkoxy (especially methoxy, ethoxy), C 1-3 -Fluoroalkyl, C 1-3 -Fluoroalkoxys, halogens (especially fluoro, chloro, bromo), hydroxy-C 1-3 -alkyl, 5 or 6-membered heteroaryl (especially pyrazolyl, triazolyl, pyrimidinyl, pyrazinyl) or -NR N41 R N42 (Independently, R N41is hydrogen or C 1-4 -It is alkyl, R N42 is hydrogen or C 1-4 -It is alkyl. ) It is. ); - -L 2 -HET 1 ;(L 2 -CH2-CH2-, -CH2-CF2- * or -CH2-CH(OH)- * It represents; the asterisk is L 2 HET 1 This shows a bond that connects to (especially L 2 represents -CH2-CH2-. );HET 1 is a 5 or 6-membered heteroaryl (in particular thiophenyl, furanyl, thiazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl), and the 5 or 6-membered heteroaryl is independently unsubstituted or substituted with one or two substituents, and the substituents are independently C 1-4 -Alkyl (especially methyl, tert-butyl); C 1-4 -alkoxy (especially methoxy); C 1-3 -centre Luoroalkyl; halogen; C 3-6 -Cycloalkyl;benzyl;or phenyl, which is unsubstituted or substituted with one substituent, wherein the substituent is independently C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy) or C 1-4 -It is a phenyl that is a fluoroalkoxy (especially trifluoromethoxy); - -CH2-CH2-HET 2 (HET 2 HET represents a 9 or 10-membered bicyclic heteroaryl (in particular, benzoxazolyl, benzoisoxazolyl, benzofuranil, benzo[d][1,2,3]triazolyl, or [1,2,4]triazolo[1,5-a]pyrimidinil), and the HET 2 It is not substituted. - -CH2-CH2-HCy 1 (HCy 1represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a 5-7 member saturated heterocycle having one or two oxygen atoms; the phenyl ring of the partially aromatic bicyclic ring system is either unsubstituted or substituted with one substituent, the substituent being independently C 1-4 -Alkyl (especially methyl), C 1-4 -It is an alkoxy (especially methoxy) or halogen (especially chloro, bromo); or, - -CH2-CH2-HCy 2 (HCy 2 This represents a partially aromatic bicyclic ring system consisting of a 5-membered heteroaryl compound fused to a saturated carbon ring of 5-7 members. This relates to a compound that conforms to any one of embodiments 1) to 8).

[0052] 11) Another aspect is R 4 is the base-CO-NH-R 41 Represents; R 41 but:

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka] Representing a group selected from; relating to a compound that follows any one of embodiments 1) to 8); The above groups A), B), C), D), E), F), G), H), I), J), K), L), M), N), O), and P) each form a specific sub-configuration; in particular, groups A) and B) together form a specific sub-configuration, and groups D) and E) together form another specific sub-configuration. Another specific sub-configuration is formed by groups A), D), E), and I), particularly A), D), and E). Another specific sub-configuration is formed by groups A), B), D), E), I), and K), particularly A), B), D), and K).

[0059] 12) Another aspect is, Ar 2 The present invention relates to compounds that conform to any one of embodiments 1) to 11) where phenyl is represented.

[0060] 13) Another aspect is, Ar 1 but, - Phenylene or a 5- or 6-membered heteroarylene, independently substituted with one or two substituents, wherein the substituents are C 1-4 -Alkyl (especially methyl), C 1-4 - Phenylene or 5- or 6-membered heteroarylene independently selected from alkoxys (especially methoxy, ethoxy) and halogens (especially fluoro, chloro); - Phenylene condensed to a 5- or 6-membered saturated heterocycle having one or two oxygen atoms, wherein the 5- or 6-membered saturated heterocycle is independently unsubstituted; or, - A bicyclic aromatic ring selected from naphthylene and 8-10 membered bicyclic heteroarylenes; independently, unsubstituted or substituted with one substituent, wherein the substituent is C 1-4 - A bicyclic aromatic ring independently selected from alkyl (especially methyl) and halogen (especially fluoro and chloro); Represents; relating to compounds that conform to any one of embodiments 1) to 12) [the above group Ar 1 In this, -CO- group and oxygen (i.e., Ar 1 The group that connects to the rest of the molecule is Ar 1It shall be bonded in an ortho configuration to the aromatic ring carbon atom.

[0061] 14) Another aspect is, Ar 1 but,

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] [ka] Represents a group selected from; in the above groups, the asterisk represents the group to oxygen (i.e., Ar 1 This refers to a bond that connects to the oxygen that binds to the rest of the molecule; relating to a compound that follows any one of embodiments 1) to 12); The above groups A), B), C), D), E), F), and G) each form a specific sub-mode.

[0066] 15) A second aspect of the present invention relates to a compound of formula (II) for use in the treatment of cystic fibrosis:

[0067] [ka] (In the formula, X, R 1 , R 2 , R 3 , R 4 Ar 2 This is defined independently for the compound of formula (I) in any one of embodiments 1), 2), or 4) to 12); Ar 1 teeth, - Phenylene, specifically unsubstituted phenylene; - 5- or 6-membered heteroarylenes, which are unsubstituted (especially pyridine-3,4-diyl, thiophene-2,3-diyl); - Phenylene or a 5- or 6-membered heteroarylene; independently substituted with 1, 2, or 3 substituents, wherein the substituents are C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy, ethoxy), C 1-3 -Fluoroalkyl, C 1-3 - Phenylene or 5- or 6-membered heteroarylene independently selected from fluoroalkoxy, cyano, and halogen (especially fluoro and chloro); - Phenylene condensed to a 5- or 6-membered saturated heterocycle having 1 or 2 oxygen atoms, wherein the 5- or 6-membered saturated heterocycle is independently unsubstituted or substituted with 2 fluorocarbons; or, - A bicyclic ring selected from naphthylene and 8-10 membered bicyclic heteroarylenes; independently, unsubstituted or substituted with one or two substituents, wherein the substituents are C 1-4 -Alkyl (especially methyl), C 1-3 -Fluoroalkyl, C 1-4 -alkoxy, C 1-3 - The bicyclic ring independently selected from fluoroalkoxy, cyano, and halogen (especially fluoro and chloro); or, - Quinoline-diyl, wherein the quinoline-diyl exists in the form of each N-oxide; the quinoline-diyl N-oxide is unsubstituted or substituted with one methyl or fluoro group; [The above base Ar represents 1 In this, -CO- group and oxygen (i.e., Ar 1 The group that connects to the rest of the molecule is Ar 1 It is assumed that it is bonded in an ortho configuration to the aromatic ring carbon atom.

[0068] 16) Another aspect is, Ar1 The present invention relates to a compound of formula (II) according to embodiment 15) for use in the treatment of cystic fibrosis, in which represents an unsubstituted phenylene; or represents a group as defined in embodiment 13) or 14).

[0069] 17) Further aspects are given by equation (II E The compound is of the form ); relating to the compound of formula (II) for use according to embodiment 15) or 16):

[0070] [ka] Compounds of formula (I) / formula (II) have at least three stereogenic or asymmetric centers that exist in (R)- or (S)- configuration as defined in each embodiment defining such compounds of formula (I) / formula (II). In addition, compounds of formula (I) / formula (II) may have one or more further stereogenic or asymmetric centers, such as one or more further chiral carbon atoms. Thus, compounds of formula (I The compounds of formula (II) may exist as a mixture of stereoisomers, or preferably as pure stereoisomers. The mixture of stereoisomers may be separated by methods known to those skilled in the art. Where the chemical name described indicates that any stereoisomer is in the (RS)-configuration, this means that such stereoisomer in such compound may exist in the (R)-configuration, the (S)-configuration, or in any mixture of epimers relating to such center.

[0071] Therefore, for example, the compound (3S,7S,10RS,13R)-13-benzyl-10-(tert-butoxymethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-3-carboxamide is (3S,7S,10R,13R)-13-benzyl-10-(tert-butoxymethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11 This includes -tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadesine-3-carboxamide, the compound (3S,7S,10S,13R)-13-benzyl-10-(tert-butoxymethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadesine-3-carboxamide, and any mixture thereof. Similarly, in a given chemical structure (as in Tables 3, 4, and 5), a stereo or chiral center labeled "abs" represents that stereo or chiral center in its respective (R)- or (S)- configuration. A stereo or chiral center labeled "&1" represents that stereo or chiral center in its respective (RS)- configuration, i.e., encompassing any mixture of epimers in each (R)- or (S)- configuration.

[0072] The compounds of formula (I) / formula (II) may further include compounds having one or more double bonds, which may exist in Z- and E- configurations, and / or compounds having substituents in the ring system, which may exist in cis- and trans- configurations relative to each other.

[0073] When a particular compound (or comprehensive structure) is described as an (R)- or (S)-enantiomer, such description is understood to mean each compound (or comprehensive structure) in an enriched, particularly essentially pure, enantiomer form. Similarly, when a particular chiral center of a compound is described as being in an (R)- or (S)- configuration, or in a particular relative configuration, such description is understood to mean the compound in an enriched, particularly essentially pure form with respect to each configuration of the chiral center. Similarly, a cis- or trans- description is understood to mean each stereoisomer in an enriched, particularly essentially pure form with respect to each relative configuration. Similarly, when a particular compound (or comprehensive structure) is described as a Z- or E-stereoisomer (or when a particular double bond in a compound is described as being in a Z- or E- configuration), such description is understood to mean each compound (or comprehensive structure) in an enriched, particularly essentially pure, stereoisomer form (or the compound in an enriched, particularly essentially pure form with respect to each configuration of the double bond).

[0074] When the term "enriched" is used in relation to stereoisomers, in the context of this invention, it means that each stereoisomer is present in a ratio of at least 70:30, particularly at least 90:10, relative to the total of the other stereoisomers (i.e., with a purity of at least 70% by weight, particularly at least 90% by weight). It is understood to mean what it signifies.

[0075] When the term "essentially pure" is used in relation to stereoisomers, in the context of this invention, it is understood to mean that each stereoisomer exists in a purity of at least 95 percent by weight, and in particular at least 99 percent by weight, relative to the other stereoisomers / the other respective stereoisomers as a whole.

[0076] The present invention also relates to isotope-labeled, particularly 2This also includes compounds of formula (I) / formula (II) according to H (deuterium) labeled embodiments 1) to 21), and such isotope-labeled compounds are identical to compounds of formula (I) / formula (II), except that one or more atoms are replaced by atoms having the same atomic number but with atomic weights different from those normally found in nature. Isotope-labeled, in particular 2 Compounds of formula (I) / formula (II) labeled with H (deuterium) and salts thereof are included in the scope of the present invention. Where a substituent is specifically described as representing hydrogen, it refers to all isotopes of the atom "H", i.e., the term hydrogen used for a particular substituent refers to all isotopes. 2 It is understood to include H (deuterium); preferably an isotope. 1 It means H (hydrogen). A heavier isotope of hydrogen. 2 Substitution with H (deuterium) increases metabolic stability, which can lead to, for example, a longer in vivo half-life, a reduction in the required dose, or reduced inhibition of cytochrome P450 enzymes, thus improving the safety profile. In one embodiment of the present invention, the compounds of formula (I) / formula (II) are either unlabeled or labeled only by one or more deuterium atoms. In a secondary embodiment, the compounds of formula (I) / formula (II) are not isotopically labeled at all. Isotopically labeled compounds of formula (I) / formula (II) may be prepared in the same manner as described below, except that appropriate reagents or suitable isotopes of the starting materials are used.

[0077] In this patent application, dotted lines represent the bonding points of the described groups. For example, the following groups

[0078] [ka] This is a 2,3-dihydrobenzofuran-2-yl group.

[0079] When the plural form is used for compounds, salts, pharmaceutical compositions, diseases, etc., it is intended to also refer to a single compound, salt, etc.

[0080] Any reference to compounds of formula (I) / formula (II) according to aspects 1) to 21) means the compound in the form of a free base or salt, and therefore, depending on the context, it is understood to also refer to salts of such compounds (especially pharmaceutically acceptable salts).

[0081] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the target compound while exhibiting minimal undesirable toxic effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the target compound. For reference, see, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use," P. Heinrich Stahl, Camille G. Wermuth (Eds.) ), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc See Quere (Eds.), RSC Publishing, 2012.

[0082] The definitions set forth herein apply uniformly to compounds of formula (I) / formula (II) as defined in any one of embodiments 1) to 17), and shall apply throughout this specification and claims with necessary modifications unless a broader or narrower definition is provided by a specific definition. Naturally, a definition or preferred definition of a term may independently (and together with) define and replace any or all of the terms defined herein or each term in a preferred definition.

[0083] Whenever a substituent is described as optional, such substituents may not be present (i.e., each residue is unsubstituted with respect to such optional substituents), in which case all sites with free valence (e.g., ring carbon atoms and / or ring nitrogen atoms in an aromatic ring to which such optional substituents may be attached) are understood to be substituted with hydrogen as appropriate. Similarly, when the term “optional” is used with respect to (ring) heteroatoms, it means that each optional heteroatom etc. is either absent (i.e., a group has no heteroatoms / is a carbocyclic / etc.) or each optional heteroatom etc. is present as explicitly defined.

[0084] The term "halogen" means fluorine / fluoro, chlorine / chloro, or bromine / bromo; preferably fluorine / fluoro or chlorine / chloro.

[0085] The term "alkyl," whether used alone or in combination, refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. x-y The term "alkyl" (where x and y are integers) refers to the previously defined alkyl group having x to y carbon atoms. For example, C 1-6 -Alkyl groups have 1 to 6 carbon atoms. Typical examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, and 3,3-dimethyl-butyl. To avoid any ambiguity, when a group is described as, for example, propyl or butyl, it means that it is n-propyl or n-butyl, respectively. X2 C 1-6 -When referring to an alkyl group, this term is especially C 1-4 -Alkyl, particularly methyl, ethyl, isopropyl, or isobutyl; preferably meaning methyl. 1 ga-C 1-8-When referring to alkyl, this term specifically means methyl or 3,3-dimethylbuta-1-yl; preferably methyl. X C 1-4 -When referring to alkyl groups, this term specifically means methyl, ethyl, isopropyl, or isobutyl. 1-4 -R represents alkyl OX1 Regarding this, the term specifically refers to methyl or isobutyl. 1-4 -R represents alkyl OX2 In this regard, this term specifically means methyl or ethyl. 1-4 -R represents alkyl 2 Regarding this term, it specifically means methyl or ethyl; preferably methyl. 3 ga-C 1-6 -When referring to alkyl, this term specifically means methyl or isobutyl; preferably isobutyl. 1 R 11 C replaced by 1-6 -Alkyl groups, in particular, -(CH2) m -Base (m represents an integer 1 or 2), or one R as explicitly defined. 11 C replaced by 3-6 - This refers to an alkyl group.

[0086] "-C x-y The term "-alkylene-", whether used alone or in combination, refers to the previously defined alkyl group having x to y carbon atoms and bonded bivalently at two points. Preferably, -C 1-y - The alkylene group's bonding site is in a 1,1-diyl, 1,2-diyl, or 1,3-diyl configuration.

[0087] The alkylene group (or substituted alkyl group) connecting the two heteroatoms is preferably separated from the heteroatoms by at least two carbon atoms.

[0088] The term "alkoxy," whether used alone or in combination, refers to an alkyl-O- group, where alkyl is defined as previously defined. x-y The term "alkoxy" (where x and y are integers) refers to the previously defined alkoxy group having x to y carbon atoms. For example, C 1-4 -Alkyl is "C 1-4 The term "-alkyl" has the meaning described above, formula C 1-4 This refers to an alkyl-O- group. Typical examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Methoxy is preferred.

[0089] The term "fluoroalkyl," whether used alone or in combination, refers to the previously defined alkyl group having 1 to 3 carbon atoms, in which one or more (and possibly all) hydrogen atoms are replaced by fluorine. x-y The term "-fluoroalkyl" (where x and y are integers) refers to the previously defined fluoroalkyl group having x to y carbon atoms. For example, C 1-3 -Fluoroalkyl groups have 1 to 3 carbon atoms and 1 to 7 hydrogen atoms replaced by fluorine. Typical examples of fluoroalkyl groups include C1-fluoroalkyls such as trifluoromethyl and difluoromethyl, as well as 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. X2 C 1-4 -When referring to fluoroalkyl groups, this term specifically means 2,2-difluoroethyl or 2,2,2-trifluoroethyl.

[0090] "-C x-y The term "fluoroalkylene," whether used alone or in combination, refers to the previously defined fluoroalkyl group having x to y carbon atoms bonded at two points.

[0091] The term "fluoroalkoxy," whether used alone or in combination, refers to the previously defined alkoxy group having 1 to 3 carbon atoms, in which one or more (and possibly all) hydrogen atoms are replaced by fluorine. x-y The term "-fluoroalkoxy" (where x and y are integers) refers to the previously defined fluoroalkoxy group having x to y carbon atoms. For example, C 1-3 -Fluoroalkoxy groups have 1 to 3 carbon atoms and 1 to 7 hydrogen atoms are replaced by fluorine. Typical examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. Preferably, (C1) fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy are used.

[0092] The term "alkynyl," whether used alone or in combination, refers to a straight or branched hydrocarbon chain having 2 to 4 carbon atoms and 1 carbon-carbon triple bond. x-y The term "-alkynyl" (where x and y are integers) refers to the previously defined alkynyl group having x to y carbon atoms. For example, C 2-4 - The alkynyl group has 2 to 4 carbon atoms. 3 ga-C 2-4 -When referring to alkinyl, this term specifically means propa-1-in-3-yl. 2-3 - An example of an alkynyl is ethynyl.

[0093] The term "cycloalkyl," whether used alone or in combination, specifically refers to a saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms. x-y The term "cycloalkyl" (where x and y are integers) refers to the previously defined cycloalkyl group having x to y carbon atoms. For example, C 3-6- The cycloalkyl group has 3 to 6 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. R X2 When R 3-6 represents C 11 -cycloalkyl, this term preferably means cyclopropyl, cyclobutyl or cyclopentyl. R 3-6 When R

[0094] represents C x-y -cycloalkylene-, this term, whether used alone or in combination, means a cycloalkyl group having x to y carbon atoms and bonded at two positions, as defined above. Preferably, the bonding points of any cycloalkyl group bonded at two positions are in a 1,1-diyl configuration. Examples are cyclopropane-1,1-diyl, cyclobutane-1,1-diyl and cyclopentane-1,1-diyl; preferably cyclopropane-1,1-diyl.

[0095] Examples of C 3-6 -cycloalkan-1,1-diyl- are cyclopropane-1,1-diyl, cyclobutane-1,1-diyl and cyclopentane-1,1-diyl. Examples of C 5-6 -cycloalkan-1,1-diyl- groups fused to a benzene ring are 1,3-dihydro-2H-inden-2,2-diyl.

[0096] The term "heterocycloalkyl", whether used alone or in combination, means a monocyclic saturated hydrocarbon ring having 1 or 2 ring heteroatoms independently selected from nitrogen, sulfur and oxygen, unless a broader or narrower definition is explicitly indicated. The term "C x-y -heterocycloalkyl" means such a heterocycle having x to y ring atoms. Examples are tetrahydrofuranyl, tetrahydropyranyl and piperidinyl. The heterocycloalkyl group is unsubstituted or substituted as explicitly defined. R11 When representing a 5- or 6-membered saturated heterocycloalkyl having 1 or 2 ring heteroatoms, this term particularly means tetrahydropyranyl and tetrahydrofuranyl. C 5-6 Examples of C

[0097] “C 4-6 -heterocycloalkanediyl having one ring oxygen atom, the C 4-6 -heterocycloalkanediyl” means a heterocycloalkyl group bonded at two positions having one ring oxygen atom and the remaining ring carbon atoms. “C 4-6 -heterocycloalkanediyl having one ring oxygen atom, the C 4-6 -heterocycloalkanediyl” example is tetrahydropyran-4,4-diyl. “C 4-6 -heterocycloalkanediyl having one ring nitrogen atom, the C 4-6 -heterocycloalkanediyl” means a heterocycloalkyl group bonded at two positions having one ring nitrogen atom and the remaining ring carbon atoms. “C 4-6 -heterocycloalkanediyl having one ring nitrogen atom, the C 4-6 -heterocycloalkanediyl” example is piperidine-4,4-diyl.

[0098] The term “aryl” means phenyl or naphthyl, particularly phenyl, whether used alone or in combination. The above aryl groups are unsubstituted or substituted as explicitly defined.

[0099] For example, a heterocycle “having 1 or 2 heteroatoms independently selected from oxygen and nitrogen” or “having one oxygen atom” has exactly the indicated number and types of heteroatoms, and unless otherwise explicitly stated, the remaining ring atoms are carbon atoms.

[0100] The substituent "HCy" represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a 5-7 member saturated heterocycle having one or two heteroatoms independently selected from oxygen and nitrogen. 1 Examples of "" include benzodioxolyl, dihydrobenzofuranil, dihydrobenzodioxynyl, chromanil, tetrahydrobenzooxepinyl, dihydrobenzooxazinyl; more specifically, benzo[d][1,3]dioxol-5-yl, 1,3-dihydroisobenzofuran-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[b][1,4]dioxin-2-yl, croman-6-yl, croman-7-yl, 2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, and 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl. The above HCy 1 The base is either unsubstituted or substituted as explicitly defined.

[0101] The substituent "HCy" represents a partially aromatic bicyclic ring system consisting of a 5-membered heteroaryl compound fused to a saturated carbon ring of 5 to 7 members. 2 A preferred example of this is 5,6-dihydro-4H-cyclopenta[d]thiazole-2-yl.

[0102] The substituent "HCy" represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a saturated heterocycle with 5-7 members and one oxygen atom. 3 A preferred example of this is chroman-3-yl.

[0103] Base Ar 1 / fragment:

[0104] [ka] Examples include: - Phenylene or 5- or 6-membered heteroarylenes (e.g., thiophene-diyl, thiazole-diyl, or pyridine-diyl); - Phenylene condensed into a 5- or 6-membered saturated heterocycle having one or two oxygen atoms (e.g., benzo[d][1,3]dioxol-diyl or 2,3-dihydrobenzofuran-diyl); - Bicyclic aromatic rings selected from naphthylene and 8-10 membered bicyclic heteroarylenes (e.g., naphthalene-diyl, benzofuran-diyl, benzo[d]oxazole-diyl, benzo[d]isoxazole-diyl, imidazo[1,2-a]pyridine-diyl, 1H-indazole-diyl, 1H-benzo[d]imidazole-diyl, quinoline-diyl, or isoquinoline-diyl); and - Quinoline diyl, which exists in the form of each N-oxide (e.g., quinoline-1-oxide-diyl); That is the case.

[0105] Base Ar 1 Examples include, in particular, Ar 1 The -CO- group and oxygen (i.e., Ar) are bonded in an ortho configuration to the carbon atom of the aromatic ring. 1 Those that include a group that connects to the rest of the molecule, especially those mentioned above. In addition, the group Ar 1 It is either left unsubstituted or substituted as explicitly defined.

[0106] Fragment:

[0107] [ka] Specific examples include: - Phenylene or 5- or 6-membered heteroarylenes (e.g., 1,2-phenylene, thiophene-2,3-diyl, thiazole-4,5-diyl, pyridine-3,4-diyl, or pyridine-2,3-diyl); - Phenylene condensed into a 5- or 6-membered saturated heterocycle having one or two oxygen atoms (e.g., benzo[d][1,3]dioxol-4,5-diyl, benzo[d][1,3]dioxol-5,6-diyl, 2,3-dihydrobenzofuran-6,7-diyl, or 2,3-dihydrobenzofuran-4,5-diyl); - Bicyclic aromatic rings selected from naphthylenes and 8-10 membered bicyclic heteroarylenes (e.g., naphthalene-1,2-diyl, naphthalene-2,3-diyl, benzofuran-6,7-diyl, benzo[d]oxazole-4,5-diyl, benzo[d]oxazole-5,6-diyl, benzo[d]oxazole-6,7-diyl, benzo[d]isoxazole-6,7-diyl, imidazo[1,2-a]pyridine-2,3-diyl, 1H-indazole-4,5-diyl, 1H-benzo[d]imidazole-6,7-diyl, quinoline-7,8-diyl, quinoline-3,4-diyl, quinoline-5,6-diyl, isoquinoline-3,4-diyl, or isoquinoline-5,6-diyl); - Quinoline diyl, which exists in the form of each N-oxide (e.g., quinoline-1-oxide-3,4-diyl or quinoline-1-oxide-5,6-diyl); That is the case.

[0108] The above base Ar 1 It is either left unsubstituted or substituted as explicitly defined.

[0109] The term "heteroaryl," whether used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring having 1 to 4 heteroatoms, each independently selected from oxygen, nitrogen, and sulfur, unless a broader or narrower definition is explicitly stated. Typical examples of such heteroaryl groups include 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridadinyl, and pyrazinyl; and indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, and be These are 8- to 10-membered bicyclic heteroaryl groups such as nzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthilidinyl, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrrolopyradinyl, imidazopyridinyl, imidazopyridadinyl, and imidazothiazolyl. The above heteroaryl groups are either unsubstituted or substituted as explicitly defined.

[0110] R OX1 When this term refers to a 5- or 6-membered heteroaryl, it specifically means a 6-membered heteroaryl (e.g., pyrazinyl or pyridinyl) having one or two nitrogen atoms. do.

[0111] The substituent HET represents a "5 or 6-membered heteroaryl." 1In this regard, this term particularly means the above-mentioned 5 or 6-membered groups such as pyridinyl, pyrimidinyl, pyrazinyl, furanyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or thiophenyl. In particular, this term refers to five-membered groups such as thiophen-2-yl, thiazole-2-yl, thiazole-4-yl, 1,2,3-triazole-4-yl, 1,2,4-triazole-3-yl, fran-2-yl, isothiazole-5-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, 1,2,4-oxadiazole-5-yl, 1,2,4-oxadiazole-3-yl, 2H-[1,2,3]triazole-2-yl, 2H-[1,2,3]triazole-4-yl, and 2H-tetrazole-2-yl; and especially to six-membered groups such as pyridine-2-yl, pyridine-4-yl, pyrazine-2-yl, pyrimidine-4-yl, and pyrimidine-5-yl. The above base is replaced to be explicitly defined.

[0112] Substituent Ar represents "5 or 6-membered heteroaryl" 2 In this regard, this term specifically refers to pyridinyl, and more particularly pyridine-2-yl.

[0113] The substituent HET represents a "9 or 10-membered bicyclic heteroaryl." 2 In this regard, the term specifically means benzoxazolyl, benzoisoxazolyl, and benzofuranil; as well as benzo[d][1,2,3]triazolyl or [1,2,4]triazolo[1,5-a]pyrimidinyl. The above groups are either unsubstituted or substituted as explicitly defined. Specific examples include benzofuran-6-yl, benzoisoxazole-3-yl, benzoxazole-2-yl, and in addition, 2H-benzo[d][1,2,3]triazol-2-yl and [1,2,4]triazolo[1,5-a]pyrimidin-2-yl.

[0114] Substituent Ar representing "9 or 10-membered heteroaryl"2 In this context, this term specifically refers to benzothiophenyl, and more particularly benzothiophen-3-yl.

[0115] Regarding the substituent HET representing "5- to 10-membered heteroaryl," this term means, in particular, the 5 or 6-membered heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group as defined above; in particular, pyridinyl, pyrimidinyl, pyrazinyl, furanil, pyrazolyl, triazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiophenyl or benzoxazolyl, benzoisoxazolyl, benzofuranil; or, in addition, benzo[d][1,2,3]triazolyl or [1,2,4]triazolo[1,5-a]pyrimidinyl. The above groups are either unsubstituted or substituted as explicitly defined.

[0116] Substituent Ar representing a 5- to 10-membered heteroaryl X2 Such heteroaryls are as previously defined; in particular, a 5- or 6-membered monocyclic heteroaryl [in particular a 5-membered heteroaryl having 1 to 3 heteroatoms selected from oxygen and nitrogen (especially oxadiazolyl, triazolyl, or isoxazolyl); or a 6-membered heteroaryl having 1 or 2 nitrogen atoms (especially pyridinyl)] represents such monocyclic heteroaryl, either unsubstituted or substituted as explicitly defined; or an 8- to 10-membered bicyclic heteroaryl [in particular a 10-membered heteroaryl having 1 nitrogen atom (especially quinolinyl)] represents such bicyclic heteroaryl, either unsubstituted or substituted as explicitly defined. Substituents Ar representing 5- to 10-membered heteroaryls X2 Specific examples include 3-phenyl-[1,2,4]-oxadiazole-5-yl, 3-(5-fluoropyridine-2-yl)-[1,2,4]-oxadiazole-5-yl or 3 It is trifluoromethyl-[1,2,4]-oxadiazole-5-yl.

[0117] Substituent Ar representing a 5- or 6-membered heteroaryl X3Regarding such heteroaryls, in particular a six-membered heteroaryl having one or two nitrogen atoms, especially pyridinyl; such five or six-membered heteroaryls are unsubstituted or substituted as explicitly defined. A specific example is 5-fluoropyridine-2-yl.

[0118] Fragment:

[0119] [ka] Examples include 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and 2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl.

[0120] The term "cyano" means the base -CN.

[0121] The term "oxo" refers to a group = O that is bonded to a carbon atom, preferably in a chain or ring, such as a carbonyl group -(CO)-.

[0122] In some cases, compounds of formula (I) / formula (II) may include tautomers. Such tautomers are included within the scope of the present invention. If a tautomer exists at a particular residue and only one form of such residue is disclosed or defined, other tautomers shall be encompassed by such disclosed residue. For example, the 2-oxo-2,3-dihydrobenzo[d]oxazole-yl group shall also encompass its tautomer, (2-hydroxybenzo[d]oxazole-yl).

[0123] Whenever the word "between" is used to describe a range of numbers, the endpoints of the indicated range are explicitly included within that range. For example, if the temperature range is described as being between 40°C and 80°C, it means that the endpoints, 40°C and 80°C, are included within that range; or if a variable number is defined as an integer between 1 and 4, it means that the variable number is the integer 1, 2, 3, or 4.

[0124] Where not used in relation to temperature, the term "about" placed before a number "X" means in this application between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X. In specific cases of temperature, the term "about" placed before a temperature "Y" means in this application between Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C. Furthermore, as used herein, the term "room temperature" means a temperature of about 25°C.

[0125] 18) Another embodiment is the compound (disclosed in the section on experiments below) in the Examples: 1;2;3;4;5;6;7;8;9;10;11;12;13;14;15;16;17;18;19;20;21;22;23;24;25;26;27;28;29;30;31;32;33;34;35;36;37;38;39;40;41;42;43; 44;45;46;47;48;49;50;51;52;53;54;55;56;57;58;59;60;61;62;63;64;65;66;67;68;69;70;71;72;73;74;75;76;77;78;79;80;81;82;83;84;85;86;87;88;89;90;91;92;93;94;95;96;97;98;99;100;101;102;103;104;105;106;107;108;109;110;111;112;113;114;115;116;117;118;119;120;121;122;123;124;125;126;127;128;129;130;131;132;133;134;135;136;137;138;139;140;141;142;143;144;145;146;147;148;149;150;151;152;153;154;155;156;157;158;159;160;161;162;163;164;165;166;167;168;169;170;171;172;173;174;175;176;177;178;179;180;181;182;183;184;185;186;187;188;189;190;191;192;193;194;195;196;197;198;199;200;201;202;203;204;205;206;207;208;209;210;211;212;213;214;215;216;217;218;219;220;221;222;223;224;225;226;227;228;229;230;231;232;233;234;235;236;237;238;239;240;241;242;243;244;245;246;247;248;249;250;251;252;253;254;255;256;257;258;259;260;261;262;263;264;265;266;267;268;269;270;271;272;273;274;275;276;277;278;279;280;281;282;283;284;285;286;287;288;289;290;291;292;293;294;295;296;297;298;299;300;301;302;303;304;305;306;307;308;309;310;311;312;313;314;315;316;317;318;319;320;321;322;323;324;325;326;327;328;329;330;331;332;333;334;335;336;337;338;339;340;341;342;343;344;345;346;347;348;349;350;351;352;353;354;355;356;357;358;359;360;361;362;363;364;365;366;367;368;369;370;371;372;373;374;375;376;377;378;379;380;381;382;383;384;385;386;387;388;389;390;391;392;393;394;395;396;397;398;399;400;401;402;403;404;405;406;407;408;409;410;411;412;413;414;415;416;417;418;419;420;421;422;423;424;425;426;427;428;429;430;431;432;433;434;435;436;437;438;439;440;441;442;443;444;445;446;447;448;449;450;451;452;453;454;455;456;457;458;459;460;461;462;463;464;465;466;467;468;469;470;471;472;473;474;475;476;477;478;479;480;481;482;483;484;485;486;487;488;489;490;491;492;493;494;495;496;497;498;499;500;501;502;503;504;505;506;507;508;509;510;511;512;513;514;515;516;517;518;519;520;521;522;523;524;525;526;527;528;529;530;531;532;533;534;535;536;537;538;539;540;541;542;543;544;545;546;547;548;549;550;551;552;553;554;555;556;557; 558;559;560;561;562;563;564;565;566;567;568;569;570;571;572;573;574;575;576;577;578;579;580;581;582;583;584;585;586;587;588;589;590;591;592;593;594;595;596;597;598;599;600;601;602;603;604;605;606;607;608;609;610;6 11;612;613;614;615;616;617;618;619;620;621;622;623;624;625;626;627;628;629;630;631;632;633;634;635;636;637;638;639;640;641;642;643;644;645;646;647;648;649;650;651;652;653;654;655;656;657;658;659;660;661;662;663;66 4;665;666;667;668;669;670;671;672;673;674;675;676;677;678;679;680;681;682;683;684;685;686;689;690;691;692;693;694;695;696;697;698;699;700;701;702;703;704;705;706;707;708;709;710;711;712;713;714;715;716;717;718;719 The present invention relates to a compound of formula (I) according to embodiment 1), selected from the compounds of 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, and 764.

[0126] 19) In addition to the compounds described in Embodiment 18), further compounds of formula (I) according to Embodiment 1) are (disclosed in the Experiments section below) Examples: 765;766;767;768;769;770;771;772;773;774;775;776;777;778;779;780;781;782;783;784;785;786;787;788;789;790;791;792;793;794;795;796;797;798; Selected from compounds 799;800;801;802;803;804;805;806;807;808;809;810;811;812;813;814;815;816;817;818;819;820;821;822;823;824;825;826;827;828; and 829. 20) In addition to the compounds described in aspects 18) and 19), further compounds of formula (I) according to aspect 1) are shown in the examples (disclosed in the Experiments section below): 830;831;832;833;834;835;836;837;838;839;840;841;842;843;844;845;846;847;848;849;850;851;852;853;854;855;856;857;858;859;860;861;862;863;864;865;866;867;868;8 69;870;871;872;873;874;875;876;877;878;879;880;881;882;883;884;885;886;887;888;889;890;891;892;893;894;895;896;897;898;899;900;901;902;903;904;905;906;907;90 8;909;910;911;912;913;914;915;916;917;918;919;920;921;922;923;924;925;926;927;928;929;930;931;932;933;934;935;936;937;938;939;940;941;942;943;944;945;946;947 Selected from compounds 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, and 983. 21) Another embodiment is the compound (disclosed in the section on experiments below) Examples: 72;127;131;132;140;171;256;275;276;281;282;315;316;355;372;374;379;380;381;383;389;391;393;395;509;524;538;539;548;563;571;578;610;613;617;618;637 ;640;641;655;660;665;672;673;682;692;693;697;713;714;716;717;719;721;722;724;769;778;791;794;795;801;804;808;809;811;813;815;820;822;827;829;838;8 39;840;843;849;851;853;854;855;856;858;859;865;867;868;871;873;874;875;876;878;879;880;883;884;885;886;887;889;890;895;897;898;902;903;908;909;918 The present invention relates to a compound of formula (I) according to embodiment 1), selected from the compounds of 919, 923, 924, 927, 930, 934, 935, 936, 937, 941, 944, 945, 948, 949, 960, 962, 964, 965, 966, 967, 969, 970, 972, 973, 975, 978, 980, and 981.

[0127] To avoid any doubt, the chemical names of the example compounds described in aspects 18), 19), and 21) are disclosed in the experimental section; the corresponding structures of the example compounds are shown in Tables 3, 4, or 5 below, and in case of any doubt, the shown structure shall prevail.

[0128] Therefore, for example, the compound of Example 713: (3S,7S,10R,13R)-13-benzyl-10-((benzyloxy)methyl)-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadesine-3-carboxamide has the structure shown in Table 3, and the compound is in the absolute configuration described:

[0129] [ka] Similarly, the compound of Example 724: (3R,6RS,9S,13S)-3-benzyl-6-((benzyloxy)methyl)-N-(2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadesine-13-carboxamide has the structure shown in Table 3, and with respect to the chiral centers at carbon atoms 3, 9 and 13, the compound is in the absolute configuration described; with respect to the chiral center at carbon atom 6, (marked with &1) in that chiral... The absolute configuration of the mind can be either (R) or (S):

[0130] [ka] Similarly, the compound of Example 769: (9S,13S,19aR,22R)-22-benzyl-5-fluoro-13-isobutyl-N-(2-(3-methoxyisoxazole-5-yl)ethyl)-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacycloheptadesino[16,17-f]quinoline-9-carboxamide has the structure shown in Table 4, and the compound is in the absolute configuration described:

[0131] [ka] Similarly, the compound of Example 820: (3R,6R,9S,13S)-3-benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)ethyl)-9-isobutyl-16-methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadesine-13-carboxamide has the structure shown in Table 4, and the compound is in the absolute configuration described:

[0132] [ka] Compounds of formula (I) / formula (II) according to embodiments 1) to 21) and pharmaceutically acceptable salts thereof can be used as pharmaceuticals, for example, in the form of pharmaceutical compositions for enteral administration (e.g., in the form of tablets or capsules, particularly orally) or parenteral administration (including topical application or inhalation).

[0133] The manufacture of the pharmaceutical composition may be carried out by methods well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]), by combining the compounds of formula (I) / formula (II) described above or pharmaceutically acceptable salts thereof, optionally with other therapeutically beneficial substances, with a suitable non-toxic, inert, therapeutically compatible solid or liquid carrier material and, if necessary, a conventional pharmaceutical adjuvant, to form a pharmaceutical dosage.

[0134] The present invention also relates to a method for preventing or treating a disease or disorder described herein, comprising administering to a subject a pharmaceutically effective amount of a compound of formula (I) / formula (II) according to embodiments 1) to 21).

[0135] Compounds of formula (I) / formula (II) according to aspects 1) to 21) are useful for the treatment of CFTR-related diseases and disorders, particularly cystic fibrosis.

[0136] CFTR-related diseases and disorders may be defined to include cystic fibrosis in particular, as well as further CFTR-related diseases and disorders selected from the following: - Chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral vas deferens aplasia (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis deficiencies such as protein C deficiency; and diabetes mellitus. - Asthma; COPD; smoking-induced COPD; and dry eye diseases; and - Idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; especially I-cell disease; pseudo-Hurler's lysosomal storage disorders; mucopolysaccharidosis; Sandhoff / Tay-Sachs disease; osteogenesis imperfecta; Fabry disease; Sjögren's disease; osteoporosis; osteopenia; bone healing and bone growth (including bone repair, bone regeneration, decreased bone resorption and increasing bone deposition); chloride channelopathies such as congenital myotonia (Thomson and Becker forms); Bartter's syndrome type 3; epilepsy; lysosomal storage disorders; primary ciliary dysplasia (PCD) - a term for genetic disorders of ciliary structure and / or function (Kartagener syndrome) This includes PCD with situs inversus, PCD without situs inversus, and ciliary aplasia, also known as PCD syndrome. Generalized epilepsy with febrile seizures plus (GEFS+); generalized epilepsy with febrile and afebrile seizures; myotonia; congenital paramyotonia; potassium-aggravated myotonia; hyperkalemic periodic paralysis; long QT syndrome (LQTS); LQTS / Brugada syndrome; autosomal dominant LQTS with hearing loss; autosomal recessive LQTS; LQTS with dysmorphic features; congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteopetrosis; and Bartter syndrome type 3.

[0137] The term "treatment of cystic fibrosis" means any treatment of cystic fibrosis, and in particular includes treatments that reduce the severity of cystic fibrosis and / or reduce the symptoms of cystic fibrosis.

[0138] The term “cystic fibrosis” means any type of cystic fibrosis, in particular cystic fibrosis associated with one or more gene mutations. Preferably, such cystic fibrosis is associated with impaired CFTR trafficking (class II mutation) or reduced CFTR stability (class VI mutation) [particularly CFTR trafficking impairment / class II mutation], and such impaired CFTR trafficking or reduced CFTR stability may be associated with another disease-causing mutation of the same or any other class. Such further disease-causing CFTR gene mutations include class I mutations (loss of functional CFTR protein), (further) class II mutations (CFTR trafficking impairment), class III mutations (CFTR dysregulation), class IV mutations (CFTR conductance impairment), class V mutations (reduced CFTR protein due to splicing impairment), and / or (further) class VI mutations (reduced CFTR protein due to reduced CFTR stability). The one or more gene mutations include, for example, F508del, A561E, and N1303K, and at least one mutation selected from I507del, R560T, R1066C, and V520F; in particular, F508del may be included. In addition to the above, further CFTR gene mutations include, for example, G85E, R347P, L206W, and M1101K. The gene mutations may be heterozygous, homozygous, or compound heterozygous. In particular, the gene mutation is heterozygous with one F508del mutation. Further CFTR gene mutations (particularly class III and / or IV mutations) include G551D, R117H, D1152H, A455E, S549N, R347H, S945L, and R117C.

[0139] The severity of specific gene mutations associated with cystic fibrosis and the effectiveness of their correction can generally be measured by testing chloride transport performed by CFTR. For example, the mean sweat chloride content of patients. Ride content may be used in such evaluations.

[0140] The term “symptoms of cystic fibrosis” specifically refers to elevated chloride levels in sweat; symptoms of cystic fibrosis also include chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral vas deferens aplasia (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation and fibrinolytic defects such as protein C deficiency; and / or diabetes mellitus.

[0141] To avoid any doubt, if a compound is described as useful for the treatment of a certain disease, then such a compound is also suitable for use in the manufacture of a medicine for the treatment of that disease. Similarly, such a compound is also suitable in a method for the treatment of such disease, which involves administering an effective amount of such compound to a subject in need.

[0142] As used herein, the term “subject” means mammals, in particular humans.

[0143] The present invention further relates to a method for treating cystic fibrosis comprising administering an effective amount of a macrocyclic compound (particularly a 17 or 18-membered macrocyclic compound) or a pharmaceutically acceptable salt thereof to a subject in need; the cyclic core of the macrocyclic compound having one aromatic moiety (e.g., an arylene or a 5-10 membered heteroarylene), wherein the aromatic moiety is particularly connected to the rest of the molecule / ring members of the macrocyclic compound via (i) a carbonyl group and (ii) A arylene or 5-10 membered heteroarylene, etc., bonded via an oxygen atom, in particular, in which the carbonyl group and the oxygen atom are bonded to the aromatic moiety in a 1,2-diyl or 1,3-diyl relationship, at least one beta-amino acid (in particular, the beta-amino acid is bonded to the carbonyl group bonded to the aromatic moiety via its amino group), and at least one N-alkylated alpha-amino acid (in particular, the N-alkylated alpha-amino acid is bonded to the carbonyl group of the beta-amino acid via its N-alkylated amino group, in particular, Such alpha-amino acids are glycine or natural or non-natural amino acids having hydrocarbon substituents; the macrocyclic compound is a collector of class II mutations in human CFTR (in particular, the folding, stability, degradation and / or trafficking of the CFTR, especially human F508del-CFTR, are modified), and preferably, the activity of the CFTR is modified to at least the same effect as that which can be achieved using lumacaftor (the activity / effect may be tested according to the methods disclosed in the Experiments section below).

[0144] Furthermore, any suitability and (sub)aspects shown for the compound of formula (II) (whether relating to the compound itself, its salts, compositions containing the compound or its salts, or the use of the compound or its salts, etc.) can be applied to the compound of formula (I) with necessary modifications.

[0145] Preparation of the compounds of formula (I) / formula (II): Formula (I), Formula (II), Formula (I E ), formula (IIE The compounds of ) can be prepared by well-known literature methods, by the methods described below, by the methods described in the experimental section below, or by similar methods. The optimal reaction conditions vary depending on the specific reactants or solvents used, but such conditions can be determined by routine optimization procedures by those skilled in the art. In some cases, the reaction scheme and / or the order of the reaction steps described below may be modified to facilitate the reaction or to avoid undesirable reaction products. In the general reaction sequence outlined below, the comprehensive group, R 1 , R 2 , R 3 , R 4 Ar 1 and Ar 2 is equation (I), equation (II), equation (I E ), formula (II E ) As stated herein, other abbreviations are either expressly defined or as defined in the Experimental section. In some cases, the comprehensive group, R 1 , R 2 , R 3 , R 4 Ar 1 and Ar 2 The preparation method illustrated in the scheme below may not be suitable, and the use of protecting groups (PGs) may be necessary. The use of protecting groups is well known in the art (see, for example, "Protective Groups in Org. Synthesis," TW Greene, PGMWuts, Wiley-Interscience, 1999). For this purpose, we assume that such protecting groups are introduced as needed. In some cases, the final product may be further modified, for example, by manipulating substituents to obtain new final products. Such manipulations include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and transition metal-catalyzed cross-coupling reactions, which are well known to those skilled in the art. The resulting compounds may be converted to salts, in particular pharmaceutically acceptable salts, by methods known in themselves.

[0146] Formulas (I), (II), and (I) of the present invention E ) and formula (II E The compounds can be prepared according to the general reaction sequence outlined below.

[0147] The compound of formula (I) is prepared according to one of the schemes shown below.

[0148] [ka] Reaction Scheme A: Synthesis can be carried out using racemic or enantiomer-enriched amino acid building blocks. Appropriately protected amine building block A and acid B-acid, prepared according to the literature or the procedures well described in Reaction Schemes I and J respectively, are treated with peptide coupling reagents such as HATU, COMU, T3P, PyBop, or EDCI / HOBt in a solvent such as THF, DMF, or NMP, in the presence of a base such as TEA or DIPEA, at a temperature between -20°C and +75°C, preferably at RT, to produce the corresponding amide intermediate AB. Deprotection of the amine functional group of intermediate AB is carried out according to methods known to those skilled in the art, for example, by treatment with 4M HCl in dioxane or preferably TFA in the case of a Boc protecting group, or by treatment with piperidine or diethylamine in the case of an Fmoc protecting group, or by appropriate treatment in the case of other protecting groups such as Cbz or Alloc protecting groups. Next, the deprotected intermediate AB-amine is subjected to appropriately protected acid C (as described in the section on literature or experiments). The intermediates are then reacted according to the peptide coupling conditions described above for the formation of the AB intermediate. Next, the resulting linear intermediate ABC is deprotected before the final peptide coupling macrolactamization. In some cases, the protecting groups PG1 and PG3 are removed sequentially, but preferably, they are removed simultaneously in a single step. For example, tThe Bu ester and Boc protecting groups are removed by treatment with 4M HCl in dioxane, preferably TFA, or the allyl ester and Alloc protecting groups can be removed by palladium catalytic treatment, as widely reported in the literature. The linear ABC deprotection intermediate is then cyclized under standard conditions, i.e., this intermediate can be treated with a coupling reagent such as COMU, T3P, PyBop, EDCI / HOBt, or preferably HATU, in the presence of a base such as TEA or DIPEA, at a temperature between -20°C and +75°C, preferably RT, under dilution conditions such as a solution of less than 0.1M of the ABC starting material in a solvent such as DMF or NMP, or a mixture of solvents such as DMF / DCM (1:1), at a temperature between -20°C and +75°C, preferably RT, to produce the corresponding macrocyclic compound cABC. Depending on the properties of the different residues, several further deprotection steps may be required to produce the final product. The target compound is obtained as a pure stereoisomer by final purification by preparative HPLC using standard reversed-phase HPLC, or if necessary, a chiral-phase column.

[0149] Reaction Scheme B: A variation of Reaction Scheme A, in which the C portion can be introduced stepwise, one amino acid at a time. The AB intermediate and the first amino acid D-1 (which is commercially available or can be produced according to the literature or the procedure described in the Experiment section below) described in Reaction Scheme A are treated according to the peptide coupling conditions described above to form the corresponding peptide bond. Selective deprotection of the amine functional group of ABD-1 is obtained by removing the Fmoc group by treatment with piperidine or diethylamine, or by removing the Cbz protecting group by hydrocracking on a catalyst such as Pd / C or Pd(OH)2 / C in a solvent such as SiO, THF, or dioxane, or preferably by removing the Boc protecting group by treatment with 4M HCl or TFA in dioxane, respectively, to obtain a free amine or its ammonium salt, which can be coupled with the second amino acid D-2 in a similar peptide coupling step. The three coupling / deprotection / coupling steps described above yield the same linear intermediate ABC as described in Reaction Scheme A. The remaining steps of the synthesis to obtain the desired macrocyclic compound cABC are the same as those described above.

[0150] [ka]

[0151] [ka] Reaction scheme C: A sequence for producing the linear intermediate ABC using an alternative approach. The following can be modified: The appropriately protected component C and the amine B-amine (prepared according to the procedures described in the literature or in reaction schemes K and J, respectively) are treated with reagents such as HATU, COMU, T3P, PyBop, or EDCI / HOBt in a solvent such as THF, DMF, or NMP, in the presence of a base such as TEA or DIPEA, at a temperature between -20°C and +75°C, preferably at RT, according to the peptide coupling conditions described above. Deprotection of the acid functional group of intermediate BC, i.e., removal of PG4, is carried out according to methods known to those skilled in the art, for example, for methyl or ethyl esters, by treatment with NaOH or LiOH in an aqueous methanol solution at a temperature in the range of 0°C to 50°C, or preferably for benzyl esters, by hydrocracking on a catalyst such as Pd / C or Pd(OH)2 / C in a solvent such as SiO, THF, or dioxane. Next, the deprotected intermediate BC-acid is reacted with a properly protected amine component A (prepared according to the procedure described in the literature or Reaction Scheme I) under the peptide coupling conditions described above. The resulting linear ABC can then be deprotected and cyclized to produce the final product cABC as described in Reaction Scheme A.

[0152] [ka] Reaction Scheme D: Similar to the transition from Reaction Scheme A to Reaction Scheme B, the C portion of Reaction Scheme C can be introduced stepwise, one amino acid at a time. The appropriately protected acid D-1 and the amine B-amine (prepared according to the procedure described in the Literature or Experiment section or Reaction Scheme J) are treated according to the peptide coupling conditions described above. Selective deprotection of the amine functional group of BD-1, i.e., removal of PG5, such as removal of the Cbz protecting group under acidic conditions, or more preferably removal of the Boc protecting group by treatment with 4M HCl in dioxane or preferably TFA, yields the corresponding ammonium salt without removing the orthogonal protecting group PG4. The resulting intermediate amine can then be coupled with the second amino acid D-2 in a similar peptide coupling step. The three coupling / deprotection / coupling steps described above yield the same protected intermediate BC as described above in Reaction Scheme C, at which point the remainder of the synthesis can be carried out as described above.

[0153] [ka] Reaction scheme E: In another variation of reaction scheme C, component A-amine is β- tThe carboxylic acid functional groups, such as α-benzyl ester or α-methyl ester in the presence of a butyl ester, are doubly protected by appropriate orthogonal protecting groups. Then, according to the sequence described in reaction scheme C, the corresponding linear intermediate ABC is produced. Double deprotection of the aspartic acid side chain and Boc amine using TFA, followed by cyclization by the method described above, produces a cyclized intermediate cABC that is still protected on A. Deprotection of the aspartic acid main chain carboxylic acid, i.e., removal of PG6, can be carried out for methyl or ethyl esters by treatment with NaOH or LiOH in methanol / water at a temperature in the range of 0°C to 50°C, or preferably by hydrolysis of the benzyl ester on a catalyst such as Pd / C or Pd(OH)2 / C in a solvent such as siRNA, THF, or dioxane. The deprotected intermediate cABC-acid is then coupled with amine AM (commercially available or prepared according to the procedure described in the literature or experimental section) according to the peptide coupling conditions described above to produce the target compound. This strategy is particularly efficient for creating libraries for exploring the AM (Antimicrobial Stem) portion.

[0154] [ka] Reaction Scheme F: The strategy described in Reaction Scheme E, which involves stepwise introduction of part A, can be applied to different sequences and yield the same cABC-acid intermediate as illustrated in Reaction Scheme F. A protected A-amine, doubly protected with appropriate orthogonal protecting groups on two carboxylic acid functional groups, such as α-benzyl or α-methyl esters in the presence of a β-allyl ester, can be coupled with the required B-acid and C components in the same sequence as described in Reaction Scheme A to yield the corresponding linear intermediate ABC. In the case of a Boc protecting group, deprotection of the amine protecting group PG3 using TFA, and then, in the case of an allyl protecting group, removal of the aspartic acid side-chain protecting group PG1 by treatment with 1,3-dimethylbarbituric acid and Pd(PPh3)4 in a solvent such as DCM, leaves only the cyclization described above to obtain intermediate cABC, which is still protected on A as described in Reaction Scheme E. The remaining steps of the synthesis to obtain the desired macrocyclic compound cABC are the same as described above.

[0155] [ka] Reaction scheme G: A variation of reaction scheme F, it is very similar to reaction schemes B and D, and partial C can be introduced stepwise, one amino acid at a time. Furthermore, amino acid D-1 itself can be produced stepwise by introducing the desired side chain R1 into the already assembled ABD1 precursor. The amine deprotection AB intermediate already described in reaction scheme F can be coupled with an unsubstituted amino acid precursor of D-1, such as NH-Boc or preferably NH-nosyl-amino acids, according to the peptide coupling conditions described above. The NH-nosyl functional group can then be alkylated by treatment with a desired alkyl halide such as bromide or preferably iodide in the presence of a base such as K2CO3, or preferably by a Mitsunobu reaction with a desired alcohol carried out according to standard conditions well known to those skilled in the art, for example, by treatment with DEAD or DIAD in a solvent such as THF or dioxane at a temperature in the range of -80°C to 60°C with a phosphine ligand such as triphenylphosphine. Next, the nosyl activation / protecting group can be removed by standard treatment with thiophenol in a solvent such as DMF in the presence of a base such as K2CO3, giving the corresponding deprotected intermediate. Amino acid D-2 can be coupled with this intermediate according to the conditions shown in reaction scheme B. The three coupling / deprotection / coupling steps described above yield the same deprotected linear intermediate ABC as described in reaction scheme F. To obtain the desired macrocyclic compound cABC... The remaining steps in the synthesis are the same as those described above.

[0156] [ka] Reaction Scheme H: In a further modification of Reaction Scheme F, the α-carboxylic acid protecting group of the A-amine component can be a solid phase such as a polymer binding support, enabling stepwise solid-phase peptide synthesis of cyclized macrocyclic compound precursors according to established methods well known to those skilled in polymer-supported peptide synthesis. For example, an amino acid, A-acid, appropriately orthogonally protected on the amine functional group by, for example, an Fmoc protecting group, and on the β-carboxylic acid functional group by, for example, an allyl ester, can be introduced onto Wang resin by treatment with HOBt and DMAP, and a coupling reagent such as DCC or DIC, in a solvent mixture such as DCM / DMF that allows for proper swelling of polymer beads. Subsequent sequences of deprotection of the Fmoc protecting group and peptide coupling using standard conditions for polymer peptide synthesis allow for the introduction of different components, B-acid, D1, and finally appropriately protected D2, e.g., alloc-protected D2, giving polymer-supported linear peptides ABC similar to those described in Reaction Scheme F. Double deprotection of the allyl ester and N-alloc protecting group can, in some cases, be carried out by treatment with a palladium catalyst in the presence of 1,3-dimethylbarbituric acid, yielding a still-supported linear peptide. In these environments, cyclization under standard peptide coupling conditions can be carried out without the risk of oligomer formation. The macrocyclic compound cABC-acid, as described in reaction scheme F, can then be liberated from the polymer support by acid treatment, for example, with a mixture of TFA / H2O(95 / 5). The liberated cABC-acid can then be coupled with a suitable AM ​​amine using the coupling conditions described above, and the target It gives the target compound.

[0157] [ka] Component A may be commercially available, manufactured as described in the literature, or manufactured as shown in reaction scheme I. N-Fmoc β- tA properly orthogonal protected A-acid, such as a butyl ester or a β-allyl ester of N-Boc aspartic acid, is coupled to a desired AM amine according to standard peptide coupling conditions by treatment with COMU or T3P, HATU, PyBop, or another peptide coupling reagent at a temperature between -20°C and +75°C, preferably at RT, in a solvent such as THF, DMF, or NMP, in the presence of a base such as TEA or DIPEA. The resulting intermediate can then be selectively deprotected on the amine functional group without removing the β-ester protecting group PG1, under standard conditions well established in the field of protecting group chemistry. Specifically, β- t By treating the mixture with piperidine or diethylamine to remove N-Fmoc in the presence of a butyl ester, or by treating it with TFA or 4M HCl in dioxane to remove N-Boc in the presence of a β-allyl ester, the target component A can be obtained as its free base or its ammonium salt, respectively.

[0158] [ka] Component B, B-acid, or B-amine may be prepared as described in the literature or as illustrated in reaction scheme J. Suitable salicylic acid derivatives protected as esters such as methyl, ethyl, or benzyl esters on the carboxylic acid functional group are commercially available or may be prepared as described in the literature or as described in the experimental section. Similarly, amino alcohols protected with a Boc or Cbz group on the amine functional group are commercially available or may be readily prepared from the corresponding amino acid as described in the literature or as described in the experimental section. The alcohol functional group of this amino alcohol may be prepared in the presence of a base such as DIPEA or TEA, or methanesulfonyl chloride or toluenesulfonyl chloride. The salicylic acid derivative can be activated by treatment with honyl or a similar activator and reacted with the phenolic functional group of the salicylic acid ester derivative in a solvent such as THF or DMF to give a double-protected B component. Alternatively, these two components can be reacted with each other according to the Mitsunobu method by treatment with a phosphine ligand such as triphenylphosphine and a DEAD or DIAD reagent in a solvent such as THF or dioxane at a temperature ranging from -20°C to 60°C. The orthogonal-protected intermediate can then be selectively deprotected on the acidic or amineic functional group to obtain the corresponding component, B-acid or B-amine. For example, the corresponding B-acid can be obtained by saponification of the methyl ester with an aqueous solution of NaOH or LiOH, or by hydrogenolysis of the benzyl ester on a palladium catalyst such as charcoal-supported Pd or Pd(OH)2. Alternatively, the corresponding B-amine can be obtained by Boc deprotection by treatment with TFA, or, in the case of methyl esters, by hydrogenolysis of the Cbz-protected amine.

[0159] [ka] Component C may be prepared from the key intermediate D-1 amine as shown in reaction scheme K. Intermediate D-1 may be commercially available, prepared as described in the literature, or prepared as shown in this scheme. A suitable PG8-protected bromoacetate derivative (e.g., methyl, ethyl, or benzyl ester) can be reacted with a suitable amine R1NH2 in a solvent such as MeCN, acetone, or DMF, in the presence of a base such as K2CO3 or DIPEA, at a temperature ranging from RT to 80°C to produce amine D-1. Alternatively, a suitable PG8-protected amino acid ester derivative (e.g., methyl, ethyl, or benzyl ester) can be reacted with nitrosulfonylbenzene chloride in a solvent such as DCM or THF, in the presence of a catalytic amount of DMAP, to produce the corresponding N-nosyl-protected amine. Next, the alkylation of sulfonamide nitrogen is carried out by the Mitsunobu method, as previously described, in a solvent such as THF or dioxane, at a temperature ranging from 0°C to 80°C, using a phosphine ligand such as triphenylphosphine and a DEAD or DIAD reagent in the presence of the desired alcohol R1OH. This can be done. Subsequent cleavage of the nosyl group can be carried out by treatment with thiophenol in a solvent such as DMF or DCM in the presence of a base such as K2CO3, yielding amine component D-1. Coupling with the D-2 amino acid, commercially available or prepared as described in the literature, by the standard peptide coupling method described above. Subsequently, deprotection of the ester can be carried out by treatment with an aqueous solution of NaOH or LiOH in the case of methyl or ethyl esters, or by hydrogenolysis of the benzyl ester on a palladium catalyst such as charcoal-supported Pd or Pd(OH)2, to produce the desired C component.

[0160] The following examples are provided for illustrative purposes only. These examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0161] Experiment section I. Chemistry All temperatures are indicated in °C. Commercially available starting materials were used in their obtained state without further purification. Unless otherwise stated, all reactions were carried out under a nitrogen atmosphere in oven-dried glassware. Compounds were purified by silica gel flash column chromatography or preparative HPLC. The compounds described in this invention are LC-MS data (retention time t R The values ​​are shown in min; the molecular weight obtained from mass spectrometry is shown in g / mol.) The characteristics are revealed using the conditions described below. When the compound of the present invention appears as a mixture of conformational isomers, and especially when they are visible in their LC-MS spectra, the retention time of the most abundant isomer is indicated.

[0162] Analytical LC-MS equipment: HPLC pump: Binary gradient pump, Agilent G4220A or equivalent. Autosampler: Gilson (with Gilson 845z injector) LH215 or equivalent Column compartment: Dionex TCC-3000RS or equivalent Gas removal machine: Dionex SRD-3200 or equivalent Makeup pump: Dionex HPG-3200SD or equivalent DAD detector: Agilent G4212A or equivalent MS detector: Single quadrupole mass spectrometer, Thermo Finnigan MSQPlus or equivalent. ELS detector: Sedere SEDEX 90 or equivalent LC-MS under acidic conditions Method A: Column: Zorbax SB-aq (3.5 μm, 4.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 1.5 min from 95% B to 5% B (flow rate: 4.5 mL / min). Detection: UV / Vis + MS.

[0163] Method B: Column: Zorbax RRHD SB-aq (1.8 μm, 2.1 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 2.0 min from 95% B to 5% B (flow rate: 0.8 mL / min). Detection: UV / Vis + MS.

[0164] Method C: Column: Waters XBridge C18 (5 μm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 1.5 min from 95% B to 5% B (flow rate: 4.5 mL / min). Detection: UV / Vis + MS.

[0165] Method D: Column: Waters BEH C18 (2.1 x 50 mm, 2.5 μm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 2.0 min from 95% B to 5% B (flow rate: 0.8 mL / min). Detection: UV / Vis + MS.

[0166] Method E: Column: Waters XBridge C18 (2.5 μm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 1.5 min from 95% B to 5% B (flow rate: 4.5 mL / min). Detection: UV / Vis + MS.

[0167] Method F: Column: Waters XSelect CSH C18 (3.5 μm, 2.1 x 30 mm). Conditions: MeCN + 0.1% formic acid [eluent A]; Water + 0.1% formic acid [eluent B]. Gradient: 1.6 min from 95% B to 2% B (flow rate 1 mL / min), Detection: UV / Vis + MS.

[0168] Method G: Column: Waters Atlantis T3 (3.0 μm, 2.1 x 50 mm). Conditions: MeCN + 0.1% formic acid [eluent A]; Water + 0.1% formic acid [eluent B]. Gradient: From 95% B to 2% B over 5 min (flow rate 0.8 mL / min). Detection: UV / Vis + MS.

[0169] Method H: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector or Xevo TQD or SYNAPT G2 MS, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: Waters Acquity Binary temperature controlled at 60°C in an Acquity UPLC Column Manager. UPLC CSH C18 1.7μm 2.1x50mm. Elution: A: H2O + 0.05% formic acid; B: MeCN + 0.045% formic acid. Method: Gradient: 2.0 min from 2% B to 98% B. Flow rate: 1.0 mL / min. Detection: UV 214 nm, ELSD, and MS. R The value should be expressed in min.

[0170] LC-MS under basic conditions Method I: Column: Waters BEH C18 (2.5 μm, 2.1 x 50 mm). Conditions: Water / NH3 [c(NH3) = 13 mmol / l] [Eluten A]; MeCN [Eluten B]. Gradient: From 5% B to 95% B over 2 min (flow rate 0.8 mL / min). Detection: UV / Vis+MS.

[0171] Method J: Column: Waters XSelect CSH C18 (3.5 μm, 2.1 x 30 mm). Conditions: 95% MeCN + 5% water / NH4HCO3 [c(NH4HCO3) = 10 mmol / l] [Eluten A]; Water / NH4HCO3 [c(NH4HCO3) = 10 mmol / l] [Eluten B]. Gradient: 1.6 min from 95% B to 2% B (flow rate 1 mL / min), Detection: UV / Vis + MS.

[0172] GC-MS Agilent 6890N / Column: RXi-5MS 20m, ID 180μm, df 0.18μm; Speed ​​50cm / s, He carrier gas; Temperature rise from 100°C to 250°C in 4.5 min; Detection: MS.

[0173] Preparative HPLC equipment: Gilson LH215, Gilson 333 / 334 HPLC pump with Dionex SRD-3200 gas remover, Dionex ISO-3100A Makeup Pump, Dionex DAD-3000 DAD Detector, Single Quadrupole Mass Spectrometer MS Detector, Thermo Finni gan MSQ Plus, MRA100-000 Flow Splitter, Polymer Laboratories PL-ELS1000 ELS detector HPLC for preparative separation under basic conditions Column: Waters XBridge (10 μm, 75 x 30 mm). Conditions: MeCN [eluent A]; Water + 0.5% NH4OH (25% aqueous solution) [eluent B]; Gradient Prep. HPLC (see Table 1) (flow rate: 75 mL / min). The initial percentage (x) of eluent A is determined according to the polarity of the compound to be purified. Detection: UV / Vis+MS

[0174] [Table 1] HPLC for preparative separation under acidic conditions Column: Waters Atlantis T3 (10 μm, 75 x 30 mm). Conditions: MeCN [eluent A]; Water + 0.5% HCO2H [eluent B]; Gradient Prep. HPLC (see Table 2) (flow rate: 75 mL / min). The initial percentage (x) of eluent A is determined according to the polarity of the compound to be purified. Detection: UV / Vis+MS

[0175] [Table 2] Preparative HPLC for chiral separation In most cases, the desired diastereomers can be isolated or purified by standard preparative scale HPLC following standard methods well known to those skilled in the art. In some cases, the use of chiral chromatography columns is recommended for separating complex mixtures of diastereomers. Best results are obtained using chiral stationary phase columns, such as Chiralpak IA, IB, or IC columns based on an immobilized amylose or cellulose chiral phase, with a gradient eluent based on a mixture of MeCN with EtOH or MeCN in a ratio varying from 9:1 to 1:9. To compensate for the presence of ionizable functional groups in the compound to be purified, modifiers such as 0.1% diethylamine for basic derivatives or 0.1% formic acid for acidic derivatives may be added to the solvent mixture. In some cases, supercritical fluid chromatography was used, employing the same chiral stationary phase columns as described above, with a gradient eluent consisting of 50% to 90% supercritical carbon dioxide, along with EtOH, MeOH, or a 1:1 EtOH:MeCN mixture. Detection: UV / Vis.

[0176] Abbreviations (used in the above or below sections): Acetic acid (ACOH) Ac2O Acetic anhydride Alloc: Allyloxycarbonyl anh. anhydrous aq. aqueous solution ATM atmosphere BnBr Benzyl bromide Boc tert-butoxycarbonyl Boc2O Di-tert-butyl dicarbonate BOP Hexafluorophosphate (benzotriazole-1-yloxy)-tris(dimethylamino)-phosphonium BuLi n-butyllithium CDI 1,1'-Carbonyldiimidazole CD3I Iodomethane-d3 CHCl3 Chloroform COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate Cu(OAc)2 Copper(II) Acetate d day DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-eneDCC N,N'-Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCM Dichloromethane DEAD Diethyl Azodicarboxylate DIAD (Diisopropyl Azodicarboxylate) DIBAL / DIBAL-H Diisobutylaluminum Hydrogenate DIC N,N'-Diisopropylcarbodiimide DIPEA diisopropylethylamine, Huenig's base DMAP 4-dimethylaminopyridine DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) DPPA Diphenyl Phosphate Azide dppf 1,1'--bis(diphenylphosphin)ferrocene EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ethyl Et2O Diethyl ether HCl ethyl acetate EtOH Ethanol Evaporated. Evaporated under vacuum. Example FC Silica Gel Flash Chromatography FDPP (Pentafluorophenyldiphenylphosphine) Fmoc 9-Fluorenylmethoxycarbonyl h time HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) Heptane Hex (hexane) HOBT 1-hydroxybenzotriazole HPLC (High-Performance Liquid Chromatography) HV high vacuum conditions i Bu isobutyl i Pr isopropyl i PrOH (Isopropyl alcohol) i PrOAc Isopropyl Acetate KO t Bu potassium tert-butoxide LAH Lithium Aluminum Hydrogen LC-MS Liquid Chromatography-Mass Spectrometry Lit. Literature M mol / l mCPBA (m-chloroperbenzoic acid) Me methyl MeCN acetonitrile MeI iodomethane Meldrum acid 2,2-dimethyl-1,3-dioxane-4,6-dione MeOH methanol mL (milliliter) min mix. mixture MOM Methoxymethyl MW microwave NaBH(OAc)3 sodium triacetoxyborohydride NCS N-chlorosuccinimide NMP N-methyl-2-pyrrolidone Nosyl 4-nitrobenzenesulfonyl n Pr n-propyl OAc Acetate org.organic Pd( t Bu3P)2 Bis(tri-tert-butylphosphine)palladium(0) Pd(OAc)2 Palladium(II) acetate Pd / C Palladium on Activated Carbon Pd(OH)2 / C Palladium hydroxide on activated carbon (Perlman catalyst) Pd2(dba)3 Tris(dibenzylideneacetone) Dipalladium(0) PdCl2(PPh3)2-bis(triphenylphosphine)palladium(II) dichloride Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2·DCM [1,1'-bis(diphenylphosphin)-ferrocene]dichloropalladium(II) dichloromethane complex Pd(PPh3)4Tetrakis(triphenylphosphine)Palladium(0)Ph Phenyl PhMe Toluene PPh3 Triphenylphosphine prep. for preparative preparation PTFE (Polytetrafluoroethylene) PyBOP Hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium PyClop Chlorotripyrrolidinophosphonium Hexafluorophosphate rac racemic RM reaction mixture Rochelle salt, potassium sodium tartrate RT room temperature RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl s seconds sat. saturation Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SM Starting Material soln. solution TBAF Tetrabutylammonium Fluoride TBDMSCl tert-butyldimethylsilyl chloride TBME tert-butyl methyl ether tBu tert-butyl = tertiary butyl TEA (Triethylamine) Tf Trifluoromethanesulfonyl TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) TMEDA N,N,N',N'-Tetramethylethylenediamine TMS (trimethylsilyl) Tosyl p-toluenesulfonyl T3P n-propylphosphonic anhydride t R retention time Triflate trifluoromethanesulfonate pTsOH p-toluenesulfonic acid Xantphos 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene XPhos 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl

[0177] A. Production of precursors and intermediates Amine: Commercially available amines are shown in Table AM-1.

[0178] [Table 3]

[0179] [Table 4]

[0180] Non-commercial amines are synthesized as follows.

[0181] 2-Chroman-6-ylethylamine,HCl(AM-2.1) Step 1: Potassium tert-butyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (693 mg, 2. Add 76 mmol of 6-bromochromane (600 mg, 2.73 mmol) and Cs2CO3 (2.67 g, 8.19 mmol) to a solution of RT in PhMe (9.2 mL) and water (3 mL). After degassing the RM by passing argon through the solution, add RuPhos 95% (134 mg, 0.273 mmol) and Pd(OAc)2 (30.7 mg, 0.137 mmol), and stir the resulting mix at 95°C for 18 hours. Cool this mix to RT, then add water and siRNA, and filter the RM through Celite. Extract the filtrate with siRNA (3x), wash with brine, dry (MgSO4), filter, and concentrate. Purification by FC (elution with 5% to 25% ethyl ethyl in hept) yields (2-chroman-6-yl-ethyl)-carbamate tert-butyl ester (543 mg, 72%) as a pale yellow solid. LC-MS B:t R =0.97min;[M+H] + = 222.04.

[0182] Step 2: Add 4M HCl (4 mL) in dioxane to a solution of (2-chroman-6-yl-ethyl)-carbamate tert-butyl ester (540 mg, 1.95 mmol) in dioxane (0.5 mL) with RT. Stir RM in RT for 4 hours, then concentrate this mix under vacuum to obtain AM-2.1 (412 mg, 99%) as a white solid. LC-MS B:t R =0.51min;[M+H] + =219.41.

[0183] Table AM-2 below lists the amines that are produced from the corresponding starting materials using the same two-step sequence as described in AM-2.1.

[0184] [Table 5]

[0185] [Table 6]

[0186] 2-(3-(1,1-Difluoroethyl)phenyl)ethan-1-amine hydrochloride (AM-2.22) Step 1: A mixture of 1-bromo-3-(1,1-difluoroethyl)benzene (200 mg, 0.91 mmol) and potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (273 mg, 1.09 mmol) in PhMe (7 mL) and H2O (2 mL) was degassed with Ar for 10 min, then Cs2CO3 (884 mg, 2.71 mmol) and Pd(dppf)Cl2.DCM (74 mg, 0.09 mmol) were added. The RM was degassed with Ar for a further 2 min and then heated to 100 °C for 2 h. After cooling to RT, the RM was fractionated between saturated aqueous NH4Cl and DCM and extracted. The layers were separated and the aqueous phase was re-extracted with DCM (2x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under vacuum. The crude product was purified by FC (eluting with 20% - 100% EtOAc in hept) to give tert-butyl (3-(1,1-difluoroethyl)phenethyl)carbamate as a white solid. LC-MS J:t R = 2.17 min; [M+H] + = 208.1。

[0187] Step 2: The title compound was prepared from tert-butyl (3-(1,1-difluoroethyl)phenethyl)carbamate in the same manner as described for the procedure of AM-2.1 Step 2. LC-MS J:t R = 1.77 min; [M+H] + = 186.1。

[0188] 2-(2-Cyclopropyl-2H-1,2,3-triazol-4-yl)ethan-1-amine hydrochloride (AM-2.23) Step 1: Cu(OAc)2 (1.23 g, 6.61 mmol) was added to a solution of 4,5-dibromo-2H-1,2,3-triazole (1.5 g, 6.61 mmol) and cyclopropylbor Add a mixture of nic acid (1.17 g, 13.2 mmol), Na2CO3 (1.4 g, 13.2 mmol), and 2,2'-bipyridine (1.04 g, 6.61 mmol) in DCE (15 mL) and 2-methylfuran (15 mL), and heat RM at 80°C for 48 hours. Filter RM and rinse the filter cake with ethyl acetate. Wash the filtrate with brine, dry with Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 0%~30% ethyl acetate in hept) to obtain 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole as a yellow solid. LC-MS D:t R = 0.92 min; non-ionization.

[0189] Step 2: Prepare tert-butyl (2-(5-bromo-2-cyclopropyl-2H-1,2,3-triazole-4-yl)ethyl) carbamate from 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole according to the procedure described in AM-2.1 Step 1. LC-MS B:t R =0.91min;[M+H] + = 331.06.

[0190] Step 3: After evacuating / purging (3x) the solution of tert-butyl (2-(5-bromo-2-cyclopropyl-2H-1,2,3-triazole-4-yl)ethyl) carbamate (110 mg, 0.33 mmol) in EtOH (3 mL) with N2, 10% Pd / C (23 mg, 5 mol%) is added. Evacuating / purging RM with H2 (3x) and stirring under an H2 atmosphere for 16 hours. Filtering RM through a Celite pad and concentrating the filtrate under vacuum yields tert-butyl (2-(2-cyclopropyl-2H-1,2,3-triazole-4-yl)ethyl) carbamate as a white solid. LC-MS I:t R =0.83min;[M+H] + = 253.28.

[0191] Step 4: The title compound is prepared from tert-butyl (2-(2-cyclopropyl-2H-1,2,3-triazole-4-yl)ethyl) carbamate in the same manner as described in Step 2 of AM-2.1. LC-MS I:t R =0.46min;[M+H] + = 153.24.

[0192] 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-ethylamine.HCl(AM-3.1) Step 1: Add di-tert-butyl dicarbonate (2.33 g, 10.5 mmol) to a suspension of dopamine hydrochloride (2.0 g, 10.5 mmol) and NaHCO3 (886 mg, 10.5 mmol) in RT in THF (50 mL), and stir this mix in RT for 2 hours. Extract the product with SiO2 (3x), combine the organic layers, dry (MgSO4), filter, and concentrate. Purify by FC (elution with 5% MeOH in DCM) to obtain tert-butyl (3,4-dihydroxyphenethyl)carbamate (2.34 g, 88%) as a white solid. LC-MS I:t R =0.64min;[MH] - = 252.00.

[0193] Step 2: Add 1,3-dibromopropane (1.01 mL, 9.75 mmol) to a suspension of tert-butyl (3,4-dihydroxyphenethyl) carbamate (2.24 g, 8.86 mmol) and K2CO3 (3.13 g, 22.2 mmol) in DMF (10 mL) of RT, and stir the resulting mix overnight in RT. Purify the RM directly by prep.HPLC (basic) to obtain tert-butyl (2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethyl) carbamate (1.25 g, 48%) as a slightly brownish oil. LC-MS I:t R =0.98min;[M+H] + =294.05.

[0194] Step 3: Add 4M HCl (5.4 mL) to dioxane and tert-butyl (2-( Add 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl(ethyl)carbamate (1.25 g, 4.28 mmol) to a solution of RT in dioxane (20 mL). Stir RM in RT for 18 hours, then concentrate the mix under vacuum to obtain AM-3.1 (931 mg, 100%) as a white solid. LC-MS I:t R =0.68min;[M+H] + = 194.13.

[0195] 2-(3-(methoxy-d3)phenyl)ethane-1-amine.HCl(AM-3.2) Step 1: Add CD3I (0.25 mL, 4.0 mmol) to a mix of tert-butyl (3-hydroxyphenethyl) carbamate (638 mg, 2.7 mmol) and K2CO3 (557 mg, 4.0 mmol) in DMF (5 mL) of RT, and heat RM at 50°C for 36 hours. Cool RM to RT, fractionate between H2O and HCl, and extract. Separate the layers, and re-extract the aqueous phase with HCl (2x). Combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain the crude product, which is purified by FC (eluting with 0%~100% HCl in hept) to obtain tert-butyl (3-(methoxy-d3)phenethyl) carbamate as a colorless oil. LC-MS J:t R =2.09min;[M+H-Me] + = 240.1.

[0196] Step 2: The title compound is prepared from tert-butyl (3-(methoxy-d3)phenethyl) carbamate in the same manner as described in AM-2.1 Step 2. LC-MS J:t R =1.47min;[M+H] + = 155.1.

[0197] 2-(2-fluoro-4-methoxyphenyl)-ethylamine.HCl(AM-4.1) Step 1: Molecular sieve 4A (100 mg) is added to a solution of 2-fluoro-4-methoxybenzaldehyde (1.25 g, 7.95 mmol) in nitromethane (16 mL) of RT, then butylamine (0.1 mL, 0.938 mmol) and acetic acid (0.01 mL, 1.62 mmol) are added, and the mix is ​​heated at 90°C for 1 hour. RM is concentrated, and the residue is fractionated between ethyl acetate and water. The organic layer is washed with water and brine, and concentrated under vacuum. Purified by FC (eluting with 0% to 20% ethyl acetate in hept) to obtain 2-fluoro-4-methoxy-1-2-nitro-vinylbenzene (1.06 g, 68%) as a yellowish solid. LC-MS B:t R = 0.92 min; non-ionization.

[0198] Step 2: Add boron trifluoride diethyl etherate (4.19 mL, 32.3 mmol) to a solution of NaBH4 (996 mg, 25.8 mmol) in THF (40 mL) at 0°C. Stir the mix at 0°C for 10 min, then at RT for 15 min. Add the solution of 2-fluoro-4-methoxy-1-2-nitro-vinylbenzene (1.06 g, 5.38 mmol) in THF (10 mL) dropwise, reflux the mix at 70°C for 3 hours, then allow it to reach RT overnight. After cooling RM to 0°C, add 2N HCl (35 mL, 69.9 mmol) dropwise. After addition, stir the mix at 0°C for 10 min, then at RT for 15 min, then heat the mix at 80°C for 1 hour. The RM was cooled to RT, the organic solvent was evaporated, and the remaining aqueous layer was cooled to 0°C. The mixture was then basicized with a 10% NaOH aqueous solution. The product was extracted with ELISA (3x), the organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The well-dried residue under HV was dissolved in DCM (10 mL), cooled to 0°C, and then 4M HCl (1.61 mL, 6.45 mmol) in dioxane was added. The resulting mix was stirred for 1 hour. The RM was concentrated and ground over Et2O (2x) to obtain the title compound AM-4.1 (957 mg, 87%) as a beige powder. LC-MS B:t R =0.49min;[M+H] + = 170.08.

[0199] The title compound 2-(4-bromo-2,6-difluorophenyl)-ethylamine (AM-4.2) is prepared from 4-bromo-2,6-difluorobenzaldehyde in the same manner as the synthesis described for AM-4.1. LC-MS B:t R =0.53min;[M+H] + = 235.98.

[0200] 2-(2,6-difluoro-4-methoxyphenyl)-ethylamine(AM-4.3) Step 1: Add ammonium acetate (179 mg, 2.28 mmol) to a solution of 2,6-difluoro-4-methoxybenzaldehyde (1.0 g, 5.69 mmol) in nitromethane (7 mL) of RT, and reflux the resulting mix for 40 min. Evaporate the RM and fractionate the residue between water and DCM. Extract the aqueous layer with DCM (2x), combine the organic layers, wash with brine, dry (MgSO4), filter, and concentrate to obtain 1,3-difluoro-5-methoxy-2-(2-nitro-vinyl)-benzene (1.25 g) as an orange oil, which is used directly in the next step. LC-MS B:t R =0.96min;[M+H] + = 216.12.

[0201] Step 2: Prepare the title compound from 1,3-difluoro-5-methoxy-2-(2-nitro-vinyl)benzene in the same manner as described in AM-4.1 Step 2. LC-MS B:t R =0.51min;[M+H] + = 188.32.

[0202] 2-(3,4-difluorophenyl)-ethylamine.HCl AM-4.4 Step 1: 1,2-difluoro-4-(2-nitro-vinyl)benzene is prepared in the same manner as described in AM-4.1, Step 1. LC-MS C:t R = 0.75 min; non-ionization.

[0203] Step 2: Add concentrated H2SO4 (0.710 mL) to a suspension of LiAlH4 (1.06 g, 26.65 mmol) in THF (35 mL) at 0°C. After stirring for 20 minutes, add the solution of 1,2-difluoro-4-(2-nitro-vinyl)-benzene (1.10 g, 5.97 mmol) in THF (5 mL) dropwise, continue stirring for 10 minutes, then remove the cooling bath and slowly heat the RM under gentle reflux. After 5 minutes, cool the mix to 0°C. i Carefully hydrolyze by adding PrOH (4.4 mL), followed by 2 M NaOH aqueous solution (3.1 mL) dropwise. Filter the resulting suspension and rinse the filter cake with THF. Concentrate the filtrate and remove the free amine. i The compound is dissolved in Et2O (20 mL) containing PrOH (0.72 mL) and acidified with 2 M HCl (11.4 mL) in the Et2O. The resulting suspension is filtered, and the filter cake is washed with Et2O to obtain the title compound (440 mg, 38%) as a white solid, which is then dried under HV conditions. LC-MS C:t R =0.40min;[M+H] + = 199.3.

[0204] 2-(4,5-dimethylisoxazole-3-yl)ethane-1-amine (AM-5.1) Step 1: In a Dean-Stark apparatus, add pTsOH monohydrate (11.1 mg, 0.06 mmol) to a solution of RT in PhMe (50 mL) containing ethyl acetoethyl (1.46 mL, 11.4 mmol) and pyrrolidine (1.92 mL, 22.8 mmol), and reflux the resulting mix for 2 hours. After removing volatile matter, use the orange oil obtained from 3-pyrrolidine-1-ylbuta-2-enoic acid ethyl ester (2.03 g, 97%) directly in the next step. LC-MS B:t R =0.39min;[M+H] + = 184.45.

[0205] Step 2: Dissolve the SO3 pyridine complex (11.0 g, 69.2 mmol) in DMSO (39.3 mL) and add 3-(Boc-amino)-1-propanol (4.88 mL, 2 Add dropwise to a solution of 7.7 mmol) and DIPEA (14.2 mL, 0.83 mmol) in DCM (83.1 mL) at 0°C. Stir in RM at 0°C for 1 hour, then in RT for 1 hour. Dilute the mix with HCl and water, then extract with DCM (3x). Combine the organic extracts, wash with water and brine, dry with (Na2SO4), filter, and concentrate to obtain (3-oxo-propyl)-carbamate tert-butyl ester (4.81 g, 100%) as a colorless oil, which is used directly in the next step.

[0206] Step 3: Add the solution of hydroxylamine hydrochloride (3.90 g, 0.06 mol) in H2O (25 mL) and the solution of sodium acetate (9.20 g, 0.11 mol) in H2O (25 mL) to the vigorously stirred solution of (3-oxo-propyl)-carbamate tert-butyl ester (4.81 g, 0.028 mol) in EtOH (100 mL). Stir the resulting suspension at RT for 18 hours, then at 50°C for a further 3 hours. Remove volatiles and fractionate the residue between ethyl acetate and water. Separate the layers and further extract the aqueous layer with ethyl acetate. Combine the organic extracts, wash with brine, dry (Na2SO4), filter, and concentrate. Purify by FC (eluting with 50% ethyl acetate in hept) to obtain (3-hydroxyimino-propyl)-carbamate tert-butyl ester (4.5 g, 86%) as a colorless oil. LC-MS B:t R =0.58min;[M+H] + = 189.43.

[0207] Step 4: Add NCS (2.23 g, 16.4 mmol) to a solution of (3-hydroxyimino-propyl)-carbamate tert-butyl ester (2.80 g, 14.9 mmol) in DCM (80 mL) with RT, and stir the resulting mix in RT for 2 hours. Evaporate the mix and purify directly by FC (eluting with 50% ethyl acetate in hept) to obtain tert-butyl (3-chloro-3-(hydroxyimino)propyl)carbamate (2.02 g, 61%) as an orange oil. LC-MS B:t R=0.72min;[M( 35 Cl)+H] + = 223.37.

[0208] Step 5: Add a solution of 3-pyrrolidine-1-ylbuta-2-enoic acid ethyl ester (1.83 g, 10 mmol) in DCM (15 mL), then TEA (2.56 mL, 0.0181 mol), to a solution of tert-butyl (3-chloro-3-(hydroxyimino)propyl) carbamate (2.02 g, 9.07 mmol) in DCM (15 mL) of RT, and stir the resulting mix for 15 min. Concentrate RM, and purify the residue directly by FC (elution with 50% ethyl phosphate in hept) to obtain 3-(2-tert-butoxycarbonylaminoethyl)-5-methylisoxazole-4-carboxylic acid ethyl ester (1.60 g) still containing the starting material. Dissolve this product in DCM and wash with 2 M aqueous HCl. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to obtain 3-(2-tert-butoxycarbonylaminoethyl)-5-methylisoxazole-4-carboxylic acid ethyl ester (1.25 g, 46%) as a slightly yellow oil. LC-MS B:t R =0.93min;[M+H] + =299.30.

[0209] Step 6: Add LAH (76 mg, 2.01 mmol) in Et2O (15 mL) dropwise to a solution of 3-(2-tert-butoxycarbonylaminoethyl)-5-methylisoxazole-4-carboxylic acid ethyl ester (500 mg, 1.68 mmol) in Et2O (5 mL) at 0°C. After addition, warm the resulting mix to RT and stir for 1.5 hours. Cool the mix to 0°C and quench very carefully with ethyl phosphate, then with saturated Rochelle salt aqueous solution. Warm the resulting mix to RT and stir vigorously for 30 minutes, after which two layers are formed. Separate the layers and re-extract the aqueous layer with ethyl phosphate (2x). Combine the organic extracts, wash with brine, dry (Na2SO4), filter, and evaporate. Elute with FC (50% ethyl phosphate in hept), then prep.HPLC Purified under basic conditions, [2-(4-hydroxymethyl-5-methyl-isoxazole-3-yl)-ethyl]-carbamate tert-butyl ester (135 mg, 31%) is obtained as a white solid. LC-MS I:t R =0.67min;[M+H] + = 257.20.

[0210] Step 7: Add 4M HCl (1 mL, 3.99 mmol) in dioxane to a solution of [2-(4-hydroxymethyl-5-methyl-isoxazole-3-yl)-ethyl]carbamate tert-butyl ester (100 mg, 0.39 mmol) in dioxane (2 mL) in RT, and stir the resulting mix in RT for 6d. Concentrate the mix to obtain 2-(4-chloromethyl-5-methyl-isoxazole-3-yl)-ethylamine (HCl salt) (77 mg, 93%) as a colorless oil, which is used directly in the next step. LC-MS I:t R = 0.56 min; deionization.

[0211] Step 8: Add Pd / C (10 mg, 0.01 mmol) to a solution (degassed) of 2-(4-chloromethyl-5-methyl-isoxazole-3-yl)-ethylamine (HCl salt) (19 mg, 0.09 mmol) in EtOH (0.5 mL) and  (0.5 mL) of RT. Stir RM under an H2 atmosphere in RT for 30 min. Filter the mix and evaporate the filtrate to obtain AM-5.1 (45 mg, 89%) as a yellow solid, which is used directly in the next step. LC-MS I:t R =0.51min;[M+H] + = 141.20.

[0212] 2-(3-cyclopropylisoxazole-5-yl)ethane-1-amine.HCl(AM-5.2) Step 1: A solution of DIAD (61.7 mL, 318 mmol) in THF (350 mL) is added dropwise to a solution of buta-3-in-1-ol (22.9 mL, 318 mmol), isoindorin-1,3-dione (44.5 g, 302 mmol), and PPh3 (83 g, 318 mmol) in THF (1500 mL) at 0°C, and the RM is stirred for 1 hour. The RM is concentrated under vacuum, and the residue is dissolved in hot PhMe (370 mL), after which MeOH (210 mL) is slowly added. The RM is cooled to RT, and MeOH is added until a white solid precipitates. After partial concentration of the RM, the solid is collected by filtration washing with cold PhMe, and then air-dried to obtain 2-(buta-3-in-1-yl)isoindorin-1,3-dione. LC-MS F:t R = 1.81 min; deionization.

[0213] Step 2: Carefully add Na2CO3 (22.7 g, 214 mmol) to the solution of hydroxylamine HCl (37.2 g, 535 mmol) in H2O (125 mL) of RT, then slowly add the solution of cyclopropanecarbaldehyde (26.7 mL, 357 mmol) in EtOH (100 mL). Stir RM for 1 hour, then fractionate and extract between H2O and siRNA. Separate the layers and re-extract the aqueous phase with siRNA (2x). Combine the organic layers, wash with brine, dry over Na2SO4, filter, evaporate under vacuum to obtain the crude product, which is recrystallized from n-hept to obtain E / Z-cyclopropanecarbaldehyde oxime as a white solid. LC-MS F:t R = 2.13 and 2.30 min; deionization.

[0214] Step 3: Gradually add NCS (34.3 g, 257 mmol) to a solution of cyclopropanecarboxyl oxime (19.3 g, 226 mmol) and pyridine (0.83 mL, 10.3 mmol) in DMF (100 mL) at 0°C, and stir RM for 3 hours. Add a solution of 2-(buta-3-in-1-yl)isoindorin-1,3-dione (21.0 g, 103 mmol) in DMF (100 mL), then TEA (28.7 mL, 206 mmol), and stir RM for 3 hours. Fractionate RM between H2O and DCM and extract. Separate the layers and re-extract the aqueous phase with DCM (2x). Combine the organic layers and wash with brine, then Na2 The crude product is dried with SO4, filtered, and evaporated under vacuum. This crude product is then pulverized with MeOH to obtain 2-(2-(3-cyclopropylisoxazole-5-yl)ethyl)isoindorin-1,3-dione as a white solid. LC-MS J:t R =1.91min;[M+H] + = 283.1.

[0215] Step 4: Add hydrazine H2O (9.44 mL, 194 mmol) to a suspension of 2-(2-(3-cyclopropylisoxazole-5-yl)ethyl)isoindoline-1,3-dione (28.0 g, 97 mmol) in EtOH (100 mL) of RT, and heat RM at 80°C for 5 hours. Cool RM to RT and wash by filtration with EtOH. Concentrate the filtrate under vacuum, suspend the residue in Et2O, and wash again by filtration with Et2O. After partially concentrating the filtrate, add 1M HCl (100 mL) in Et2O, filter the precipitate, and dry under vacuum to obtain the title compound as a white solid. LC-MS J:t R =1.42min;[M+H] + = 153.1.

[0216] 2-(3-(difluoromethyl)isoxazole-5-yl)ethane-1-amine(AM-5.3) Step 1: Add imidazole (1.94 g, 28.5 mmol), then TBDMSCl (2.58 g, 17.1 mmol), to the RT solution in 25 mL of THF with buta-3-in-1-ol (1.0 mL, 14.3 mmol), and stir the RM for 16 hours. i Add Pr2O (25 mL), filter the precipitate, i The mixture is further washed with Pr2O. The filtrate is washed with saturated NaHCO3 aqueous solution and brine, dried with Na2SO4, filtered, and evaporated under vacuum to obtain (buta-3-in-1-yloxy)(tert-butyl)dimethylsilane as a colorless oil. 1 H NMR (CDCl3) δ: 3.76 (t, J=7.1Hz, 2H), 2.43 (td, J=7.1, 2.7Hz, 2H), 1.98 (t, J=2.7Hz, 1H), 0.92 (s, 9H), 0.10 (s, 6H).

[0217] Step 2: Add nBuLi (1.6 M in hex, 7.9 mL, 12.6 mmol) to a solution of (buta-3-in-1-yloxy)(tert-butyl)dimethylsilane (1.85 g, 9.0 mmol) in THF (15 mL) at -78°C. Warm the RM to -15°C, stir for 15 minutes, then recool to -40°C. Next, add ethyl difluoroethyl (1.24 mL, 11.7 mmol), followed by boron trifluoride etherate (1.55 mL, 12.2 mmol) dropwise. Warm the RM to RT and stir for 16 hours. Quench the reaction with cold saturated NH4Cl aqueous solution and extract with ELISA (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (eluting with 20% to 50% DCM in hept) to obtain 6-((tert-butyldimethylsilyl)oxy)-1,1-difluorohexa-3-in-2-one as a yellow oil. 1 H NMR(CDCl3) δ:5.73(t, J=54.2Hz, 1H), 3.82(t, J=6.5Hz, 2H), 2.68(t, J=6.6Hz, 2H), 0.89(s, 9H), 0.08(s, 6H).

[0218] Step 3: Hydroxylamine hydrochloride (0.71 g, 10.2 mmol), followed by CuO (121 mg, 0.85 mmol), is added to a solution of RT in THF (20 mL) with 6-((tert-butyldimethylsilyl)oxy)-1,1-difluorohexa-3-in-2-one (2.22 g, 8.5 mmol), and the RM is stirred for 16 hours. NaHCO3 (0.85 g, 10.2 mmol) is added, and the RM is stirred for 1 hour. The RM is then filtered through a silica gel short pad (eluting with Et2O:THF 1:1) to obtain a mixture of 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)isoxazole and 2-(3-(difluoromethyl)isoxazole-5-yl)ethane-1-ol.

[0219] Step 4: Add TBAF (1.0 M, 6.0 mL, 6.0 mmol in THF) to a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)isoxazole and 2-(3-(difluoromethyl)isoxazole-5-yl)ethane-1-ol (2.35 g, 8.5 mmol - approximate) in THF (50 mL) and RT (50 mL) and stir RM for 16 hours. Fractionate and extract RM between saturated NH4Cl aqueous solution and ethyl acetate. Separate the layers and re-extract the aqueous phase with ethyl acetate (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (eluting with 0% to 6% MeOH in DCM) to obtain 2-(3-(difluoromethyl)isoxazole-5-yl)ethane-1-ol as a yellow oil. 1 H NMR (DMSO) δ:7.23(t, J=53.2Hz, 1H), 6.64(s, 1H), 4.93(t, J=5.3Hz, 1H), 3.72(q, J=6.0Hz, 2H), 2.96(t, J=6.3Hz, 2H).

[0220] Step 5: A solution of DIAD (0.59 mL, 3.0 mmol) in THF (2 mL) is added dropwise to a solution of 2-(3-(difluoromethyl)isoxazole-5-yl)ethane-1-ol (412 mg, 2.5 mmol), isoindorin-1,3-dione (409 mg, 2.8 mmol), and PPh3 (7.95 g, 3.0 mmol) in THF (20 mL) at 0°C, and the RM is stirred for 16 hours. The RM is concentrated under vacuum, and the residue is purified by FC (eluted with 0% to 30% ethyl in hept) to obtain 2-(2-(3-(difluoromethyl)isoxazole-5-yl)ethyl)isoindorin-1,3-dione. LC-MS J:t R =1.98min;[M+H] + =293.1.

[0221] Step 6: Add hydrazine H2O (380 μL, 0.77 mmol) to a suspension of 2-(2-(3-(difluoromethyl)isoxazole-5-yl)ethyl)isoindoline-1,3-dione (113 mg, 0.39 mmol) in EtOH (4 mL) of RT, and heat RM at 80°C for 2 hours. Cool RM to RT and wash by filtration with EtOH. Concentrate the filtrate under vacuum, suspend the residue in Et2O, and wash again by filtration with Et2O. Concentrate the filtrate under vacuum to obtain the title compound as a white solid. LC-MS I:t R =0.53min;[M+H+MeCN] + = 204.32.

[0222] 2-(2,4,6-trifluorophenyl)-ethylamine.HCl(AM-6.1) A 1M solution of borane tetrahydrofuran complex in THF (15.5 mL, 15.5 mmol) is added dropwise to a solution of 2,4,6-trifluorophenylacetonitrile (1.00 g, 5.73 mmol) in THF (10 mL) at 0°C, and the mixture is stirred overnight in RT. After cooling the mixture to 0°C, 5 mL of MeOH is added dropwise, and the solution is stirred in RT for 1 hour, then concentrated. The residue is cooled to 0°C, and 15.0 mL of 1.25 M HCl in MeOH is added dropwise. The resulting suspension is stirred in RT for 2 days, then the solvent is removed, and the residue is ground in Et2O. The product is isolated by filtration and washed with Et2O to obtain AM-6.1 (833 mg, 69%) as a white solid. LC-MS B:t R =0.45min;[M+H] + = 176.26.

[0223] 2-[3-(3-methoxyphenyl)-[1,2,4]oxadiazole-5-yl]ethylamine(AM-7.1) Step 1: Add NaHCO3 (1.55 g, 18.4 mmol), then hydroxylamine hydrochloride (1.29 g, 18.4 mmol) to a solution of 3-methoxybenzonitrile (1.0 g, 7.36 mmol) in MeOH (15 mL) of RT, and reflux the resulting white suspension overnight (70°C). Concentrate the mix, dilute the residue with SiO2, wash with brine, dry (MgSO4), filter, and concentrate to obtain N-hydroxy-3-methoxybenzamidine (1.67 g, 137%) as a yellow oil, which is then used in the next step. It will be used. LC-MS B:t R =0.38min;[M+H] + = 167.11.

[0224] Step 2: Add TBTU (3.49 g, 10.9 mmol) to a solution of Boc-beta-ala-OH (1.73 g, 9.06 mmol), N-hydroxy-3-methoxy-benzamidine (1.67 g, 9.06 mmol), and DIPEA (4.65 mL, 27.2 mmol) in DCM (45 mL) at 0°C. Remove the ice bath and stir the mix at RT for 18 hours. Concentrate the RM and fractionate the residue between Depositphotos (50 mL) and water (50 mL). Filter the resulting solid to obtain the intermediate (2-{[[hydroxyimino]-(3-methoxyphenyl)-methyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester (1.856 g, 61%). Add dioxane (50 mL) to this white solid and reflux the RM for 24 hours (90°C). The mix is ​​concentrated to obtain {2-[3-(3-methoxyphenyl)-[1,2,4]oxadiazole-5-yl]-ethyl}carbamate tert-butyl ester (1.90g, 109%) as a colorless oil, which is used directly in the next step. LC-MS B:t R =0.95min;[M+H] + = 320.12.

[0225] Step 3: Add TFA (4.59 mL, 60 mmol) to a solution of {2-[3-(3-methoxyphenyl)-[1,2,4]oxadiazole-5-yl]-ethyl}carbamate tert-butyl ester (1.915 g, 6.0 mmol) in RT in DCM (40 mL), and stir the mix in RT for 1d. Neutralize the mix with saturated aqueous solution of NaHCO3 (50 mL), then add DCM (50 mL). Separate the two layers, and extract the aqueous layer with DCM (50 mL). Combine the organic layers, dry (MgSO4), filter, and concentrate to obtain AM-7.1 (1.14 g, 86%) as a yellow oil. LC-MS B:t R =0.54min;[M+H] + = 220.22.

[0226] 2-[3-(3,5-dimethylphenyl)-[1,2,4]oxadiazole-5-yl]ethylamine(AM-7.2) The title compound is prepared from 3,5-dimethylbenzonitrile according to the three-step synthesis described in AM-7.1. LC-MS E:t R =0.53min;[M+H] + = 218.22.

[0227] 2-[3-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazole-5-yl]-ethylamine.HCl(AM-7.3) Steps 1 and 2: The title compound is prepared from 3,2-trifluoromethoxybenzonitrile according to the synthesis described in AM-7.1, Steps 1 and 2, to obtain {2-[3-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazole-5-yl]-ethyl}carbamate tert-butyl ester. LC-MS E:t R =0.88min;[M+H] + =318.04.

[0228] Step 3: Add 4M HCl (6 mL) in dioxane to a solution of {2-[3-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazole-5-yl]-ethyl}carbamate tert-butyl ester (425 mg, 1.14 mmol) in dioxane (3 mL) with RT, and stir the mix in RT for 18 hours. Concentrate RM to obtain AM-7.3 (0.41 g, 119%) as a brownish oil. LC-MS E:t R =0.53min;[M+H] + = 273.93.

[0229] 2-[5-(2-trifluoromethoxyphenyl)-4H-[1,2,4]triazole-3-yl]ethylamine(AM-8.1) Step 1: K2CO3 (487 mg, 3.53 mmol) is mixed with tert-butyl N-(2-cyanoethyl)carbamate (1.20 g, 7.05 mmol) and 2-(triflu Olomethoxybenzoic acid hydrazide (1.55 g, 7.05 mmol) is added to a solution of RT in n-butanol (50 mL). The resulting suspension is heated at 120°C for 6.5 hours, then stirred overnight in RT, and reheated at 120°C for another 4.5 hours. The mix is ​​concentrated, the residue is diluted with DCM, and acidified with 1N HCl. The two layers are separated, and the aqueous layer is extracted with DCM. The organic layers are combined, concentrated, and purified by FC (eluting with 10%-30% siRNA in hept) to obtain {2-[5-(2-trifluoromethoxyphenyl)-4H-[1,2,4]triazole-3-yl]-ethyl}carbamic acid tert-butyl ester (678 mg, 26%) as a colorless oil. LC-MS A:t R =0.80min;[M+H] + = 373.15.

[0230] Step 2: Add 4M HCl (30 mL, 30 mmol) in dioxane dropwise to a solution of {2-[5-(2-trifluoromethoxyphenyl)-4H-[1,2,4]triazole-3-yl]-ethyl}carbamate tert-butyl ester (678 mg, 1.82 mmol) in DCM (20 mL) at 0°C. Stir the resulting RM in RT for 2 hours, then concentrate the RM to obtain AM-8.1 (515 mg, 104%) as a yellow oil, which is used directly in the next step. LC-MS A:t R =0.52min;[M+H] + = 273.14.

[0231] 2-(3-methoxy-4-[1,2,3]triazole-2-ylphenyl)-ethylamine.HCl(AM-9.1) Step 1: Dilute 1H-1,2,3-triazole (5.0 g, 0.072 mmol) with water (35 mL), heat to 50°C, and then add Br2 (23.1 g, 0.145 mmol) dropwise (exothermic). Replace the oil bath with a water bath and maintain the internal temperature below 50°C. After 15 min, quench the resulting orange suspension with 2 M NaOH aqueous solution (5 mL) and 40% sodium bisulfite solution (2 mL). Next, add 32% NaOH aqueous solution until the pH reaches 7, then add 40% sodium bisulfite solution (10 mL). Due to the exothermic reaction, cool the suspension to RT and then filter it. Rinse the cake with water (3 x 10 mL), concentrate the filtrate to obtain 4,5-dibromo-2H-[1,2,3]triazole (14.86 g, 90%) as a slightly yellowish solid.

[0232] Step 2: Add K2CO3 (3.96 g, 28.6 mmol) and 4,5-dibromo-2H-[1,2,3]triazole (6.50 g, 28.6 mmol) to a solution of RT in DMF (40 mL) of 2-fluoro-5-nitroanisole (5.00 g, 28.6 mmol), and stir the mix for 3d at 45°C. Dilute the mix with H2O, filter the formed precipitate, wash with water, and dry the collected solid under HV to obtain 4,5-dibromo-2-(2-methoxy-4-nitrophenyl)-2H-[1,2,3]triazole (7.51 g, 69%) as a white solid. LC-MS B:t R = 1.03 min; non-ionization.

[0233] Step 3: Add Pd(OH)2 (20%, 1.04g, 1.96 mmol) to a solution (degassed) of 4,5-dibromo-2-(2-methoxy-4-nitrophenyl)-2H-[1,2,3]triazole (7.4g, 0.020mol) in MeOH (70mL) with RT, and stir the resulting mix in RT under an H2 atmosphere for 2 hours. Filter the mix through Celite and then wash with a large amount of MeOH. Concentrate the filtrate and purify by FC (eluting first with siRNA / hept, then with 100% siRNA, and finally with 10% MeOH in DCM). Re-purify the isolated product (130%) by prep.HPLC (basic) to obtain 3-methoxy-4-[1,2,3]triazole-2-ylphenylamine (2.87g, 75%) as a brown oil. LC-MS I:t R =0.53min;[M+H] + = 191.33.

[0234] Step 4: Slowly add tert-butyl nitrite (0.314 mL, 2.65 mmol) to a solution of CuBr2 (537 mg, 2.41 mmol) in MeCN (3 mL) at 60°C. Add the solution of 3-methoxy-4-[1,2,3]triazole-2-ylphenylamine (500 mg, 2.41 mmol) in MeCN (3 mL) dropwise, and after addition, bring the mix to RT. Quench the mix by adding a solution of sulfamic acid (47 mg, 0.48 mmol) in water (1 mL), then 2 M aqueous HCl (3 mL). After evaporating the MeCN, add siRNA and separate the layers. The organic layer is washed with 2 M aqueous HCl, water and brine, then dried (Na2SO4), filtered and concentrated. Purification by FC (elution with 10%-20% ethyl acetate in hexadecimal) yields 2-(4-bromo-2-methoxyphenyl)-2H-1,2,3-triazole (0.27g, 46%) as a yellow oil. LC-MS I:t R =0.87min;[M+H] + = 254.13.

[0235] Steps 5 and 6: The title compound is prepared from 2-(4-bromo-2-methoxyphenyl)-2H-1,2,3-triazole according to the two-step sequence described for AM-2.1. LC-MS I:t R =0.61min;[M+H] + = 260.26.

[0236] 2-(4-pyrazine-2-ylphenyl)-ethylamine (AM-10.1) Step 1: Add 2 mL of K2CO3 2M in water to a solution of 4-(2-nitroethyl)phenylboronic acid (200 mg, 1.03 mmol) and 2-bromopyrazine (168 mg, 1.03 mmol) in dioxane (8 mL) with RT. Degas this solution with argon for 2 min, then add Pd(PPh3)4 (35.6 mg, 0.0308 mmol), and heat the mix at 80°C for 18 hours. Add water and siRNA to this mix. Separate the layers, and re-extract the aqueous layer with siRNA. Combine the organic layers, dry (MgSO4), filter, and concentrate. Purify by FC (siRNA / hept 2:3) to obtain 2-[4-(2-nitro-ethyl)-phenyl]pyrazine (88 mg, 37%) as a yellow oil. LC-MS B:t R =0.84min;[M+H] + = 230.10.

[0237] Step 2: Add Pd / C (10%, 13.5 mg, 0.019 mmol) to a solution of 2-[4-(2-nitro-ethyl)-phenyl]-pyrazine (88 mg, 0.384 mmol) in EtOH / THF in RT, and stir the mix in RT under an H2 atmosphere for 18 hours. Filter the mix and concentrate. Purify by prep.HPLC (basic) to obtain AM-10.1 (65 mg, 85%) as a yellow solid. LC-MS B:t R =0.48min;[M+H] + = 200.20.

[0238] 2-(3-pyrazine-2-ylphenyl)-ethylamine(AM-10.2) The title compound is prepared from (3-(2-nitroethyl)phenyl)boronic acid using the two-step procedure described for AM-10.1. LC-MS B:t R =0.48min;[M+H] + = 200.19.

[0239] 2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine.HCl(AM-11.1) Step 1: Gradually add NBS (8.89 g, 50 mmol) to a solution of 2,3-dihydro-1,4-benzodioxin-6-ol (8.0 g, 50 mmol) in RT in DMF (80 mL), stir the mix for 2 hours, then add NBS (3.0 g) and stir the mix for another 30 minutes. Dilute the mix with water and extract with ELISA (3x). Combine the organic extracts, wash with water (2x) and brine, dry in a phase separator, and concentrate. Purify with FC (elute with 0%~30% ELISA in hept) to obtain 7-bromo-2,3-dihydro-benzo[1,4]dioxin- Obtain 6-ol (5.98g, 90%) as a red oil. LC-MS B:t R = 0.74 min; deionization.

[0240] Step 2: Add MeI (3.26 mL, 51.8 mmol) to a solution of 7-bromo-2,3-dihydro-benzo[1,4]dioxin-6-ol (5.981 g, 25.9 mmol) and Cs2CO3 (10.12 g, 31.1 mmol) in DMF (60 mL) of RT, and stir the mix for 1.5 hours. Dilute this mix with water and extract with Et2O (3x). Combine the organic layers, wash with water and brine, dry with a phase separator, and concentrate. Purify by FC (eluting with 0%~30% siRNA in hept) to obtain 6-bromo-7-methoxy-2,3-dihydro-benzo[1,4]dioxin (5.85 g, 92%) as a white powder. LC-MS B:t R =0.90min;[M+H] + = 244.13.

[0241] Steps 3 and 4: The title compound is prepared from 6-bromo-7-methoxy-2,3-dihydro-benzo[1,4]dioxin according to the two-step procedure described for AM-2.1. LC-MS B:t R =0.52min;[M+H] + = 210.24.

[0242] 2-(7-chloro-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine.HCl(AM-12.1) Step 1: Add 1,2-dibromoethane (8.85 mL, 101 mmol) to a solution of 3-methylcatechol (5.0 g, 40.3 mmol) and K2CO3 (22.27 g, 161 mmol) in DMF (70 mL) of RT, and stir the resulting mix for 18 hours. Dilute this mix with water and extract with Et2O (3x). Combine the organic layers, wash with water and brine, dry in a phase separator, and concentrate. Purify by FC (eluting with 0%~25% siRNA in hept) to obtain 5-methyl-2,3-dihydro-benzo[1,4]dioxin (3.05 g, 50%) as a colorless oil. LC-MS B:t R = 0.83 min; non-ionization.

[0243] Step 2: Gradually add NBS (3.39 g, 19.1 mmol) to a solution of 5-methyl-2,3-dihydro-benzo[1,4]dioxin (2.864 g, 19.1 mmol) in THF (60 mL) at 0°C, and stir RM in RT for 18 hours. Add NBS (286 mg) to this mix and continue stirring for another 30 minutes. Dilute the mix with water and extract with ELISA (3x). Combine the organic extracts, wash with water (2x) and brine, dry in a phase separator, and concentrate. Purify by FC (eluting with 0%~30% ELISA in hept) to obtain 6-bromo-5-methyl-2,3-dihydro-benzo[1,4]dioxin (4.40 g, 100%) as a bright orange oil. LC-MS B:t R = 0.96 min; deionization.

[0244] Step 3: [2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-carbamate tert-butyl ester is prepared from 6-bromo-5-methyl-2,3-dihydro-benzo[1,4]dioxin according to the reaction described in AM-2.1, Step 1. LC-MS B:t R = 0.95 min; non-ionization.

[0245] Step 4: Gradually add NCS (307 mg, 2.25 mmol) to a solution of RT in DMF (10 mL) of [2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-carbamate tert-butyl ester (600 mg, 2.05 mmol), and heat the mix at 50°C for 18 hours. Dilute this mixture with water and extract with ethyl acetate (3x). Combine the organic extracts, wash with water and brine, dry in a phase separator, and concentrate. Purify by FC (eluting with 0%-20% ethyl acetate in hept). Then, [2-(7-chloro-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-carbamate tert-butyl ester (581 mg, 87%) is obtained as a slightly orange oil.

[0246] Step 5: The title compound is prepared from [2-(7-chloro-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-carbamate tert-butyl ester according to the reaction described in AM-2.1, Step 2. LC-MS B:t R =0.58min;[M+H] + = 228.11.

[0247] 2-(7-chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine.HCl(AM-12.2) The title compound is prepared from 6-bromo-2,3-dihydrobenzo[b][1,4]dioxin according to the three-step reaction sequence described in AM-12.1, steps 3-5. LC-MS B:t R=0.54min;[M+H] + = 214.22.

[0248] 2-(3-methoxyisoxazole-5-yl)ethane-1-amine hydrochloride (AM-13.1) Step 1: Add DPPA (1.32 mL, 6.1 mmol) dropwise to a solution of 3-(3-methoxyisoxazole-5-yl)propanoic acid (1.0 g, 5.55 mmol) and TEA (0.93 mL, 6.66 mmol) in PhMe (25 mL) in RT, and heat RM at 100°C for 1.5 hours. Add 2-methylpropan-2-ol (1.06 mL, 11.1 mmol) and heat RM under reflux for 16 hours. Cool RM to RT and fractionate between saturated NaHCO3 aqueous solution and ethyl acetate, separating the layers. Re-extract the aqueous phase with ethyl acetate (2x), combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (elution with 0% to 100% ethyl in hept) to obtain tert-butyl(2-(3-methoxyisoxazole-5-yl)ethyl)carbamate as a colorless oil. LC-MS F:t R =1.80min;[M+H] + = 243.1.

[0249] Step 2: The title compound is prepared from tert-butyl(2-(3-methoxyisoxazole-5-yl)ethyl) carbamate in the same manner as described in AM-2.1 Step 2. LC-MS B:t R =0.28min;[M+H] + = 143.09.

[0250] 2-(3-(methoxy-d3)isoxazole-5-yl)ethane-1-amine hydrochloride (AM-13.2) Step 1: Add H2SO4 (136 μL, 2.55 mmol) to the solution of penta-4-ic acid (5.0 g, 51 mmol) in EtOH (50 mL) in RT, and heat RM at 70°C for 2 hours. Fractionate RM between water and siRNA and separate the layers. Wash the organic phase with H2O (2x), add the solution of KHCO3 (10.21 g, 102 mmol) in H2O (25 mL), then add the solution of hydroxycarbonimide dibromide (10.34 g, 51 mmol) in siRNA (200 mL) dropwise. Stir RM in RT for 48 hours, then wash with H2O and brine, dry with Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (elution with 1% to 15% ethyl in hept) to obtain ethyl 3-(3-bromoisoxazole-5-yl)propanoate as a white solid. LC-MS F:t R =1.87min;[M+H] + = 247.0.

[0251] Step 2: Gradually add Na (1.15 g, 50 mmol) to methanol-d3 (11.53 mL, 285 mmol) in the ice bath, and when all the solids have dissolved, add ethyl Add 3-(3-bromoisoxazole-5-yl)propanoate (1.0 g, 4.0 mmol), and irradiate the resulting solution in a MW oven at 110°C for 75 minutes. Dilute RM with H2O, then pour into 2M HCl (35 mL) and extract with Â13 (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (elution with 5-10% MeOH in DCM) to obtain 3-(3-(methoxy-d3)isoxazole-5-yl)propanoic acid as a white solid. LC-MS F:t R =1.07min;[M+H] + = 175.0.

[0252] Step 3-4: Prepare the title compound from 3-(3-(methoxy-d3)isoxazole-5-yl)propanoic acid in the same manner as described in AM-13.1. LC-MS F:t R=0.13min;[M+H] + = 146.0.

[0253] 2-(4-(3-methoxypropyl)-1H-pyrazole-1-yl)ethane-1-amine dihydrochloride (AM-14.1) Step 1: A mixture of carbamic acid, N-[2-(4-bromo-1H-pyrazole-1-yl)ethyl]-,1-dimethylethyl ester (300 mg, 1.03 mmol) and trans-3-methoxy-1-propenylboronic acid pinacol ester (0.71 mL, 1.07 mmol) in dioxane (3 mL) and H2O (3 mL) is degassed with Ar for 10 min, then Cs2CO3 (1.18 g, 3.62 mmol) and Pd(dppf)Cl2.DCM (25.3 mg, 0.03 mmol) are added. The RM is further degassed with Ar for 2 min, and then irradiated in a MW oven at 90°C for 20 min (cooling function on). After cooling to RT, the RM is fractionated and extracted between water and DCM. The layers are separated, and the aqueous phase is re-extracted with DCM (2x). The organic extracts are combined, washed with brine, dried (Mg2SO4), filtered, and evaporated under vacuum. The crude product is purified by prep.HPLC (acidic, 5%~95%) to obtain tert-butyl (2-(4-(3-methoxypropane-1-en-1-yl)-1H-pyrazole-1-yl)ethyl)carbamate (187 mg, 64%) as a colorless oil. LC-MS B:t R =0.78min;[M+H] + = 282.29.

[0254] Step 2: Add Pd / C (10%, 34 mg, 0.032 mmol) to a solution of tert-butyl (2-(4-(3-methoxypropane-1-en-1-yl)-1H-pyrazole-1-yl)ethyl) carbamate (180 mg, 0.64 mmol) in MeOH and stir the mix in RT for 1 hour under an H2 atmosphere. Filter and concentrate the mix to obtain tert-butyl (2-(4-(3-methoxypropyl)-1H-pyrazole-1-yl)ethyl) carbamate (180 mg, 99%) as a colorless oil. LC-MS B:t R=0.78min;[M+H] + = 284.28.

[0255] Step 3: Add 4M HCl (4.4 mL, 6.18 mmol) in dioxane to a solution of tert-butyl (2-(4-(3-methoxypropyl)-1H-pyrazole-1-yl)ethyl) carbamate (175 mg, 0.62 mmol) in dioxane (5 mL) and stir the resulting mix for 30 min. Concentrate RM under vacuum to obtain the title compound AM-14.1 (157 mg, 99%) as a colorless oil. LC-MS B:t R =0.42min;[M+H] + = 184.40.

[0256] 2-(4-cyclopropyl-1H-pyrazole-1-yl)ethane-1-amine dihydrochloride (AM-15.1) Step 1: A mixture of carbamic acid, N-[2-(4-bromo-1H-pyrazole-1-yl)ethyl]-,1-dimethylethyl ester (500 mg, 1.72 mmol), and cyclopropylboronic acid (459 mg, 5.34 mmol) in THF (10 mL) is degassed with Ar for 10 min, then Cs2CO3 (1.97 g, 6.03 mmol) and Pd(dppf)Cl2.DCM (42.2 mg, 0.052 mmol) are added. The RM is further degassed with Ar for 2 min, and then irradiated in a MW oven at 70°C for 30 min. (Cooling function on). After cooling to RT, RM is fractionated and extracted between water and DCM. The layers are separated and the aqueous phase is re-extracted with DCM (2x). The organic extracts are combined, washed with brine, dried (Mg2SO4), filtered, and evaporated under vacuum. The crude product is eluted with 15%-50% ethyl acetate in FC (hept), and ethyl acetate / hept 1:1 in R f= Purified using 0.48), tert-butyl(2-(4-cyclopropyl-1H-pyrazole-1-yl)ethyl)carbamate (187 mg, 64%) is obtained as a colorless oil. LC-MS B:t R =0.78min;[M+H] + = 282.29.

[0257] Step 2: i 5M HCl (2.3 mL, 11.5 mmol) in PrOH was added to tert-butyl(2-(4-cyclopropyl-1H-pyrazole-1-yl)ethyl) carbamate (580 mg, 2.31 mmol) by RT, and the RM was stirred for 30 minutes. This RM was concentrated under vacuum to obtain the title compound AM-15.1 (157 mg, 99%) as a colorless oil. LC-MS B:t R =0.42min;[M+H] + = 184.40.

[0258] 2-(4-methoxy-1H-pyrazole-1-yl)ethane-1-amine dihydrochloride (AM-16.1) Step 1: Add tert-butyl N-(2-bromoethyl)carbamate (1.61 g, 7.06 mmol) to a suspension of RT in MeCN (16.3 mL) containing 4-methoxy-1H-pyrazole hydrochloride (1.00 g, 7.06 mmol) and Cs2CO3 (6.97 g, 21.2 mmol), and heat the RM at 80°C for 18 hours. Allow the RM to reach RT, then filter it and rinse the filter cake with DCM. Elute FC (20%~60% ethyl in hept), R f= Purified with 0.18 (hept / SiO2 1:1), tert-butyl (2-(4-methoxy-1H-pyrazole-1-yl)ethyl)carbamate (1.473 g, 87%) is obtained as a white solid.

[0259] Step 2: Add 4M HCl (13.8 mL, 55.3 mmol) in dioxane to a suspension of tert-butyl (2-(4-methoxy-1H-pyrazole-1-yl)ethyl) carbamate (1.47 g, 5.53 mmol) in DCM (9.5 mL) at 0°C, and allow the RM to reach RT overnight. The RM is concentrated and co-evaporated with DCM under HV to obtain the title compound AM-16.1 (1.36 g, 94%) as a grayish-white solid. LC-MS B:t R = 0.36 min; deionization.

[0260] 2-(5-cyclopropyl-2H-tetrazol-2-yl)ethane-1-amine hydrochloride (AM-16.2) The title compound is prepared from 5-cyclopropyl-2H-1,2,3,4-tetrazole, using K2CO3 instead of Cs2CO3, according to the reaction sequence described for AM-16.1. LC-MS I:t R =0.44min;[M+H] + = 154.25.

[0261] 2-(3-ethynylphenyl)ethane-1-amine.TFA(AM-17.1) Step 1: Prepare tert-butyl(3-bromophenethyl)carbamate from 2-(3-bromophenyl)ethane-1-amine in the same manner as described in AM-3.1 Step 1. LC-MS B:t R =1.00min;[M+H-Me] + = 285.12.

[0262] Step 2: The degassed mixture of tert-butyl (3-bromophenethyl) carbamate (10.51 g, 35 mmol), trimethylsilylacetylene (14.8 mL, 105 mmol), XPhos Pd G2 (1.38 g, 1.75 mmol), and TEA (14.6 mL, 105 mmol) in DMF (120 mL) is stirred at 60°C for 18 hours. This RM is fractionated between water and Et2O, and the layers are separated. The aqueous phase is re-extracted with Et2O (2x), the organic extracts are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluting with 0%~60% ethyl acetate in hept) to obtain tert-butyl (3-((trimethylsilyl)ethynyl)phenethyl)carbamate as a brown oil. LC-MS B:t R =1.13min;[M+H- t AD] + = 262.27.

[0263] Step 3: Add TFA (15 mL, 196 mmol) to a solution of RT in DCM (100 mL) of tert-butyl (3-(trimethylsilyl)ethynyl)phenethyl) carbamate (10.36 g, 32.6 mmol), stir RM for 1 hour, and then concentrate under vacuum. Co-evaporate the residue with DCM (2x) to obtain the title compound as a yellow solid. LC-MS B:t R =0.49min;[M+H] + = 146.19.

[0264] 2-(3-Methoxy-1,2,4-Oxadiazole-5-yl)ethane-1-amine hydrochloride (AM-18.1) Step 1: Add HATU (11.82 g, 31.1 mmol) to a solution of boc-beta-Ala-OH (5.0 g, 25.9 mmol), o-methylisourea bisulfate (4.5 g, 25.9 mmol), and DIPEA (18.1 mL, 104 mmol) in RT in DMF (150 mL), and stir RM in RT for 1.5 hours. Add water and siRNA to this RM, then separate the two layers, and extract the inorganic layer with siRNA (2x). Combine the organic layers, wash with brine, dry (Na2SO4), filter, and concentrate to obtain the crude product, which is purified by FC (eluting with 20% to 100% siRNA in hept) to obtain tert-butyl (3-((imino(methoxy)methyl)amino)-3-oxopropyl) carbamate as a white solid. LC-MS I:t R =0.64min;[M+H] + = 246.36.

[0265] Step 2: Add 1,8-diazabicyclo[5.4.0]undeca-7-ene (8.96 mL, 59.3 mmol) to a solution of tert-butyl (3-((imino(methoxy)methyl)amino)-3-oxopropyl) carbamate (6.19 g, 24.7 mmol) and NBS (10.56 g, 59.3 mmol) in SiO2 (120 mL) and stir RM for 5 hours. Add 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.85 mL, 12.4 mmol) and NBS (2.2 g, 12.4 mmol) and continue stirring for 16 hours. Filter this suspension and wash the filtrate with water, saturated NaHCO3 aqueous solution and brine, then evaporate to dryness. The crude product is purified by FC (elution with 20% to 100% ethyl in hept) to obtain tert-butyl (2-(3-methoxy-1,2,4-oxadiazole-5-yl)ethyl)carbamate as a colorless oil. LC-MS I:t R =0.75min;[M+H] + = 244.33.

[0266] Step 3: Add 4M HCl (0.62 mL, 2.47 mmol) in dioxane to a solution of tert-butyl (2-(3-methoxy-1,2,4-oxadiazole-5-yl)ethyl) carbamate (150 mg, 0.62 mmol) in DCM (2 mL) with RT, and stir with RM in RT for 4 days, then at 50°C for 6 hours. Evaporate the mixture to obtain the title compound A-18.1 (79 mg, 71%) as a white solid. LC-MS I:t R =0.35min;[M+H] + = 144.21.

[0267] 2-(4-cyclopropyl-2H-1,2,3-triazole-2-yl)ethane-1-amine hydrochloride (AM-19.1) Step 1: Pd(OAc)2 (17.1 mg, 0.076 mmol) is mixed with tert-butyl N-[2-(4-bromo-2H-1,2,3-triazole-2-yl)ethyl]carbamate (291 mg, 1 mmol) and cyclopropylboronic acid (112 mg, 1.3 Add potassium phosphate, tribasic acid (758 mg, 3.5 mmol), and tricyclohexylphosphine (45.1 mg, 0.156 mmol) to a solution of RT in toluene (22 mL) and water (0.22 mL). Heat this mixture at 100°C for 18 hours. Cool this RM to RT, then filter the mixture and concentrate the filtrate. Elute FC (5%-40% ethyl in hept, eluting at hept / ethyl 7:3) f Purified with 0.27 (=0.27), tert-butyl (2-(4-cyclopropyl-2H-1,2,3-triazole-2-yl)ethyl)carbamate (194 mg, 77%) is obtained as a yellow oil. LC-MS B:t R =0.82min;[M+H] + = 253.34.

[0268] Step 2: Add 4M HCl (4.9 mL, 19.6 mmol) in dioxane to a solution of tert-butyl (2-(4-cyclopropyl-2H-1,2,3-triazole-2-yl)ethyl) carbamate (550 mg, 1.96 mmol) in DCM (3.4 mL) with RT. Stir RM in RT for 30 min, then concentrate RM to obtain the title compound AM-19.1 (432 mg, 98%) as a white solid, which is used directly in the next step. LC-MS B:t R =0.37min;[M+H] + = 153.11.

[0269] 2-(2-aminoethyl)-2H-1,2,3-triazole-4-carbonitride trifluoroacetate (AM-19.2) Step 1: Add vinylboronic anhydride pyridine complex (355 mg, 1.47 mmol) and 2M K2CO3 aqueous solution (2.5 mL) to a solution of tert-butyl N-[2-(4-bromo-2H-1,2,3-triazole-2-yl)ethyl]carbamate (429 mg, 1.47 mmol) in 1,2-dimethoxyethane (7 mL) in RT. Purge RM with Ar for 10 min, then add Pd(PPh3)4 (34.8 mg, 0.03 mmol). Heat this mixture at 80°C for 18 hours. Cool this RM to RT, filter, and fractionate the filtrate between water and ethyl acetate to separate the layers. Re-extract the aqueous phase with ethyl acetate (2x), combine the organic extracts, wash with brine, dry with Na2SO4, filter, and evaporate under vacuum. The crude product is purified by prep.HPLC (acidic) to obtain tert-butyl (2-(4-vinyl-2H-1,2,3-triazole-2-yl)ethyl)carbamate as a brown oil. LC-MS B:t R =0.81min;[M+H] + = 239.14.

[0270] Step 2: Add KMnO4 (401 mg, 1.0 mmol) to a solution of tert-butyl (2-(4-vinyl-2H-1,2,3-triazole-2-yl)ethyl)carbamate (118 mg, 0.50 mmol) in a 1:1 water:acetone mixture (6 mL), and stir the RM for 18 hours. Filter the RM, evaporate under vacuum, and purify the crude product by prep.HPLC (acidic) to obtain 2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-1,2,3-triazole-4-carboxylic acid as a white solid. LC-MS B:t R =0.61min;[M+H] + = 257.11.

[0271] Step 3: Add HATU (294 mg, 0.77 mmol) to a solution of RT in DMF (1 mL) of 2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-1,2,3-triazole-4-carboxylic acid (66 mg, 0.26 mmol), stir RM for 1 hour, then add to a 25% NH3 aqueous solution. (Add 0.99 mL (6.4 mmol) and continue stirring for 1 hour. Purify this RM directly by prep.HPLC (basic) to obtain tert-butyl (2-(4-carbamoyl-2H-1,2,3-triazole-2-yl)ethyl)carbamate as a white solid. LC-MS B:t R =0.58min;[M+H] + = 256.13.

[0272] Step 4: Add Burgess reagent (97 mg, 0.38 mmol) to tert-butyl (2-(4-carbamoyl-2H-1,2,3-triazole-2-yl)ethyl) Add rubamate (49 mg, 0.19 mmol) to a solution of ret in DCM (2 mL), and stir the RM for 18 hours. Pour this RM into water, dilute with DCM, and extract. Separate the layers, and re-extract the aqueous phase with DCM (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by prep.HPLC (acidic) to obtain tert-butyl (2-(4-cyano-2H-1,2,3-triazole-2-yl)ethyl)carbamate as a colorless oil. LC-MS B:t R =0.80min;[M+H] + = 238.14.

[0273] Step 5: The title compound is prepared from tert-butyl (2-(4-cyano-2H-1,2,3-triazole-2-yl)ethyl) carbamate in the same manner as described in Step 3 of AM-17.1. LC-MS B:t R =0.22min;[M+H] + = 138.16.

[0274] 2-(4-ethynyl-5-methyl-2H-1,2,3-triazole-2-yl)ethane-1-amine(AM-19.3) Step 1: Gradually add a 60% NaH dispersion (1.48 g, 37 mmol) in mineral oil to a solution of 4,5-dibromo-2H-1,2,3-triazole (4.0 g, 17.6 mmol) in DMF (120 mL) at 0°C. Warm the RM to RT, stir for 30 minutes, and then cool to 0°C. Gradually add N-(2-bromoethyl)phthalimide (9.9 g, 37 mmol), warm the RM to RT, and stir for 42 hours. Quench this RM in ice water and collect the precipitate by filtration. Wash the filter cake with Et2O to obtain 2-(2-(4,5-dibromo-2H-1,2,3-triazole-2-yl)ethyl)isoindorin-1,3-dione as a white solid. LC-MS I:t R = 0.98 min; deionization.

[0275] Step 2: Add ZnMe2 (2M in PhMe, 0.50 mL, 1.0 mmol) dropwise to a solution of 2-(2-(4,5-dibromo-2H-1,2,3-triazole-2-yl)ethyl)isoindoline-1,3-dione (500 mg, 1.25 mmol) and Pd(dppf)Cl2.DCM (10 mg, 0.013 mmol) in dioxane (2 mL) of RT, heat RM to 70°C, and stir for 3 hours. Concentrate this RM under vacuum, and fractionate the residue between water and ethyl acetate and extract. Separate the layers and re-extract the aqueous phase with ethyl acetate (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by prep.HPLC (basic) to obtain 2-(2-(4-bromo-5-methyl-2H-1,2,3-triazole-2-yl)ethyl)isoindoline-1,3-dione as a white solid. LC-MS I:t R = 0.92 min; non-ionization.

[0276] Step 3: The degassed mixture in DMF (2 mL) of 2-(2-(4-bromo-5-methyl-2H-1,2,3-triazole-2-yl)ethyl)isoindoline-1,3-dione (85 mg, 0.25 mmol), (tert-butyldimethylsilyl)acetylene (73 mg, 0.51 mmol), XPhos Pd G2 (20 mg, 0.03 mmol), and KOAc (75 mg, 0.76 mmol) is stirred at 70°C for 30 min. This RM is filtered through a Whatman filter and purified directly by prep.HPLC (basic) to obtain 2-(2-(4-((tert-butyldimethylsilyl)ethynyl)-5-methyl-2H-1,2,3-triazole-2-yl)ethyl)isoindoline-1,3-dione as a white solid. LC-MS I:t R =1.32min;[M+H] + = 395.29.

[0277] Step 4: Add hydrazine monohydrate (0.18 mL, 2.43 mmol) to 2-(2-(4-((tert-butyldimethylsilyl)ethynyl)-5-methyl-2H-1,2,3 Add a solution of triazole-2-yl)ethyl)isoindoline-1,3-dione (32 mg, 0.08 mmol) to RT in EtOH (1 mL), and heat RM under reflux for 2.5 hours. Cool this RM to RT and add MeCN. Filter the resulting suspension and discard the filter cake. Concentrate the filtrate under vacuum to obtain 2-(4-((tert-butyldimethylsilyl)ethynyl)-5-methyl-2H-1,2,3-triazole-2-yl)ethane-1-amine as a yellow oil. LC-MS I:t R =1.14min;[M+H+MeCN] + = 306.14.

[0278] Step 5: Add a 1M NaOH aqueous solution (0.25 mL, 0.25 mmol) to a solution of RT in EtOH (0.75 mL) of 2-(4-((tert-butyldimethylsilyl)ethynyl)-5-methyl-2H-1,2,3-triazole-2-yl)ethane-1-amine (26 mg, 0.1 mmol), and heat the RM at 60°C for 3 hours. After concentrating this RM, water and DCM are added. The layers are separated, and the aqueous phase is extracted with DCM (1x). The organic layers are combined, dried using a phase separator, and concentrated under vacuum to obtain the title compound as a yellow oil. LC-MS I:t R =0.51min;[M+H] + = 151.22.

[0279] 2-(4-fluoro-3-methoxyisoxazole-5-yl)ethane-1-amine hydrochloride (AM-20.1) Step 1: In a microwave tube, phthalic anhydride (354 mg, 2.36 mmol) is added to a suspension of RT in dioxane (12 mL) containing AM-13.1 (402 mg, 2.25 mmol) and DIPEA (0.47 mL, 2.7 mmol). The tube is sealed and heated at 100°C for 48 hours. Water is added to RM, the mixture is acidified with 1 M HCl, the product is extracted with siRNA, dried (MgSO4), filtered, and concentrated to obtain 2-(2-(3-methoxyisoxazole-5-yl)ethyl)isoindoline-1,3-dione (718 mg) as a white solid, which is used directly in the next step. LC-MS B:t R =0.85min;[M+H] + =273.09.

[0280] Step 2: Add Selectfluor (1.07 g, 2.87 mmol) to a 40°C solution of 2-(2-(3-methoxyisoxazole-5-yl)ethyl)isoindoline-1,3-dione (710 mg, 2.61 mmol) in tetramethylene sulfone (21.7 mL, 226 mmol), and heat RM at 120°C for 18 hours. Cool the resulting dark brown solution to around 50°C, then pour RM into pre-stirred H2O (30 mL), followed by siRNA (10 mL). Separate the two layers, and extract the inorganic layer with siRNA (5 mL). Combine the organic layers, wash with brine, dry (Na2SO4), filter, and concentrate. Prep: Purified by HPLC (acidic) to obtain 2-(2-(4-fluoro-3-methoxyisoxazole-5-yl)ethyl)isoindoline-1,3-dione (89 mg, 12%) as a colorless oil. LC-MS B:t R =0.90min;[M+H] + = 291.02.

[0281] Step 3: Add hydrazine monohydrate (0.222 mL, 2.93 mmol) to a solution of 2-(2-(4-fluoro-3-methoxyisoxazole-5-yl)ethyl)isoindoline-1,3-dione (85 mg, 0.293 mmol) in EtOH (3 mL) of RT, and heat RM at 80°C for 1 hour. Cool this RM to RT, and a white precipitate will form. Add ether, grind the solid (by-product), and then filter. Concentrate the filtrate to obtain the title compound AM-20.1 (40 mg, 85%) as a colorless oil, which is used directly in the next step. LC-MS B:t R =0.33min;[M+H] + = 161.08.

[0282] General method 1 for the synthesis of component A tert-butyl (S)-3-amino-4-((3-methoxyphenethyl)amino)- 4-Oxygen Pork Art (A-1.1) Step 1: Add HATU (4.53 g, 11.9 mmol) to a solution of RT in DMF (40 mL) containing Fmoc-L-aspartate beta-tert-butyl ester (5.0 g, 11.9 mmol), 3-methoxyphenethylamine (AM-1.4, 2.0 g, 13.1 mmol), and DIPEA (4.08 mL, 23.8 mmol), and stir the RM for 1 hour. Fractionate the RM between water and SiO and separate the layers. Re-extract the aqueous phase with SiO (2x), combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (elution with 20% to 80% ELISA in hept) to obtain tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoate as a white solid. LC-MS B:t R =1.12min;[M+H] + = 545.11.

[0283] Step 2: Add piperidine (4.95 mL, 49.5 mmol) to a solution of tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoate (5.45 g, 9.9 mmol) in DCM (60 mL), and stir the RM for 2 hours. Concentrate this RM under vacuum, and purify the residue directly by FC (elution at DCM:MeOH:NH3100:2:0.5) to obtain the title compound as a colorless oil. LC-MS B:t R =0.67min;[M+H] + = 323.34.

[0284] Table A-1 below lists component A, which is manufactured in the same manner as the two-step process sequence described above for A-1.1.

[0285] [Table 7]

[0286] [Table 8]

[0287] [Table 9]

[0288] General method 2 for the synthesis of component A 4-Allyl 1-benzyl L-aspartate hydrochloride (A-2.1) Step 1: Add benzyl bromide (2.15 mL, 17.7 mmol) to a mixture of Boc-L-aspartic acid-beta-allyl ester (5.0 g, 17.7 mmol) and KHCO3 (1.8 g, 17.7 mmol) in DMF (30 mL) of RT, and stir the RM for 16 hours. Concentrate this RM under vacuum, and fractionate the residue between H2O and EtOAC and extract. Separate the layers and re-extract the aqueous phase with ELISA (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain 4-allyl 1-benzyl (tert-butoxycarbonyl)-L-aspartate as a yellow oil. LC-MS B:t R =1.01min;[M+H] + = 364.45.

[0289] Step 2: Add 4M HCl (17.7 mL, 71 mmol) to dioxane, then add 4-allyl Add the solution of 1-benzyl (tert-butoxycarbonyl)-L-aspartate (6.43 g, 17.7 mmol) to dioxane (40 mL), and stir with RM for 5 hours. Mix. Remove volatile matter under vacuum, and grind the residue with Et2O to obtain the title compound as a white solid. LC-MS B:t R =0.61min;[M+H] + = 264.34.

[0290] Allyl (S)-3-amino-4-((2-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-4-oxobutanoate hydrochloride (A-2.2) Step 1: Allyl (S)-4-((2-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoate is prepared from (S)-4-(allyloxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid in the same manner as described in A-1.1 Step 1. LC-MS B:t R =0.94min;[M+H] + = 421.16.

[0291] Step 2: The title compound is prepared from (S)-4-(allyloxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid in the same manner as described in Step 2 of A-2.1. LC-MS B:t R =0.61min;[M+H] + = 321.20.

[0292] Table A-2 below lists component A, which is manufactured in the same manner as the two-step process sequence described above for A-2.2.

[0293] [Table 10]

[0294] General method 1 for the synthesis of component B Benzyl (R)-2-(2-amino-3-phenylpropoxy)-4,6-dimethoxybenzoate hydrochloride (B-1.1) Step 1: Add KHCO3 (1.6 g, 15.8 mmol) and benzyl bromide (2.1 mL, 17.3 mmol) to a solution of 2-hydroxy-4,6-dimethoxybenzoic acid (3 g, 14.4 mmol) in DMF (40 mL), and stir the RM for 16 hours. Filter the RM and concentrate the filtrate under vacuum. Fractionate the residue between water and siRNA and extract. Separate the layers and re-extract the aqueous phase with siRNA (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 5%-40% siRNA in hept) to obtain benzyl 2-hydroxy-4,6-dimethoxybenzoate as a white solid. LC-MS B:t R =1.04min;[M+H] + = 289.23.

[0295] Step 2: Add DIAD (3.0 mL, 15 mmol) to a mixture of 2-hydroxy-4,6-dimethoxybenzoate (3.16 g, 10.7 mmol), tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (4.12 g, 16.1 mmol), and PPh3 (4.27 g, 16.1 mmol) in THF (40 mL) at 0°C, and stir RM at RT for 16 hours. Concentrate this mix and remove the residue from F Direct purification with C (eluted with 20% to 100% ethyl acetate in hept) yields benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-4,6-dimethoxybenzoate as a colorless oil. LC-MS B:t R =1.16min;[M+H] + = 522.26.

[0296] Step 3: Add 4M HCl (21 mL, 86.3 mmol) in dioxane to a solution of benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-4,6-dimethoxybenzoate (4.64 g, 8.63 mmol) in dioxane (40 mL), and stir RM under RT for 5 hours. Remove volatile matter under vacuum, and grind the residue with Et2O (3x) to obtain the title compound as a white solid. LC-MS B:t R =0.84min;[M+H] + = 422.36.

[0297] Table B-1 below lists component B, which is manufactured in the same manner as the three-step sequence described above for B-1.1. If the HCl salt is highly hygroscopic, the amine is subjected to a basic post-treatment to release the free base.

[0298] [Table 11]

[0299] Benzyl (R)-2-(2-amino-3-phenylpropoxy)-6-ethoxybenzoate hydrochloride (B-1.17) Step 1: Add benzyl bromide (0.92 mL, 7.6 mmol) to a mixture of 2,6-dihydroxybenzoic acid (1.0 g, 6.3 mmol) and NaHCO3 (582 mg, 6.9 mmol) in DMF (16 mL) of RT, and heat the RM at 60°C for 6 hours. Fractionate and extract the RM between water and ethyl acetate. Separate the layers and re-extract the aqueous phase with ethyl acetate. (2x). The organic extracts are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (elution with 0%-10% siRNA in hept) to obtain benzyl 2,6-dihydroxybenzoate as a colorless oil. LC-MS B:t R =0.98min;[M+H] + = 245.35.

[0300] Step 2: Add ethyl iodide (0.086 mL, 1.1 mmol) to a mixture of benzyl 2,6-dihydroxybenzoate (376 mg, 1.1 mmol) and Cs2CO3 (351 mg, 1.1 mmol) in DMF (15 mL) of RT, and stir the RM for 16 hours. This RM is fractionated between water and ethyl ammonium, and the layers are separated. The aqueous phase is re-extracted with ethyl ammonium (2x), the organic layers are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluted with 0%-10% ethyl ammonium in hept) to obtain benzyl 2-ethoxy-6-hydroxybenzoate as a yellow solid. LC-MS B:t R =1.01min;[M+H] + = 273.29.

[0301] Steps 3-4: The title compound is prepared from benzyl 2-ethoxy-6-hydroxybenzoate according to steps 2 and 3 described for B-1.1. LC-MS B:t R =0.85min;[M+H] + = 406.40.

[0302] Benzyl (R)-4-(2-amino-3-phenylpropoxy)-2-methoxynicotinate (B-1.18) Step 1: Add CDI (615 mg, 3.8 mmol) to a solution of 4-hydroxy-2-methoxynicotinic acid (452 ​​mg, 2.7 mmol) in DMF (5 mL), and heat RM at 60°C for 2 hours. After cooling to 0°C, add DMF (5 mL), benzyl alcohol (0.5 mL, 4.8 mmol), and NaH (118 mg, 2.95 mmol), and heat RM to RT, stirring for 16 hours. Fractionate RM between 1N HCl and DCM and separate the layers. Re-extract the aqueous phase with DCM (1x), combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 0%~35% siRNA in hept) to obtain benzyl 4-hydroxy-2-methoxynicotinate as a white solid. LC-MS F:t R =2.07min;[M+H] + = 260.0.

[0303] Step 2: Benzyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotinate is prepared from benzyl 4-hydroxy-2-methoxynicotinate and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the same manner as described in Step 2 of B-1.1. LC-MS J:t R =2.34min;[M+H] + = 493.2.

[0304] Step 3: Add TFA (3.65 mL, 4.77 mmol) to a 0°C solution of benzyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotinate (235 mg, 0.48 mmol) in DCM (6 mL), warm the RM to RT, and stir for 3 hours. Concentrate the RM under vacuum, and fractionate the residue between DCM and saturated NaHCO3 aqueous solution, separating the layers. Re-extract the aqueous phase with DCM (1x), combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain the title compound as a yellow oil. LC-MS I:t R =1.01min;[M+H] + = 393.15.

[0305] (R)-2-(2-((tert-butoxycarbonyl)amino)-3-(pyridine-2-yl)propoxy)-1-naphthoic acid (B-1.24) Step 1: Benzyl 2-hydroxy-1-naphthoate It is manufactured from 2-hydroxy-1-naphthoic acid in the same manner as described in Step 1 of B-1.1. LC-MS B:t R =1.08min;[M+H] + = 279.51.

[0306] Step 2: Add (R)-2-((tert-butoxycarbonyl)amino)-3-(pyridine-2-yl)propanoic acid (500 mg, 1.8 mmol) to a suspension of LAH (85 mg, 2.2 mmol) in Et2O (13 mL) at 0°C, warm the RM to RT, and stir for 1 hour. Cool the RM to 0°C, quench with ethyl acetate, add saturated Rochelle salt aqueous solution, maintain vigorous stirring for 30 min, and then separate the layers. Re-extract the aqueous phase with ethyl acetate (3x), combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain tert-butyl (R)-(1-hydroxy-3-(pyridine-2-yl)propan-2-yl)carbamate as a yellow oil. LC-MS I:t R =0.63min;[M+H] + = 253.22.

[0307] Step 3: Benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-(pyridine-2-yl)propoxy)-1-naphthoate is prepared from the products of Steps 1 and 2 in the same manner as described in B-1.1 Step 2. LC-MS I:t R =1.23min;[M+H] + = 514.18.

[0308] Step 4: A solution of benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-(pyridine-2-yl)propoxy)-1-naphthoate (108 mg, 0.17 mmol) in MeOH (3 mL) is evacuated / purged with N2 (3x), and then 10% Pd / C (18 mg, 10 mol%) is added. RM is evacuated / purged with H2 (3x), and stirred under an H2 atmosphere for 2 hours. RM is filtered through a Celite pad, and the filtrate is concentrated under vacuum to obtain the title compound as a white solid. LC-MS I:t R =0.48min;[M+H] + = 423.23.

[0309] (R)-3-(3-(benzo[b]thiophen-3-yl)-2-((tert-butoxycarbonyl)amino)propoxy)quinoline-4-carboxylic acid (B-1.25) Step 1: Add a solution of TMS-diazomethane (2M in Et2O, 0.6 mL, 1.2 mmol) to a solution of (R)-3-(benzo[b]thiophen-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (128 mg, 0.4 mmol) in MeOH (2 mL) at 0°C. Warm the RM to RT and stir for 2 hours. Next, purify this RM by prep.HPLC (basic) to obtain methyl (R)-3-(benzo[b]thiophen-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate as a white solid. LC-MS I:t R =1.08min;[M+H] + = 336.25.

[0310] Step 2: Add NaBH4 (30 mg, 0.78 mmol) to a mixture of methyl (R)-3-(benzo[b]thiophen-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (130 mg, 0.39 mmol) in EtOH (1 mL) and H2O (1 mL) at 0°C. Warm the RM to RT and stir for 16 hours. Next, purify this RM by prep.HPLC (basic) to obtain tert-butyl (R)-(1-(benzo[b]thiophen-3-yl)-3-hydroxypropan-2-yl)carbamate as a colorless oil. LC-MS I:t R =0.97min;[M+H] + = 308.16.

[0311] Step 3: Benzyl 3-hydroxyquinoline-4-carboxylate is prepared from 3-hydroxyquinoline-4-carboxylic acid in the same manner as described in Step 1 of B-1.1. LC-MS B:t R =0.95min;[M+H] + = 280.19.

[0312] Step 4: Benzyl (R)-3-(3-(benzo[b]thiophen-3-yl)-2 -((tert-butoxycarbonyl)amino)propoxy)quinoline-4-carboxylate is prepared from the products of steps 2 and 3 above, in the same manner as described in B-1.1 Step 2. LC-MS I:t R =0.85min;[M+H] + = 569.24.

[0313] Step 5: Add LiOH.H2O (20 mg, 0.48 mmol) to a mixture of benzyl (R)-3-(3-(benzo[b]thiophen-3-yl)-2-((tert-butoxycarbonyl)amino)propoxy)quinoline-4-carboxylate (136 mg, 0.24 mmol) in THF:H2O 2:1 (3 mL), and heat the RM at 50°C for 16 hours. Concentrate the RM under vacuum, and fractionate and extract the residue between 1 M aqueous HCl and ELISA. Separate the layers and re-extract the aqueous phase with ELISA (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain the title compound as a yellow solid. LC-MS B:t R =0.96min;[M+H] + = 479.23.

[0314] Benzyl (R)-3-(2-amino-3-phenylpropoxy)-5-fluoroquinoline-4-carboxylate dihydrochloride (B-1.27) Step 1: Add 4-fluoroindoline-2,3-dione (4.8 g, 27.6 mmol), then bromopyruvic acid (6.47 g, 38 mmol) to the solution of RT in water (80 mL) with KOH (18.6 g, 331 mmol), and stir RM for 16 hours. Add KOH (4.6 g, 83 mmol) and bromopyruvic acid (2.88 g, 17.3 mmol), and continue stirring for another 16 hours. Pour this RM into a 1 M aqueous HCl solution, collect the resulting precipitate by filtration, wash with water and ELISA, and then dry in a vacuum oven at 40°C to obtain 5-fluoro-3-hydroxyquinoline-4-carboxylic acid as a brown solid. LC-MS B:t R =0.39min;[M+H] + = 208.09.

[0315] Step 2-4: The title compound is prepared from 5-fluoro-3-hydroxyquinoline-4-carboxylic acid according to the reaction sequence described in B-1.1. LC-MS B:t R =0.83min;[M+H] + = 431.14.

[0316] General method 2 for the synthesis of component B Methyl (R)-2-(2-amino-3-phenylpropoxy)-6-fluorobenzoate hydrochloride (B-2.1) Step 1: Methyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-6-fluorobenzoate is prepared from methyl 2-fluoro-6-hydroxybenzoate and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the same manner as described in Step 2 of B-1.1. LC-MS J:t R =2.28min;[M-Boc+H] + =304.1.

[0317] Step 2: Prepare the title compound in the same manner as described in Step 3 of B-1.1. LC-MS J:t R =1.95min;[M+H] + =304.1.

[0318] Table B-2 below lists component B, which is manufactured in the same manner as the two-step sequence described above for B-2.1. If the HCl salt is highly hygroscopic, the amine is subjected to a basic post-treatment to release the free base.

[0319] [Table 12]

[0320] Methyl (R)-6-(2-amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-7-carboxylate hydrochloride (B-2.5) Step 1: Carefully add nitric acid (0.36 mL, 6.0 mmol) to a solution of methyl 2,6-dihydroxybenzoate (1.0 g, 6.0 mmol) in acetic acid (10 mL) at 0°C. Warm the RM to RT and stir for 1 hour. Pour this RM into cold water, collect the precipitate by filtration, wash with further cold water, and dry under vacuum to obtain methyl 2,6-dihydroxy-3-nitrobenzoate as a pink solid. LC-MS B:t R = 0.75 min; non-ionization. 1 H NMR (DMSO) δ: 11.73 (s, 1H), 10.94 (s, 1H), 8.05 (d, J=9.4Hz, 1H), 6.60 (d, J=9.4Hz, 1H), 3.81 (s, 3H).

[0321] Step 2: Add 4M HCl (1.45 mL, 5.8 mmol) in dioxane to a suspension of methyl 2,6-dihydroxy-3-nitrobenzoate (500 mg, 2.3 mmol) in triethyl orthoacetate (13.5 mL, 72 mmol). After evacuating / purging RM with N2 (3x), add 10% Pd / C (173 mg, 7 mol%). Evacuate / purge RM with H2 (3x) and stir under an H2 atmosphere for 16 hours. Filter RM through a Celite pad and concentrate the filtrate under vacuum to obtain methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate as a yellow solid. LC-MS B:t R =0.78min;[M+H] + = 208.32. 1 H NMR (DMSO) δ:10.69(s, 1H), 7.76(d, J=8.7Hz, 1H), 6.96(d, J=8.7Hz, 1H), 3.97(s, 3H), 2.60(s, 3H).

[0322] Step 3-4: The title compound is prepared from methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate according to the reaction sequence described in B-2.1. LC-MS B:t R =0.69min;[M+H] +=341.35. Note: The title compound is unstable and should not be stored for long periods.

[0323] Methyl (R)-6-(2-amino-3-phenylpropoxy)benzo[d]oxazole-7-carboxylate hydrochloride (B-2.6) The title compound is prepared by replacing triethyl orthoacetate with trimethyl orthoformate in step 2, according to the reaction sequence described in B-2.5. LC-MS B:t R =0.66min;[M+H] + =327.27. Note: The title compound is unstable and should not be stored for long periods.

[0324] Methyl (R)-6-(2-amino-3-phenylpropoxy)-1-methyl-1H-benzo[d]imidazole-7-carboxylate dihydrochloride (B-2.7) Step 1: Methylamine (2M in MeOH, 7.9 mL, 15.8 mmol) is methylated. Add 2,6-difluoro-3-nitrobenzoate (5.0 g, 22.6 mmol) to the solution of RT in MeOH (40 mL), and stir RM for 1 hour. Concentrate this RM under vacuum and remove the residue. i After suspension in a mixture of PrOH and water, filter. Wash the filter cake with water, dry, and purify by FC (eluting with 0%-20% siRNA in hept) to obtain methyl 6-fluoro-2-(methylamino)-3-nitrobenzoate as a yellow solid. LC-MS B:t R =0.87min;[M+H] + = 229.38.

[0325] Step 2: Gradually add a 60% NaH dispersion in mineral oil (549 mg, 13.7 mmol) to a solution of Boc-D-phenylalaninol (2.93 g, 11.4 mmol) in THF (60 mL) at 0°C, stir for 10 minutes, then add a solution of methyl 6-fluoro-2-(methylamino)-3-nitrobenzoate (2.4 g, 10.4 mmol) in THF (10 mL). Heat this RM to RT, stir for 1 hour, then cool to 0°C and quench with water. Evaporate the THF under vacuum, dilute the remaining aqueous phase with more water, and extract with siRNA (3x). Combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (elution with 0% to 30% ELISA in hept) to obtain methyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-(methylamino)-3-nitrobenzoate as a yellow solid. LC-MS B:t R =1.09min;[M+H] + = 460.26.

[0326] Step 3-4: The title compound is prepared from methyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-(methylamino)-3-nitrobenzoate according to the hydrogenation / cyclization and Boc-cleavage reaction sequence described in B-2.6. LC-MS B:t R =0.54min;[M+H] + =340.41.

[0327] Methyl (R)-6-(2-amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-5-carboxylate hydrochloride (B-2.8) The title compound is prepared from methyl 2,4-dihydroxybenzoate according to the reaction sequence described in B-2.5. LC-MS B:t R =0.70min;[M+H] + = 341.39.

[0328] Methyl (R)-6-(2-amino-3-phenylpropoxy)-1,2-dimethyl-1H-benzo[d]imidazole-7-carboxylate hydrochloride (B-2.9) The title compound is prepared from methyl 2,6-difluoro-3-nitrobenzoate, using triethyl orthoacetate instead of trimethyl orthoformate, according to the reaction sequence described in B-2.7. LC-MS B:t R =0.50min;[M+H] + = 354.45.

[0329] Ethyl (R)-2-(2-amino-3-phenylpropoxy)imidazo[1,2-a]pyridine-3-carboxylate dihydrochloride (B-2.10) Step 1: 2-aminopyridine (7.08 g, 75 mmol) is suspended in diethyl bromomalonate (38.5 mL, 226 mmol) and heated at 100°C for 1.5 hours. This RM is fractionated between water and ethyl acetate, and the layers are separated. The organic phase is discarded, and the aqueous phase is freeze-dried to obtain the crude product, which is purified by prep.HPLC (basic) to obtain ethyl 2-hydroxyimidazo[1,2-a]pyridine-3-carboxylate as a cream-colored solid. LC-MS J:t R =0.41min;[M+H] + = 207.1.

[0330] Step 2-3: Prepare the title compound from ethyl 2-hydroxyimidazo[1,2-a]pyridine-3-carboxylate in the same manner as described in B-2.1. LC-MS I:t R =0.91min;[M+H] + = 340.28.

[0331] Methyl (R)-5-(2-amino-3-phenylpropoxy)-2,3-dihydrobenzofuran-4-carboxylate hydrochloride (B-2.11) Step 1-2: A suspension of methyl 2,5-dihydroxybenzoate (1.02 g, 6.1 mmol) and MgSO4 (2.1 g, 17.5 mmol) in Et2O (10 mL) is purged with argon for 10 min, then Ag2O (3.46 g, 14.9 mmol) is added, and the RM is stirred for 16 hours. This RM is filtered through a Celite pad, and the filtrate is concentrated under vacuum to obtain the crude product methyl 3,6-dioxocyclohexa-1,4-diene-1-carboxylate, which is redissolved in PhMe (50 mL), then n-butyl vinyl ether (1.7 mL, 13.1 mmol) is added, and the RM is heated at 45°C for 19 hours. The RM is poured into water to separate the phases. The aqueous phase is extracted with ELISA (3x), the organic phase is combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (elution with 1% to 50% ethyl acetate in hept) to obtain methyl 2-butoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate as a white solid. LC-MS J:t R =2.23min;[M+H] + = 267.1.

[0332] Step 3: Add TFA (0.9 mL, 11.75 mmol) to a solution of methyl 2-butoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate (761 mg, 2.86 mmol) in PhMe (25 mL), and heat the RM under reflux for 4.5 hours. Pour this RM into water to separate the phases. Extract the aqueous phase with ethyl acetate (3x), combine with the organic phase, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 0%~50% ethyl acetate in hept) to obtain methyl 5-hydroxybenzofuran-4-carboxylate as a white solid. LC-MS J:t R = 2.00 min; deionization. 1 H NMR(DMSO) δ: 10.83(bs, 1H), 8.12(d, J=2.2Hz, 1H), 7.82(d, J=8.9Hz, 1H), 7.19(d, J=2.1Hz, 1H), 6.95(d, J=8.9Hz, 1H), 4.00(s, 3H).

[0333] Step 4: A solution of methyl 5-hydroxybenzofuran-4-carboxylate (395 mg, 2.06 mmol) and AcOH (1.3 mL, 22.5 mmol) in siRNA (20 mL) is evacuated / purged with N2 (3x), and then 10% Pd / C (109 mg, 5 mol%) is added. The RM is evacuated / purged with H2 (3x), and stirred under an H2 atmosphere for 21 hours. The RM is filtered through a Celite pad, and the filtrate is concentrated under vacuum to obtain methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate as a white solid. LC-MS F:t R =1.88min;[M+H] + =195.0.

[0334] Steps 5-6: Prepare the title compound from methyl 5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate in the same manner as described in B-2.1. LC-MS J:t R =1.97min;[M+H] + = 328.1.

[0335] Methyl (R)-3-(2-amino-3-phenylpropoxy)-6-methoxypicolinate hydrochloride (B-2.12) Process 1: Cs2CO 3( Add 2.4 g, 7.4 mmol) and BnBr (1.31 mL, 11.1 mmol) to a solution of RT in methyl 3-hydroxypicolinate (0.94 g, 6.1 mmol) in DMF (20 mL), and heat RM at 70°C for 2 hours. Concentrate this RM under vacuum, and fractionate the residue between water and SiO, then extract. Separate the layers and extract the aqueous phase. The extract is re-extracted with ethyl acetate (2x). The organic extracts are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluting with 30%-45% ethyl acetate in hept) to obtain methyl 3-(benzyloxy)picolinate as a brown oil. LC-MS J:t R =1.86min;[M+H] + =244.0.

[0336] Step 2: Add mCPBA (1.51 g, 6.1 mmol) to a 0°C solution of methyl 3-(benzyloxy)picolinate (1.19 g, 4.9 mmol) in DCM (10 mL), warm the RM to RT, and stir for 16 hours. This RM is fractionated and extracted between saturated NaHSO3 aqueous solution and DCM. Separate the layers and re-extract the aqueous phase with DCM (2x). Combine the organic extracts, wash with saturated NaHCO3 aqueous solution, dry with Na2SO4, filter, and evaporate under vacuum to obtain 3-(benzyloxy)-2-(methoxycarbonyl)pyridine 1-oxide as a brown solid. LC-MS J:t R =1.72min;[M+H] + = 260.0.

[0337] Step 3: Add Ac2O (7.0 mL, 74.2 mmol) to 3-(benzyloxy)-2-(methoxycarbonyl)pyridine 1-oxide (1.27 g, 4.9 mmol), and heat RM at 100°C for 1 hour. Add Ac2O (7 mL, 74.2 mmol) and continue heating for 2 hours. Add EtOH (10 mL), heat RM under reflux for 1 hour, and then cool overnight in RT. Concentrate this RM under vacuum, azeotrope the residue with PhMe (1x), add 2M NaOH (10 mL) in MeOH, and heat RM at 80°C for 3 hours. Evaporate MeOH under vacuum, acidify the remaining aqueous solution with 1M HCl, and extract with DCM (4x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain 3-(benzyloxy)-6-hydroxypicolinic acid as a brown solid. LC-MS G:t R =2.74min;[M+H] + = 246.0.

[0338] Step 4: Add Ag2CO3 (4.5 g, 16.3 mmol) and MeI (0.56 mL, 9.0 mmol) to a suspension of 3-(benzyloxy)-6-hydroxypicolinic acid (1.0 g, 4.1 mmol) in acetone (60 mL), and heat the RM under reflux for 2 hours. Cool the RM to RT, acidify with 1 M HCl, and concentrate under vacuum. Fractionate the residue between water and DCM and extract. Filter the layers to separate them, and re-extract the aqueous phase with DCM (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 10%-70% siRNA in hept) to obtain methyl 3-(benzyloxy)-6-methoxypicolinate as a colorless oil. LC-MS J:t R =1.98min;[M+H] + = 274.2.

[0339] Step 5: A solution of methyl 3-(benzyloxy)-6-methoxypicolinate (847 mg, 2.94 mmol) in EtOH (20 mL) is evacuated / purged with N2 (3x), and then 10% Pd / C (157 mg, 5 mol%) is added. The RM is evacuated / purged with H2 (3x), and stirred under an H2 atmosphere for 2 hours. The RM is filtered through a Celite pad, and the filtrate is concentrated under vacuum to obtain methyl 3-hydroxy-6-methoxypicolinate as a white solid. LC-MS J:t R = 1.48 min; deionization.

[0340] Steps 6-7: Prepare the title compound from methyl 3-hydroxy-6-methoxypicolinate in the same manner as described in B-2.1. LC-MS J:t R =1.85min;[M+H] + = 317.2.

[0341] Methyl (R)-5-(2-amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-4-carboxylate hydrochloride (B-2.15) The title compound is described as B-2.5, derived from methyl 2,5-dihydroxybenzoate. The product is manufactured according to the reaction sequence provided. LC-MS D: t R =0.63min;[M+H] + = 341.37.

[0342] Methyl (R)-3-(2-amino-3-phenylpropoxy)isoquinoline-4-carboxylate dihydrochloride (B-2.16) Step 1: Gradually add NBS (1.30 g, 7.3 mmol) to a solution of isoquinoline-3-amine (1.0 g, 6.9 mmol) in DCM (20 mL) and EtOH (10 mL) at 0°C. Stir the RM for 30 minutes, then warm it overnight in RT. Concentrate this RM under vacuum, grind the residue with DCM, and filter. Concentrate the filtrate under vacuum, purify the residue with FC (eluting with 25%-40% siRNA in hept) to obtain 4-bromoisoquinoline-3-amine as a brown solid. Continued... i The purity is further increased by grinding with Pr2O. LC-MS J:t R =1.84min;[M+H] + = 223.0.

[0343] Step 2: A solution of 4-bromoisoquinoline-3-amine (796 mg, 3.6 mmol) and DIPEA (1.87 mL, 10.7 mmol) in DMF (10 mL) and MeOH (5 mL) is evacuated / purged with CO (3x), and then Pd(dppf)Cl2 (261 mg, 0.36 mmol) is added. The RM is evacuated / purged with CO (3x), and stirred at 75°C for 20 hours under a CO atmosphere. This RM is cooled to RT, concentrated under vacuum, and the residue is fractionated between water and ethyl acetate and extracted. The layers are separated, and the aqueous phase is re-extracted with ethyl acetate (2x). The organic extracts are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum to obtain methyl 3-aminoisoquinoline-4-carboxylate as a yellow solid. LC-MS J:t R =1.78min;[M+H] + = 203.1.

[0344] Step 3: A solution of NaNO2 (135 mg, 2.0 mmol) in H2O (0.6 mL) is added to a suspension of methyl 3-aminoisoquinoline-4-carboxylate (330 mg, 1.63 mmol) in a 2.5 M H2SO4 aqueous solution (4 mL, 10 mmol) at 0°C, and the RM is stirred for 1.5 hours. This RM is neutralized by adding a 2 M NaOH aqueous solution and extracted with ethyl acetate (4x). The organic extracts are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum to obtain methyl 3-hydroxyisoquinoline-4-carboxylate as a yellow solid. LC-MS F:t R =1.52min;[M+H] + =204.0.

[0345] Steps 4-5: The title compound is prepared from methyl 3-hydroxyisoquinoline-4-carboxylate according to the reaction sequence described in B-2.1. LC-MS J:t R =1.97min;[M+H] + = 337.2.

[0346] Methyl (R)-6-(2-amino-3-phenylpropoxy)imidazo[1,2-a]pyridine-5-carboxylate dihydrochloride (B-2.17) Step 1: Add Br2 (0.81 mL, 15.7 mmol) dropwise to a solution of methyl-3-hydroxypicolinate (2.41 g, 15.7 mmol) in water (110 mL) at 0°C. Warm the RM to RT and stir overnight. Quench this RM with a 40% sodium bisulfite aqueous solution and extract with DCM (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain methyl 6-bromo-3-hydroxypicolinate as a white solid. LC-MS G:t R =3.19min;[M+H] + = 231.9.

[0347] Step 2: Methyl (R)-6-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate is converted from methyl 6-bromo-3-hydroxypicolinate and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate using the same procedure as described in B-1.1 Step 2. Manufactured in the following manner: LC-MS F:t R =2.16min;[M+H- t AD] + = 409.0.

[0348] Step 3: Add Pd2(dba)3 (483 mg, 0.53 mmol) and XPhos (201 mg, 0.42 mmol) to the mixture of RT in dioxane (130 mL) containing methyl (R)-6-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (5.0 g, 10.5 mmol), benzyl carbamate (1.67 g, 11.1 mmol), and Cs2CO3 (5.15 g, 15.8 mmol), then heat RM to 95°C and stir for 48 hours. This RM is cooled to RT, filtered, and the filtrate is concentrated under vacuum. It is then purified by FC (eluting with 0%-40% ethyl acetate in hept) to obtain methyl (R)-6-(((benzyloxy)carbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate as an orange solid. LC-MS F:t R =2.24min;[M+H] + = 536.2.

[0349] Step 4: A solution of methyl (R)-6-(((benzyloxy)carbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (1.43 g, 2.19 mmol) in EtOH (20 mL) is purged (3 times) with N2 / vacuum, and then 10% Pd / C (70 mg, 0.07 mmol) is added. After further inactivation three times, an H2 balloon is attached and the RM is stirred at 55°C for 1 hour. This mix is ​​filtered through a Celite plug rinsed with EtOH. The filtrate is concentrated to obtain methyl (R)-6-amino-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate as a yellow oil. LC-MS J:t R =2.00min;[M+H] + = 402.2.

[0350] Step 5: Add a 50% aqueous solution of 2-chloroacetaldehyde (0.475 mL, 3.74 mmol) to a mixture of methyl (R)-6-amino-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (0.50 g, 1.25 mmol) and NaHCO3 (209 mg, 2.49 mmol) in EtOH (15 mL). Heat the RM to 70°C and stir for 5 hours. Concentrate the RM under vacuum, and fractionate the residue between water and ethyl acetate for extraction. Separate the layers and re-extract the aqueous phase with ethyl acetate (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (eluting with 50% to 100% ethyl acetate in hept) to obtain methyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)imidazo[1,2-a]pyridine-5-carboxylate as a white solid. LC-MS I:t R =1.01min;[M+H] + = 426.52.

[0351] Step 6: Prepare the title compound in the same manner as described in Step 3 of B-1.1. LC-MS J:t R =1.83min;[M+H] += 326.2.

[0352] General method 3 for the synthesis of component B Ethyl (R)-4-(2-amino-3-phenylpropoxy)nicotinate dihydrochloride (B-3.1) Step 1: Add H2SO4 (1.86 mL, 34.9 mmol) dropwise to a solution of 4-hydroxynicotinic acid (5.0 g, 34.9 mmol) in EtOH (50 mL) at 0°C, and heat RM for 3d under reflux. After concentration under vacuum, carefully add saturated NaHCO3 aqueous solution to the residue, filter the solid, and dry to obtain ethyl 4-hydroxynicotinate as a grayish-white solid. LC-MS D:t R =0.37min;[M+H] + = 168.05.

[0353] Step 2: Ethyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)nicotinate is prepared from ethyl 4-hydroxynicotinate and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the same manner as described in Step 2 of B-1.1. LC-MS J:t R =2.17min;[M+H] + = 401.2.

[0354] Step 3: Prepare the title compound in the same manner as described in Step 3 of B-1.1. LC-MS B:t R =0.52min;[M+H] + = 301.28.

[0355] Table B-3 below lists component B, which is manufactured in the same manner as the three-step sequence described above for B-3.1. If the HCl salt is highly hygroscopic, the amine is subjected to a basic post-treatment to release the free base.

[0356] [Table 13]

[0357] General method 4 for the synthesis of component B Benzyl (R)-2-(2-amino-3-phenylpropoxy)-6-(trifluoromethoxy)benzoate hydrochloride (B-4.1) Step 1: Add a solution of 3-(trifluoromethoxy)phenol (5.0 g, 28.1 mmol) in THF (40 mL) dropwise to a suspension of RT in THF (50 mL) with NaH (1.35 g, 33.7 mmol). Stir the resulting mix for 15 minutes, then add methoxymethyl bromide (2.98 mL, 36.5 mmol) dropwise. Stir for 1 hour, then quench this RM by adding saturated Na2CO3 aqueous solution, dilute with some water, i Extraction is performed with Pr2O. The organic phase is washed with NaHCO3 and brine, dried with Na2SO4, filtered, and evaporated under vacuum to obtain 1-(methoxymethoxy)-3-(trifluoromethoxy)benzene as a colorless oil. LC-MS J:t R = 2.13 min; non-ionization.

[0358] Step 2: A solution of 1-(methoxymethoxy)-3-(trifluoromethoxy)benzene (3.0 g, 13.5 mmol) in THF (7 mL) is added dropwise to a solution of sBuLi (1.4 M in cyclohexane, 12.54 mL, 17.55 mmol) in a mixture of THF (10 mL) and cyclohexane (15 mL) at -78°C, and the RM is stirred for 1.5 hours. This RM is quenched on freshly crushed dry ice and then heated to RT. After stirring for 15 minutes, a few drops of MeOH are added, and then the RM is concentrated under vacuum. After dissolving the intermediate lithium carboxylate in DMF (20 mL), KHCO3 (0.41 g, 4.1 mmol) and benzyl bromide (1.93 mL, 16.2 mmol) are added, and the RM is stirred for 18 hours. The RM is filtered, and the filtrate is concentrated under vacuum. The residue is fractionated between water and siRNA and extracted. The layers are separated, and the aqueous phase is re-extracted with ethyl acetate (2x). The organic extracts are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluting with 0%-15% ethyl acetate in hept) to obtain benzyl 2-(methoxymethoxy)-6-(trifluoromethoxy)benzoate as a colorless oil. LC-MS J:t R =2.24min;[M+H] + = 357.1.

[0359] Step 3: Add TFA (2 mL, 26.1 mmol) to benzyl 2-(methoxymethoxymethyl phosphate). Add the solution of (1.39 g, 3.9 mmol) of (C)-6-(trifluoromethoxy)benzoate to DCM (20 mL), and stir the resulting mix for 1 hour. Concentrate this RM under vacuum, and co-evaporate the residue with DCM (2x) to obtain benzyl 2-hydroxy-6-(trifluoromethoxy)benzoate as a white solid. LC-MS J:t R =2.22min;[MH] - =311.0.

[0360] Step 4: Benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-6-(trifluoromethoxy)benzoate is converted to benzyl 2-hydroxy-6-(trifluoromethoxy)benzoate and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate is prepared in the same manner as described in Step 2 of B-1.1. LC-MS J:t R =2.50min;[M-Boc+H] + = 446.1.

[0361] Step 5: Prepare the title compound in the same manner as described in Step 3 of B-1.1. LC-MS J:t R =2.30min;[M+H] + = 446.1.

[0362] Table B-4 below lists component B, which is manufactured in the same manner as the five-step sequence described in B-4.1. If the HCl salt is highly hygroscopic, the amine is subjected to a basic post-treatment to release the free base.

[0363] [Table 14]

[0364] Ethyl (R)-4-(2-amino-3-phenylpropoxy)-2-methylnicotinate dihydrochloride (B-4.5) Step 1: Add NaH (370 mg, 9.26 mmol) to a 0°C solution of 2-chloro-4-hydroxypyridine (1.0 g, 7.72 mmol) in DMF (20 mL). Heat the RM to RT, stir for 15 minutes, and then recool to 0°C. Add chloromethyl methyl ether (1.17 mL, 15.4 mmol), heat the RM to RT, and stir for 1 hour. Quench this RM by adding saturated Na2CO3 aqueous solution, dilute with some water, and extract with Et2O. Wash the organic phase with NaHCO3 and brine, dry with Na2SO4, filter, and evaporate under vacuum to obtain the crude product. Purify this by FC (eluting with 20% to 100% ethyl ethyl in hept) to obtain 2-chloro-4-(methoxymethoxy)pyridine as a colorless oil. LC-MS I:t R =0.72min;[M+H] + =174.09.

[0365] Step 2: Add nBuLi (2.5 M in hex, 1.18 mL, 2.94 mmol) to a solution of 2-chloro-4-(methoxymethoxy)pyridine (413 mg, 2.36 mmol) in THF (7 mL) at -78°C, stir for 30 minutes, then add this RM to a cannula. Add ethyl chloroformate (0.23 mL, 2.36 mmol) in THF (4 mL) at -78°C via cannula and stir at -78°C for 1 hour. Warm RM to RT and stir for 2 hours, then quench with NaHCO3 and extract with siRNA (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (elution with 10%-70% siRNA in hept) to obtain ethyl 2-chloro-4-(methoxymethoxy)nicotinate as a yellow oil. LC-MS B:t R =0.82min;[M+H] + = 246.29.

[0366] Step 3: Add ZnMe2 (2M in PhMe, 0.46 mL, 0.93 mmol) dropwise to a solution of ethyl 2-chloro-4-(methoxymethoxy)nicotinate (120 mg, 0.46 mmol) and Pd(dppf)Cl2.DCM (3.8 mg, 0.005 mmol) in dioxane (2 mL) of RT. Heat RM to 90°C and stir for 1 hour. Concentrate RM under vacuum, and fractionate the residue between water and ethyl and extract. Separate the layers and re-extract the aqueous phase with ethyl (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by prep.HPLC (basic) to obtain ethyl 4-(methoxymethoxy)-2-methylnicotinate as a colorless oil. LC-MS I:t R =0.71min;[M+H] + = 226.18.

[0367] Step 4: Add 4M HCl (0.55 mL) in dioxane to a solution of ethyl 4-(methoxymethoxy)-2-methylnicotinate (50 mg, 0.22 mmol) in dioxane (1 mL) of RT, and stir RM for 16 hours. Remove volatiles under vacuum, suspend the residue in Et2O, and concentrate to obtain ethyl 4-hydroxy-2-methylnicotinate hydrochloride as a white solid. LC-MS I:t R =0.30min;[M+H] + = 182.23.

[0368] Step 5: Ethyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methylnicotinate is prepared from ethyl 4-hydroxy-2-methylnicotinate hydrochloride and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the same manner as described in Step 2 of B-1.1. LC-MS B:t R =0.82min;[M+H] + = 415.41.

[0369] Step 6: Prepare the title compound in the same manner as described in Step 3 of B-1.1. LC-MS B:t R =0.52min;[M+H] + = 315.32.

[0370] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-2,3-dihydrobenzofuran-7-carboxylate hydrochloride (B-4.6) Step 1: Add benzyl bromide (8.9 mL, 74.6 mmol) and K2CO3 (14.7 g, 107 mmol) to a solution of 6-hydroxybenzofuran-3(2H)-one (8.0 g, 53.3 mmol) in DMF (80 mL) of RT, and stir the RM for 2 hours. Pour this RM into cold water, collect the precipitate by filtration, and dry in a vacuum oven at 40°C for 48 hours. Isolate 6-(benzyloxy)benzofuran-3(2H)-one as an orange solid. LC-MS J:t R =2.03min;[M+H] + = 241.0.

[0371] Step 2: Gradually add 6-(benzyloxy)benzofuran-3(2H)-one (11.25 g, 46.8 mmol) to a solution of AlCl3 (6.87 g, 51.5 mmol) and LiAlH4 (19.5 mL, 46.8 mmol, 2.4 M in THF) in THF (200 mL) at 0°C. Warm the RM to RT and stir for 2 hours. Cool the RM to 0°C, quench with 0.5 M NaOH aqueous solution (400 mL), and extract with ELISA (3x). The organic extracts were combined, washed with brine, dried with Na2SO4, filtered, and evaporated under vacuum to obtain 6-(benzyloxy)benzofuran as an orange oil. GC-MS MC:t R =4.74min;[M] + =224.1. Note: Contains a small amount of 6-(benzyloxy)-2,3-dihydrobenzofuran as a byproduct.

[0372] Step 3: 2,3-Dihydrobenzofuran-6-ol is produced from 6-(benzyloxy)benzofuran according to the procedure described in Step 4 of B-2.11. GC-MS MC:t R =3.38min;[M] + = 136.1.

[0373] Step 4-8: Prepare the title compound from 2,3-dihydrobenzofuran-6-ol in the same manner as described in B-4.1. LC-MS J:t R =2.30min;[M+H] + = 446.1.

[0374] Benzyl (R)-6-(2-amino-3-phenylpropoxy)quinoline-5-carboxylate dihydrochloride (B-4.7) Step 1: Add the solution of Br2 (0.37 mL, 7.2 mmol) in AcOH (5 mL) to the solution of quinoline-6-ol (1.0 g, 6.9 mmol) and NaOAc (0.62 g, 7.6 mmol) in AcOH (15 mL) of RT, and stir RM for 30 min. Quench RM with saturated NaHSO3 aqueous solution, neutralize with 2 M NaOH aqueous solution and Na2CO3, and extract with siRNA (2x). Combine the organic extracts, wash with brine, and concentrate under vacuum. Take the residue in PhMe and concentrate under vacuum (2x) to obtain 5-bromoquinoline-6-ol as a brown solid. LC-MS J:t R =1.16min;[M+H] + = 221.9.

[0375] Step 2: 5-Bromo-6-(methoxymethoxy)quinoline is prepared from 5-bromoquinoline-6-ol in the same manner as described in B-4.1 Step 1. LC-MS J:t R =2.30min;[M+H] + = 446.1.

[0376] Step 3: Add nBuLi (1.6 M, 5.7 mL, 9.1 mmol in hex) dropwise to a -78°C solution of 5-bromo-6-(methoxymethoxy)quinoline (2.45 g, 9.1 mmol) in THF (50 mL), and stir the RM for 30 minutes. Quench this RM with freshly crushed dry ice (12 g, 273 mmol), then heat to RT and stir for 30 minutes. Concentrate the RM under vacuum, dissolve the intermediate lithium carboxylate in DMF (30 mL), add benzyl bromide (1.3 mL, 11 mmol), and heat the RM to 60°C for 10 minutes. Cool the RM to RT, fractionate and extract between saturated NaHCO3 aqueous solution and ethyl acetate. Separate the layers and re-extract the aqueous phase with ethyl acetate (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product is purified by FC (elution with 30% to 100% ethyl acetate in hept) to obtain benzyl 6-(methoxymethoxy)quinoline-5-carboxylate as a yellow oil. LC-MS J:t R =2.02min;[M+H] + =324.1.

[0377] Steps 4-6: The title compound is prepared from benzyl 6-(methoxymethoxy)quinoline-5-carboxylate in the same manner as described in Steps 3-5 of B-4.1. LC-MS B:t R =0.77min;[M+H] + = 413.16.

[0378] Benzyl (R)-7-(2-amino-3-phenylpropoxy)quinoline-8-carboxylate dihydrochloride (B-4.8) Step 1: Add DCM (40 mL) to the solution of quinoline-7-ol (10 g, 68.9 mmol) in AcOH (20 mL), cool the resulting suspension to 0°C, then slowly add the solution of Br2 (3.87 mL, 75 mmol) in AcOH (20 mL), and RM Stir for 2 hours. Dilute this suspension with HCl, filter, wash the filter residue with HCl and Et2O, and dry under vacuum at 40°C to obtain 8-bromoquinoline-7-ol hydrobromide as a brown solid. LC-MS J:t R =0.27min;[M+H] + = 225.9.

[0379] Step 2-6: The title compound is prepared from 8-bromoquinoline-7-ol hydrobromide in the same manner as described in Step 2-6 of B-4.7. LC-MS J:t R =2.07min;[M+H] + = 413.1.

[0380] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-4.9) The title compound is prepared from 3-fluoroquinoline-6-ol in the same manner as described in B-4.7. LC-MS J:t R =2.16min;[M+H] + = 431.2.

[0381] Benzyl (R)-2-(2-amino-3-phenylpropoxy)-4-methoxynicotinate hydrochloride (B-4.10) Step 1: Benzyl 2-fluoro-4-methoxynicotinate is prepared from 2-fluoro-4-methoxypyridine in the same manner as described in Step 3 of B-4.7. LC-MS F:t R =1.96min;[M+H] + = 262.0.

[0382] Step 2: KO tA solution of Bu (258 mg, 2.3 mmol) in THF (3.5 mL) is added to a solution of benzyl 2-fluoro-4-methoxynicotinate (600 mg, 2.3 mmol) and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (577 mg, 2.3 mmol) in THF (20 mL) at 0°C. The RM is then warmed to RT and stirred for 30 minutes. The RM is concentrated under vacuum, and the residue is purified by FC (eluting with 10% to 45% ethyl acetate in hept) to obtain benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-4-methoxynicotinate as a colorless oil. LC-MS F:t R =2.30min;[M+H] + = 493.1.

[0383] Step 3: The title compound is prepared from benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-4-methoxynicotinate in the same manner as described in Step 3 of B-1.1. LC-MS F:t R =1.76min;[M+H] + =393.1.

[0384] Benzyl (R)-5-(2-amino-3-phenylpropoxy)-2-methoxyisonicotinate trifluoroacetate (B-4.11) Step 1: 2-Methoxy-5-(methoxymethoxy)pyridine is prepared from 6-methoxypyridine-3-ol in the same manner as described in B-4.1 Step 1. LC-MS J:t R =1.67min;[M+H] + = 170.1.

[0385] Step 2-5: The title compound is prepared from 2-methoxy-5-(methoxymethoxy)pyridine, replacing HCl with TFA in the Boc cleavage step, in the same manner as described in Step 3-6 of B-4.7. LC-MS J:t R =2.16min;[M+H] + =393.1.

[0386] Ethyl (R)-4-(2-amino-3-phenylpropoxy)-2-methoxy-6-methylnicotinate (B-4.12) Step 1: 4-(benzyloxy)-6-methylpyridine-2-ol is replaced with 6-methylpyridine-2-ol. It is manufactured from lysine-2,4-diol according to the procedure described in B-4.6 Step 1. LC-MS I:t R =0.71min;[2M+H] + = 431.31.

[0387] Step 2: MeI (0.438 mL, 6.97 mmol) is added to a mixture of RT in DCM (20 mL) containing 4-(benzyloxy)-6-methylpyridine-2-ol (500 mg, 2.32 mmol) and Ag2CO3 (1.29 g, 4.65 mmol). The RM is irradiated in a MW oven at 100°C for 1 hour. The RM is filtered, the solid is washed with DCM, the filtrate is concentrated under vacuum, and the residue is purified by FC (eluting with 20% to 100% siRNA in hept) to obtain 4-(benzyloxy)-2-methoxy-6-methylpyridine as a colorless oil. LC-MS I:t R =1.07min;[M+H] + = 230.25.

[0388] Step 3: Add nBuLi (2.5 M, 3.63 mL, 9.1 mmol in hex) dropwise to a solution of 4-(benzyloxy)-2-methoxy-6-methylpyridine (1.66 g, 7.3 mmol) in THF (25 mL) at -78°C. Stir the RM for 30 minutes, then add ethyl chloroformate (0.70 mL, 7.3 mmol) dropwise. Warm the RM to RT, quench by adding saturated NaHCO3 aqueous solution, and extract with ethyl. Separate the layers, re-extract the aqueous phase with ethyl ethyl ethyl ethyl ethyl methyl nicotinate as a colorless oil. LC-MS I:t R=1.11min;[M+H] + = 302.29.

[0389] Steps 4-6: Prepare the title compound from ethyl 4-(benzyloxy)-2-methoxy-6-methylnicotinate in the same manner as described in Steps 5-7 of B-2.12. Note: Boc cleavage is performed using TFA instead of HCl, and after basic post-treatment, the title compound is isolated as its free base. LC-MS I:t R =0.97min;[M+H] + = 345.32.

[0390] Ethyl (R)-4-(2-amino-3-phenylpropoxy)-2-(methoxy-d3)-6-methylnicotinate (B-4.13) The title compound is prepared in the same manner as described in B-4.12, with MeI replaced by CD3I in step 2. LC-MS I:t R =0.97min;[M+H] + = 348.35.

[0391] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-8-methylquinoline-5-carboxylate (B-4.14) Step 1: Meldram acid (6.04 g, 41.1 mmol) and triethyl orthoformate (6.06 mL, 35.7 mmol) are added to a solution of 4-methoxy-2-methylaniline (5.0 g, 35.7 mmol) in EtOH (50 mL) of RT, and the RM is heated at 80°C for 2 hours. This RM is cooled to RT, and the precipitate is collected by filtration after washing with EtOH, dried under HV, and 5-(((4-methoxy-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione is obtained as a white solid. LC-MS B:t R =0.90min;[M+H] + = 292.13.

[0392] Step 2: Dissolve 5-(((4-methoxy-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.19 g, 28.1 mmol) in Dowtherm A (50 mL) and heat at 250°C for 5 min. Cool this RM to RT, dilute with Et2O, collect the precipitate by filtration, wash with Et2O, and dry under HV to obtain 6-methoxy-8-methylquinoline-4-ol as a brown solid. Obtained by doing so. LC-MS B:t R =0.58min;[M+H] + = 190.21.

[0393] Step 3: Add phosphorus tribromide (2.16 mL, 22.7 mmol) to a solution of 6-methoxy-8-methylquinoline-4-ol (3.91 g, 20.7 mmol) in DMF (75 mL) of RT, and heat RM at 45°C for 1 hour. Cool this RM to RT, dilute with water, and adjust the pH to 8 by adding saturated NaHCO3 aqueous solution. Collect the precipitate by filtration, dissolve in ethyl acetate, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (elution with 10% ethyl acetate in hept) to obtain 4-bromo-6-methoxy-8-methylquinoline as a white solid. LC-MS B:t R =0.82min;[M+H] + = 254.03.

[0394] Step 4: Add nBuLi (1.6 M in hex, 35.7 mL, 57.1 mmol) dropwise to a solution of 4-bromo-6-methoxy-8-methylquinoline (7.2 g, 28.5 mmol) in THF at -78°C, and stir RM for 30 minutes. Quench the reaction with saturated NH4Cl aqueous solution and extract with siRNA (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (elution with 20% siRNA in hept) to obtain 6-methoxy-8-methylquinoline as a yellow oil. LC-MS B:t R =0.49min;[M+H] + = 174.26.

[0395] Step 5: 5-Bromo-6-methoxy-8-methylquinoline is prepared from 6-methoxy-8-methylquinoline in the same manner as described in Step 1 of B-4.7. LC-MS B:t R =0.74min;[M+H] + = 252.09.

[0396] Step 6: Add BBr3 (1M in DCM, 42.5 mL, 42.5 mmol) dropwise to a solution of 5-bromo-6-methoxy-8-methylquinoline (3.57 g, 14.2 mmol) in DCM (70 mL) at 0°C. Remove the cooling bath and stir this RM at RT for 2 hours. Carefully quench the RM in cold MeOH and concentrate under vacuum. Co-evaporate the residue with PhMe, siRNA and DCM to obtain 5-bromo-8-methylquinoline-6-ol as a yellow solid. LC-MS B:t R =0.55min;[M+H] + = 238.01.

[0397] Step 7: tert-butyl(R)-(1-((5-bromo-8-methylquinoline-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from 5-bromo-8-methylquinoline-6-ol and tert-butyl(R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the same manner as described in Step 2 of B-1.1. LC-MS B:t R =1.10min;[M+H] + = 472.94.

[0398] Step 8: Add nBuLi (1.6 M, 0.54 mL, 0.86 mmol in hex) dropwise to a solution of tert-butyl (R)-(1-((5-bromo-8-methylquinoline-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (185 mg, 0.39 mmol) in THF (2 mL) at -78°C. Stir the RM for 30 minutes, then add benzyl chloroformate (0.058 mL, 0.41 mmol) dropwise. Warm the RM to RT, quench by adding saturated NaHCO3 aqueous solution, and extract with ethyl acetate. Separate the layers, re-extract the aqueous phase with ethyl acetate (2x), combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. The crude product was purified by prep.HPLC (acidic) to obtain benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-8-methylquinoline-5-carboxylate as a white solid. LC-MS B:t R =1.11min;[M+H] + = 527.33.

[0399] Step 9: Add TFA (4.0 mL, 52.2 mmol) to a solution of RT in DCM (5 mL) of benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-8-methylquinoline-5-carboxylate (550 mg, 1.04 mmol), and stir RM for 1 hour. Concentrate this RM under vacuum, co-evaporate the residue with DCM (2x), and purify by prep.HPLC (basic) to obtain the title compound as a yellow oil. LC-MS B:t R =0.78min;[M+H] + = 427.23.

[0400] Benzyl (R)-4-(2-amino-3-phenylpropoxy)-2-methoxy-6-methylnicotinate (B-4.15) Step 1: Add a 16% aqueous solution of NaOH (100 mL, 472 mmol) to a solution of ethyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinate (B-4.12, Step 5) (42 g, 94.5 mmol) in MeOH (300 mL) of RT, and heat at 90°C for 4 hours. Cool this RM to RT and concentrate under vacuum. The remaining aqueous phase i Extraction with PrOAc (3x), and discard the organic phase. Cool the aqueous phase to 0°C, acidify with 1M aqueous HCl solution, filter the precipitate, and wash with water. Dissolve the solid in DCM, separate the remaining water, dry the organic phase with Na2SO4, filter, and evaporate under vacuum to obtain (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid as a yellow oil. LC-MS B:t R =0.94min;[M+H] + = 417.20.

[0401] Step 2: Add K2CO3 (1.33 g, 9.6 mmol) and BnBr (0.51 mL, 4.3 mmol) to a solution of RT in DMF (8 mL) of (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid (2.0 g, 4.8 mmol). Heat the RM to 40°C and stir for 4 hours. Pour this RM into water and extract with TBME (2x). Combine the organic extracts, wash with water, dry over Na2SO4, filter, and evaporate under vacuum to obtain benzyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinate as a colorless oil. LC-MS B:t R =1.17min;[M+H] + = 507.24.

[0402] Step 3: Prepare the title compound from benzyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinate in the same manner as described in Step 3 of B-1.1. Note: Boc cleavage is performed using TFA instead of HCl, and after basic post-treatment, the title compound is isolated as its free base. LC-MS B:t R =0.79min;[M+H] + = 407.22.

[0403] Benzyl (R)-4-(2-amino-3-phenylpropoxy)-6-methoxy-2-methylpyrimidine-5-carboxylate trifluoroacetate (B-4.16) Step 1: Add nBuLi (1.6M in hex, 34.5mL, 55.2 mmol) dropwise to a solution of DIPEA (7.74mL, 55.2 mmol) in THF (35mL) at -78°C, and stir the RM for 5 minutes. Add a solution of 4,6-dichloro-2-methylpyrimidine (5.0g, 30.7 mmol) in THF (40mL) dropwise to the newly prepared LDA, and continue stirring at -78°C for 1 hour. Quench this RM with freshly crushed dry ice (20g, 454 mmol), stir for 5 minutes, then warm to RT for 20 minutes, and stir for another 15 minutes. RM is concentrated under vacuum to obtain lithium 4,6 -Dichloro-2-methylpyrimidine-5-carboxylate is obtained as a brown solid and used further without purification. LC-MS J:t R =0.16min;[MH] - = 204.9.

[0404] Step 2: Add KHCO3 (6.15 g, 61.4 mmol) and BnBr (10.95 mL, 92 mmol) to a solution of lithium 4,6-dichloro-2-methylpyrimidine-5-carboxylate (6.54 g, 30.7 mmol) in DMF (50 mL) of RT, and stir the RM for 18 hours. Quench this RM by adding H2O and brine, and extract with ethyl acetate (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 0%~5% ethyl acetate in hept) to obtain benzyl 4,6-dichloro-2-methylpyrimidine-5-carboxylate as a colorless oil. LC-MS J:t R =2.13min;[M+H] + = 296.9.

[0405] Step 3: Add NaOMe (30% solution in MeOH, 1.0 mL, 5.41 mmol) dropwise to a solution of benzyl 4,6-dichloro-2-methylpyrimidine-5-carboxylate (2.68 g, 5.41 mmol) in THF (15 mL) at 0°C, and stir the RM for 1 hour. Quench this RM with 1 M aqueous HCl solution and extract with ethyl acetate (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 0%~7% ethyl acetate in hept) to obtain benzyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate as a colorless oil. LC-MS J:t R =2.15min;[M+H] + =293.1.

[0406] Step 4: Add NaH (60% dispersion in mineral oil, 128 mg, 3.21 mmol) to a solution of allyl alcohol (0.21 mL, 3.1 mmol) in THF (10 mL) at 0°C. Stir the resulting suspension for 10 min, then slowly add it to a solution of benzyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate in THF (15 mL) at -10°C. Stir the RM for 1 hour. Quench this RM with 1 M aqueous HCl and extract with ethyl acetate (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 0%~10% ethyl acetate in hept) to obtain benzyl 4-(allyloxy)-6-methoxy-2-methylpyrimidine-5-carboxylate as a colorless oil. LC-MS J:t R =2.24min;[M+H] + = 315.1.

[0407] Step 5: Pd(PPh3)4 (43.7 mg, 0.038 mmol) is added to a solution of RT (degassed) in MeCN (10 mL) containing benzyl 4-(allyloxy)-6-methoxy-2-methylpyrimidine-5-carboxylate (170 mg, 0.54 mmol) and 1,3-dimethylbarbituric acid (127 mg, 0.81 mmol), and the RM is heated at 50°C for 2.5 hours. The RM is filtered and concentrated to obtain benzyl 4-hydroxy-6-methoxy-2-methylpyrimidine-5-carboxylate as a gray solid. LC-MS J:t R =1.63min;[M+H] + = 275.1.

[0408] Steps 6 and 7: The title compound is prepared from benzyl 4-hydroxy-6-methoxy-2-methylpyrimidine-5-carboxylate, replacing HCl with TFA in the Boc cleavage step, in the same manner as described in Steps 2 and 3 of B-1.1. LC-MS J:t R =2.17min;[M+H] + = 408.2.

[0409] Ethyl (R)-4-(2-amino-3-phenylpropoxy)-2,6-dimethoxynicotinate (B-4.17) Step 1: Benzyl alcohol (0.82 mL, 7.85 mmol) and KO t A solution of Bu (867 mg, 7.5 mmol) in DMF (4 mL) is added to a solution of 2,4,6-trifluoropyridine (1.0 g, 7.14 mmol) in DMF (4 mL) at -78°C, and the RM is stirred for 10 minutes. This RM is quenched with water, warmed to 0°C, and then filtered. The filter residue is recrystallized from hept to obtain 4-(benzyloxy)-2,6-difluoropyridine as a white solid. LC-MS B:t R =0.99min;[M+H] + = 222.27.

[0410] Step 2: A suspension of 4-(benzyloxy)-2,6-difluoropyridine (1.71 g, 7.56 mmol) in NaOMe (25 wt.% in MeOH, 6.9 mL, 30.2 mmol) is heated at 60°C for 18 hours. This RM is concentrated under vacuum, and the residue is fractionated between water and TBME, separating the layers. The aqueous phase is re-extracted with TBME (2x), the organic extracts are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum to obtain 4-(benzyloxy)-2,6-dimethoxypyridine as a colorless oil. LC-MS B:t R =1.02min;[M+H] + = 246.29.

[0411] Steps 3-6: Prepare the title compound from 4-(benzyloxy)-2,6-dimethoxypyridine in the same manner as described in Steps 3-6 of B-4.12. Note: Perform Boc-cleavage using TFA instead of HCl, and after basic post-treatment, isolate the title compound as its free base. LC-MS B:t R =0.73min;[M+H] + = 361.23.

[0412] Benzyl (S)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-4.18) The title compound is prepared from 3-fluoroquinoline-6-ol using tert-butyl (S)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the Mitsunobu step, in the same manner as described in B-4.7. LC-MS I:t R =1.07min;[M+H] + = 431.08.

[0413] General method 5 for the synthesis of component B Benzyl (R)-2-(2-amino-3-phenylpropoxy)-6-(methoxy-d3)benzoate hydrochloride (B-5.1) Step 1: Add DMAP (120 mg, 0.99 mmol) to a solution of 2,6-dihydroxybenzoic acid (3.0 g, 19.7 mmol) in 1,2-dimethoxyethane (15 mL) at 0°C. Then, add acetone (1.9 mL, 25.8 mmol) and thionyl chloride (1.85 mL, 25.2 mmol) dropwise. Stir the RM for 30 minutes, then warm to RT and stir for 16 hours. Quench this RM by adding saturated NaHCO3 aqueous solution and extract with Et2O (4x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 0%~50% ethyl acetate in hept) to obtain 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one as a white solid. LC-MS F:t R =1.93min;[M+H] + = 195.1.

[0414] Step 2: Add CD3I (0.8 mL, 12.9 mmol) to a solution of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (1.76 g, 8.6 mmol) and K2CO3 (1.79 g, 12.9 mmol) in DMF (25 mL), and heat the RM at 50°C for 1 hour. This RM is fractionated between water and ethyl acetate, and the layers are separated. The aqueous phase is re-extracted with ethyl acetate (1x), the organic layers are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluting with 10% to 100% ethyl acetate in hept) to 5-(methoxy-d3)-2,2-dimethyl -4H-benzo[d][1,3]dioxin-4-one is obtained as a grayish-white solid. LC-MS J:t R =1.82min;[M+H] + = 212.1.

[0415] Step 3: Add NaH (0.65 g, 16.3 mmol) to a solution of benzyl alcohol (1.7 mL, 16.3 mmol) in DMF (45 mL), stir the RM for 30 minutes, then add 5-(methoxy-d3)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (1.72 g, 8.1 mmol) in DMF (5 mL), and continue stirring for 1 hour. This RM is fractionated between 1N HCl and HCl, and the layers are separated. The aqueous phase is re-extracted with HCl (1x), the organic layers are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluting with 0%~50% HCl in hept) to obtain benzyl 2-hydroxy-6-(methoxy-d3)benzoate as a colorless oil. LC-MS J:t R =2.13min;[M+H] + = 262.1.

[0416] Step 4: Benzyl (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-6-(methoxy-d3)benzoate is prepared from benzyl 2-hydroxy-6-(methoxy-d3)benzoate and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the same manner as described in Step 2 of B-1.1. LC-MS J:t R =2.39min;[M-Boc+H] + = 395.2.

[0417] Step 5: Prepare the title compound in the same manner as described in Step 3 of B-1.1. LC-MS J:t R =2.15min;[M+H] + =395.1.

[0418] Benzyl (R)-2-(2-amino-3-phenylpropoxy)-6-(difluoromethoxy)benzoate hydrochloride (B-5.2) Step 1: Add a solution of KOH (4.57 g, 81 mmol) in water (12 mL) to a solution of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (B-5.1 Step 1, 1.58 g, 8.1 mmol) in MeCN (12 mL) at 0°C. Stir the two phases of RM for 5 minutes, then add bromodifluoromethyldiethylphosphonate (2.0 mL, 11.4 mmol) dropwise. Stir for 1.5 hours, then add SiO (25 mL) to separate the phases. Re-extract the aqueous phase with SiO (1x), combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain 5-(difluoromethoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one as a brown oil. LC-MS J:t R =2.0min;[M+H] + = 245.1.

[0419] Step 2-4: The title compound is prepared from 5-(difluoromethoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one according to the reaction sequence described in B-5.1. LC-MS J:t R =2.20min;[M+H] + = 428.1.

[0420] Methyl (R)-6-(2-amino-3-phenylpropoxy)-2-methylbenzofuran-7-carboxylate hydrochloride (B-5.3) Step 1: Add K2CO3 (2.38 g, 17.2 mmol) and 3-bromopropine (80% solution in PhMe, 1.67 mL, 15.5 mmol) to a solution of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (B-5.1 Step 1, 3.0 g, 15.4 mmol) in acetone (60 mL) of RT, and heat RM at 55°C for 21 hours. Concentrate this mix and fractionate the residue between water and sorbate. Separate the layers and re-extract the aqueous layer with sorbate (2x). Combine the organic extracts and wash with brine. The solution is purified, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluting with 5%-35% ethyl phosphate in hept) to obtain 2,2-dimethyl-5-(propa-2-in-1-yloxy)-4H-benzo[d][1,3]dioxin-4-one as a white solid. LC-MS J:t R =1.83min;[M+H] + = 233.1.

[0421] Step 2: Add NaOMe (30% solution in MeOH, 1.9 mL, 10.1 mmol) to a solution of 2,2-dimethyl-5-(propa-2-in-1-yloxy)-4H-benzo[d][1,3]dioxin-4-one (1.53 g, 6.6 mmol) in DMF (15 mL) at 0°C. Warm the RM to RT and stir for 1 hour. Quench the RM with 1 M aqueous HCl solution and extract with ELISA (3x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain methyl 2-hydroxy-6-(propa-2-in-1-yloxy)benzoate as a beige solid. LC-MS J:t R =1.79min;[M+H] + = 207.0.

[0422] Step 3: A mixture of methyl 2-hydroxy-6-(propa-2-in-1-yloxy)benzoate (1.33 g, 6.5 mmol), CsF (1.5 g, 9.9 mmol), and diethylaniline (18 mL) is purged with N2 and irradiated in a MW oven at 200°C for 55 min. This RM is diluted with ethyl acetate and washed with 1 M aqueous HCl solution. The aqueous phase is extracted with ethyl acetate (2x), the organic extracts are combined and washed with 1 M HCl and brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluted with 1%-15% ethyl acetate in hept) to obtain methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate as a white solid. LC-MS F:t R =1.98min;[M+H] + = 207.0.

[0423] Steps 4-5: The title compound is prepared from methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate in the same manner as described in Steps 2-3 of B-1.1. LC-MS J:t R =1.98min;[M+H] + =340.1.

[0424] General method for the synthesis of component B 6 Methyl (R)-6-(2-amino-3-phenylpropoxy)-3-methylbenzo[d]isoxazole-7-carboxylate hydrochloride (B-6.1) Step 1: Add hexamethylenetetramine (8.1 g, 57.1 mmol) to a solution of 3-methyl-1,2-benzoisoxazole-6-ol (2.0 g, 13.4 mmol) in AcOH (40 mL), and heat the RM at 100°C for 2 hours. Add 2M aqueous HCl (40 mL) and continue stirring at 100°C for 30 minutes. Cool the RM in an ice bath, and collect the resulting solid by filtration. Concentrate the filtrate under vacuum, recool to 0°C, and collect the solid again by filtration. Combine the two and dry under vacuum to obtain 6-hydroxy-3-methylbenzo[d]isoxazole-7-carbaldehyde as a beige powder. LC-MS B:t R = 0.72 min; non-ionization. 1 H NMR (DMSO) δ: 11.67 (s, 1H), 10.43 (s, 1H), 7.94 (d, J=8.7Hz, 1H), 7.03 (d, J=8.7Hz, 1H).

[0425] Step 2: Add 2-methyl-2-butene (7.33 mL, 69.2 mmol) all at once to a solution of 6-hydroxy-3-methylbenzo[d]isoxazole-7-carbaldehyde (1.09 g, 6.1 mmol) in THF (40 mL) and tert-butanol (12 mL) in RT, then add NaClO2 (2.06 g, 18.2 mmol) and a solution of NaH2PO4.2H2O (4.3 g, 27.3 mmol) in H2O (12 mL), and stir RM in RT for 30 min. Collect the solid by filtration, wash with cold 1 M aqueous HCl solution, and dry under vacuum to obtain 6-hydroxy-3-methylbenzo[d]isoxazole-7-carboxylic acid as a white solid. LC-MS B:t R =0.63min; [M+H] + =194.31.

[0426] Steps 3-5: The title compound is prepared from 6-hydroxy-3-methylbenzo[d]isoxazole-7-carboxylic acid according to the reaction sequence described in B-3.1. LC-MS B:t R =0.70min;[M+H] + = 341.38.

[0427] Methyl (R)-5-(2-amino-3-phenylpropoxy)-1-methyl-1H-indazole-4-carboxylate hydrochloride (B-6.2) The title compound is prepared from 1-methyl-1H-indazole-5-ol according to the reaction sequence described in B-6.1. LC-MS B:t R =0.70min;[M+H] + = 340.36.

[0428] General method for the synthesis of component B 7 Methyl (R)-6-(2-amino-3-phenylpropoxy)isoquinoline-5-carboxylate dihydrochloride (B-7.1) Step 1: Add Br2 (0.78 mL, 15.2 mmol) dropwise to a suspension of isoquinoline-6-ol (2.0 g, 13.8 mmol) in CHCl3 (30 mL) in a water bath, and stir RM for 2 hours. Add siRNA, collect the solid by filtration, and wash with siRNA, then with hept. Neutralize the filter residue by suspension in saturated NaHCO3 aqueous solution, re-filter, and wash with H2O, then with hept. Suspend the filter residue in MeCN and evaporate under vacuum to obtain 5-bromoisoquinoline-6-ol as a brown solid. LC-MS J:t R =0.33min;[M+H] + = 224.0.

[0429] Step 2: tert-butyl(R)-(1-((5-bromoisoquinoline-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from 5-bromoisoquinoline-6-ol and tert-butyl(R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in the same manner as described in B-1.1 Step 2. LC-MS J:t R =2.28min;[M+H] + = 457.1.

[0430] Step 3: After purging the solution of DIPEA (0.76 mL, 4.4 mmol) in MeOH (3 mL) with Ar, Pd(OAc)2 (74 mg, 0.33 mmol) and Xantphos (190 mg, 0.33 mmol) are added, and the catalyst mixture is heated to 70°C for 20 min. In a separate flask, the solution of tert-butyl (R)-(1-((5-bromoisoquinoline-6-yl)oxy)-3-phenylpropan-2-yl) carbamate (1.0 g, 2.19 mmol) in MeOH (40 mL) is first purged with Ar, then purged with CO, and then heated to 70°C under a CO atmosphere. Next, the thermal catalyst solution is added via syringe, and the RM is stirred for 20 h. This RM is cooled to RT, concentrated under vacuum, and the residue is fractionated and extracted between saturated NaHCO3 aqueous solution and DCM. The layers are separated, the aqueous phase is re-extracted with DCM (1x), the organic layers are combined, washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product is purified by FC (eluting with 25%-80% ethyl acetate in hept) to obtain methyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)isoquinoline-5-carboxylate as a black solid. LC-MS J:t R =2.11min;[M+H] + = 437.2.

[0431] Step 4: The title compound is prepared from methyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)isoquinoline-5-carboxylate in the same manner as described in Step 3 of B-1.1. LC-MS J:t R=1.83min;[M+H] + = 337.2.

[0432] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate dihydrochloride (B-7.2) Step 1: Add trifluoromethanesulfonic anhydride (26.2 mL, 158 mmol) dropwise to a solution of 2-hydroxy-4-methoxybenzaldehyde (16 g, 105 mmol) and pyridine (42.5 mL, 526 mmol) in DCM (70 mL) at -10°C, and stir the RM for 30 minutes. Quench the RM with ice water, acidify with 1 M aqueous HCl solution, and then extract with siRNA (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum to obtain 2-formyl-5-methoxyphenyl trifluoromethanesulfonate as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 10.13(s, 1H), 7.95(d, J=8.8Hz, 1H), 7.03(dd, J=8.7, 2.3Hz, 1H), 6.88(d, J=2.3Hz, 1H), 3.93(s, 3H).

[0433] Step 2: A solution of 2-formyl-5-methoxyphenyl trifluoromethanesulfonate (19.6 g, 66.4 mmol) and TEA (93 mL, 664 mmol) in DMF (400 mL) of RT is purged with Ar for 30 min. Propa-1-in (1 M in DMF, 133 mL, 133 mmol), CuI (1.27 g, 6.64 mmol), and Pd(PPh3)4 (5.0 g, 4.33 mmol) are added sequentially, the RM is sealed, and stirred for 2 hours. The RM is filtered through a Celite pad, the filtrate is partially concentrated under vacuum, diluted with siRNA, sequentially washed with 1 M KHSO4 solution and brine, and concentrated under vacuum. The crude product is purified with FC (eluted with 0% to 30% siRNA in hept) to obtain 4-methoxy-2-(propa-1-in-1-yl)benzaldehyde as a yellow solid. LC-MS J:t R =1.80min;[M+H] + = 175.1.

[0434] Step 3: A solution of 4-methoxy-2-(propa-1-in-1-yl)benzaldehyde (10.3 g, 58.8 mmol) in MeOH (350 mL) is purged with Ar for 5 min in an autoclave. NH37M (150 mL, 1050 mmol) is added to the MeOH, and the RM is heated to 65 °C at 2 bar for 4 hours. This RM is concentrated under vacuum, and the residue is co-evaporated with DCM (2x) to obtain 6-methoxy-3-methylisoquinoline as a brown solid. LC-MS J:t R =1.81min;[M+H] + = 174.1.

[0435] Step 4: Add BBr3 (1M, 55.4 mL, 55.4 mmol in DCM) dropwise to a solution of 6-methoxy-3-methylisoquinoline (5.0 g, 27.7 mmol) in DCM (100 mL) at -78°C. Remove the cooling bath and stir the RM in RT for 30 hours. Carefully quench this RM in cold MeOH and concentrate under vacuum. Co-evaporate the residue with PhMe, siRNA and DCM to obtain 3-methylisoquinoline-6-ol as a brown solid. LC-MS J:t R =1.10min;[M+H] + = 160.1.

[0436] Steps 5-6: tert-butyl (R)-(1-((5-bromo-3-methylisoquinoline-6-yl)oxy)-3-phenylpropane-2-yl)carbamate is produced from 3-methylisoquinoline-6-ol according to steps 1 and 2 described in B-7.1. LC-MS J:t R =2.20min;[M+H] + = 471.1.

[0437] Step 7: A solution of tert-butyl (R)-(1-((5-bromo-3-methylisoquinoline-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (2.5 g, 5.30 mmol), benzyl alcohol (2.76 mL, 26.5 mmol), and DIPEA (2.78 mL, 15.9 mmol) in PhMe (20 mL) is purged with Ar for 10 min. Then, this RM is purged with CO and heated to 88 °C under a CO atmosphere, followed by Pd( t Bu3P)2 (271 mg, 0.53 mmol) PhMe( Add the solution in 5.5 mL via a syringe pump (3 mL / h). Raise the temperature to 95°C and stir the RM under a CO atmosphere for 24 hours. Cool this RM to RT, concentrate under vacuum, and fractionate and extract the residue between saturated NaHCO3 aqueous solution and ethyl acetate. Separate the layers, re-extract the aqueous phase with ethyl acetate (1x), combine the organic layers, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (eluting with 5%-65% ethyl acetate in hept) to obtain benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate as a colorless oil. LC-MS J:t R =2.19min;[M+H] + = 527.2.

[0438] Step 8: The title compound is prepared from benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate in the same manner as described in Step 3 of B-1.1. LC-MS J:t R =1.95min;[M+H] + = 427.2.

[0439] Synthesis of component B-acid (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxol-5-carboxylic acid (B-acid-1) Step 1: Benzyl 6-hydroxybenzo[d][1,3]dioxol-5-carboxylate is prepared from 6-hydroxybenzo[d][1,3]dioxol-5-carboxylic acid in the same manner as described in B-1.1 Step 1. LC-MS I:t R =1.12min;[M+H] + = 272.94.

[0440] Step 2: Benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxol-5-carboxylate is prepared from benzyl 6-hydroxybenzo[d][1,3]dioxol-5-carboxylate in the same manner as described in B-1.1 Step 2. LC-MS I:t R =1.27min;[M+H] + = 506.02.

[0441] Step 3: The title compound is prepared from benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxol-5-carboxylate in the same manner as described in Step 4 of B-1.24. LC-MS I:t R =0.53min;[M+H] + = 416.01.

[0442] (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-4,5-dimethoxybenzoic acid (B-acid-2) The title compound is prepared from 2-hydroxy-4,5-dimethoxybenzoic acid according to the three-step sequence described for B-acid-1. LC-MS B:t R =0.98min;[M+H] + = 432.18.

[0443] (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-6-methoxybenzoic acid (B-acid-3) The title compound is prepared from 2-hydroxy-6-methoxybenzoic acid according to the three-step sequence described for B-acid-1. LC-MS I:t R =0.52min;[M+H] + = 401.88.

[0444] (R)-6-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxol-5-carboxylic acid (B-acid-4) Step 1: Benzyl (R)-6-(2-(((benzyloxy)carbonyl)amino) The product is prepared by replacing benzyl 6-hydroxybenzo[d][1,3]dioxol-5-carboxylate with benzyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate, and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate with benzyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate, in the same manner as described in B-1.1 Step 2. LC-MS I:t R =1.27min;[M+H] + = 540.20.

[0445] Step 2: A solution of benzyl (R)-6-(2-(((benzyloxy)carbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxol-5-carboxylate (2.4 g, 4.45 mmol) in THF (40 mL) is evacuated / purged with N2 (3x), and then 10% Pd / C (473 mg, 10 mol%) is added. RM is evacuated / purged with H2 (3x), and stirred under an H2 atmosphere for 2 hours. RM is filtered through a Celite pad, and the filtrate is concentrated under vacuum to obtain (R)-6-(2-amino-3-phenylpropoxy)benzo[d][1,3]dioxol-5-carboxylic acid as a white solid. LC-MS B:t R =0.65min;[M+H] + = 316.13.

[0446] Step 3: Add N-(9-fluorenylmethoxycarbonyloxy)succinimide (1.45 g, 4.28 mmol) to a solution of (R)-6-(2-amino-3-phenylpropoxy)benzo[d][1,3]dioxol-5-carboxylic acid (1.35 g, 4.28 mmol) and Na2CO3 (926 mg, 8.56 mmol) in a mixture of dioxane (40 mL) and water (8 mL), and stir RM for 16 hours. Concentrate this RM under vacuum, and fractionate and extract the residue between 1 M HCl and HCl. Filter the layers to separate, and re-extract the aqueous phase with HCl (2x). Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and evaporate under vacuum. Purify the crude product by FC (elution with 0%~5% MeOH in DCM) to obtain the title compound as a white solid. LC-MS B:t R =1.09min;[M+H] + = 538.24.

[0447] (R)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-1-naphthoic acid (B-acid-5) The title compound is prepared from 2-hydroxy-1-naphthoic acid according to the three-step sequence described for B-acid-1. LC-MS B:t R =1.02min;[M+H] + = 422.33.

[0448] (R)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)quinoline-4-carboxylic acid (B-acid-6) The title compound is prepared from 3-hydroxyquinoline-4-carboxylic acid according to the three-step sequence described for B-acid-1. LC-MS B:t R =0.88min;[M+H] + = 423.35.

[0449] (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotinic acid (B-acid-7) The title compound is prepared from 4-hydroxy-2-methoxynicotinic acid according to the three-step sequence described for B-acid-1. LC-MS B:t R =0.90min;[M+H] + = 403.20.

[0450] (R)-6-(2-(((allyloxy)carbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid (B-acid-8) Step 1: Under N2 conditions, dissolve benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-4.9) (0.46 g, 0.92 mmol) in MeOH (10 mL); purge the container under N2 / vacuum (3 After x), add 10% Pd / C (50 mg). After further inactivation three times, attach the H2 balloon and stir RM under an H2 atmosphere for 1 hour. Filter the heterogeneous reaction mixture through a glass fiber filter (wash with methanol / THF). Then concentrate the filtrate under reduced pressure to dryness to obtain 0.43 g of (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid as a crude yellow oil, which is used directly in the next step. LC-MS B:t R =0.62min;[M+H] + =341.21.

[0451] Step 2: (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid (436 mg, 1.28 mmol) is placed in THF (10 mL) and water (10 mL). To the resulting light-colored suspension, NaHCO3 (430 mg, 5.12 mmol) is added, followed by allyl chloroformate (0.155 mL, 1.41 mmol). The reaction mixture is stirred at RT for 1 hour. The reaction mixture is fractionated between dilutions of water and ethyl acetate, and carefully acidified to pH ~3 with some HCl (2N). The layers are separated, and the inorganic layer is further extracted with ethyl acetate (2x). The organic extracts are combined, washed with acidified water and brine, dried over Na2SO4, filtered, and evaporated under vacuum to obtain the title compound as a yellow oil (0.39 g). No purification is performed at this stage. LC-MS B:t R =0.94min;[M+H] + = 425.23.

[0452] (R)-4-(2-(((allyloxy)carbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid (B-acid-9) The title compound is prepared from benzyl (R)-4-(2-amino-3-phenylpropoxy)-2-methoxy-6-methylnicotinate (B-4.15) as a colorless oil according to the two-step sequence described for B-Acid-8. LC-MS B:t R =0.89min;[M+H] + = 401.07.

[0453] General method 1 for the synthesis of component C N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methylglycine(C-1.1) Step 1: Add K2CO3 (7.15 g, 51.7 mmol) to a solution of Boc-N-methylglycine (7.12 g, 36.9 mmol) in acetone (100 mL) in RT, then add benzyl bromide (4.93 mL, 40.6 mmol) dropwise. Heat the resulting mix to 45°C and stir for 16 hours. After cooling the mix to RT, filter it, concentrate the filtrate to obtain benzyl N-(tert-butoxycarbonyl)-N-methylglycinate, which is used without purification. LC-MS B:t R =0.99min;[M+H] + = 280.36.

[0454] Step 2: Add 4M HCl (34.3 mL, 0.137 mol) in dioxane to a solution of benzyl N-(tert-butoxycarbonyl)-N-methylglycinate (11.0 g, 34.2 mmol) in dioxane (10 mL) and stir the resulting mix for 2 hours. Filter the suspension and wash with Et2O (2x) to obtain benzyl methylglycinate HCl as a white solid. LC-MS B:t R =0.48min;[M+H] + = 180.49.

[0455] Step 3: Add the solution of benzyl methylglycinate HCl (7.96 g, 36.9 mmol) and DIPEA (9.48 mL, 55.4 mmol) in DMF (30 mL) to the pre-mixed RT solution of Boc-N-methyl-L-leucine (9.07 g, 36.9 mmol), HATU (14.03 g, 36.9 mmol), and DIPEA (9.48 mL, 55.4 mmol) in DMF (70 mL), and mix the resulting mix for 2 hours. Concentrate this mix and fractionate the residue between water and SiO. Separate the layers and re-extract the aqueous layer with SiO (2x). Combine the organic extracts, wash with brine, dry and (MgSO) 4) Filter and evaporate to obtain the crude product, which is then ground with Et2O to obtain benzyl N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methylglycinate as a colorless oil. LC-MS B:t R=1.11min;[M+H] + = 407.47.

[0456] Step 4: A solution of benzyl N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methylglycinate (14.2 g, 34.2 mmol) in EtOH (200 mL) is purged with N2 / vacuum (3x), and then 10% Pd / C (1.82 g, 1.7 mmol) is added. After further inactivation three times, an H2 balloon is attached and the RM is stirred for 2.5 hours. This mix is ​​concentrated, rinsed with EtOH using a Celite plug, and filtered. The filtrate is concentrated to obtain the title compound as a colorless oil. LC-MS B:t R =0.84min;[M+H] + = 317.31.

[0457] (S)-1-(2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamide)cyclopropane-1-carboxylic acid (C-1,2) Step 1: Add KtOBu (49.6 g, 0.43 mol) to a solution of THF in RT (600 mL). Add the solution of 1-(Boc-amino)cyclopropanecarboxylic acid (40.0 g, 0.195 mol) in THF (400 mL) to the above suspension, then carefully add dimethyl sulfate (19.6 mL, 0.205 mol) (exothermic reaction), stir RM in RT for 2 hours, then add dimethyl sulfate (1 mL, 0.01 mol), and continue stirring in RT for another hour. Quench the reaction with H2O (400 mL) and acidify with 32% HCl aqueous solution (80 mL). Separate the layers and extract the aqueous layer with DCM (500 mL). Combine the organic layers, concentrate to reduce volume, then wash the organic layers with H2O (300 mL) and concentrate. Add Hept to this oily residue and leave the resulting suspension overnight in RT. The following morning, this mix was filtered, the resulting solid was rinsed with hept (30 mL), and dried to obtain 1-(tert-butoxycarbonylmethylamino)-cyclopropanecarboxylic acid (21.5 g, 51%) as a white solid. LC-MS B:t R =0.71min;[M+H] += 216.39.

[0458] Steps 2-5: The title compound is prepared from 1-(tert-butoxycarbonylmethylamino)-cyclopropanecarboxylic acid according to the reaction sequence described in C-1.1, Steps 1-4. LC-MS B:t R =0.87min;[M+H] + = 343.26.

[0459] 1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (C-1,3) Step 1: Add H2SO4 (92 μL, 1.72 mmol) to a solution of (S)-N-Boc-1,2,3,6-tetrahydro-2-pyridinecarboxylic acid (400 mg, 1.72 mmol) in MeOH (5 mL) at 0°C, and heat the resulting mix under reflux for 4 hours. Slowly pour this RM into a saturated solution of NaHCO3 at 0°C and extract with ELISA (3x). Combine the organic extracts, dry (MgSO4), filter, and concentrate to obtain methyl (S)-1,2,3,6-tetrahydropyridine-2-carboxylate as an orange oil. LC-MS I:t R =0.46min;[M+H] + = 142.16.

[0460] Steps 2 and 3: The title compound is prepared from Boc-N-methyl-L-leucine and (S)-1,2,3,6-tetrahydropyridine-2-carboxylate according to the reaction sequence described in C-2.1. LC-MS B:t R =0.92min;[M+H] + =355.34. Epimerization at the 2-position of tetrahydropyridine was observed, and this component was further used as part of a mixture of diastereomers.

[0461] N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-alanine(C-1.4) Step 1: Add MeI (1.0 mL, 16.06 mmol) to a solution of (tert-butoxycarbonyl)-D-alanine (2.01 g, 10.62 mmol) in THF (10 mL) at 0°C, then add NaH (1.08 g, 27.1 mmol). Let stand at 0°C for 30 min, then warm the RM to RT and continue stirring for 3 hours. Quench this mix with water and acidify with 0.5 M KHSO4 (pH 2). Separate the layers and extract the aqueous layer with ELISA (3 x 20 mL). Combine the organic layers, wash with brine, dry with (Na2SO4), filter, and evaporate to obtain N-(tert-butoxycarbonyl)-N-methyl-D-alanine as a brown oil, which is used directly in the next step.

[0462] Steps 2-5: The title compound is prepared from N-(tert-butoxycarbonyl)-N-methyl-D-alanine according to the four-step reaction sequence described in C-1.1, Steps 1-4. LC-MS F:t R =1.98min;[M+H] + = 331.20. 1 H NMR (400MHz, DMSO) δ 5.03~4.46(m, 2H), 2.95~2.83(m, 2H), 2.75~2.54(m, 4H), 1.58~1.44(m, 2H), 1.41(s, 10H), 1.31~1.23(m, 3H), 1.23~1.17(m, 1H), 0.94~0.84(m, 6H).

[0463] General method 2 for the synthesis of component C (R)-4-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)morpholine-3-carboxylic acid (C-2.1) Step 1: Gradually add HATU (4.64 g, 12.2 mmol) to a solution of Boc-N-methyl-L-leucine (3.0 g, 12.2 mmol), (R)-methylmorpholine-3-carboxylate (1.85 g, 12.2 mmol), and DIPEA (6.3 mL, 36.6 mmol) in RT in DMF (30 mL), and stir the resulting mix for 1 hour. Add water and extract this mix with ELISA (3x). Combine the organic extracts and wash sequentially with saturated NaHCO3 aqueous solution, water, and brine, dry (Na2SO4), filter, and concentrate. Purify with FC (elution with 0% to 100% ELISA in hept) to obtain methyl (R)-4-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)morpholine-3-carboxylate as a colorless oil. LC-MS B:t R =0.97min;[M+H] + = 373.50.

[0464] Step 2: Add 11.7 mL (22.6 mmol) of 2 M NaOH aqueous solution to a solution of methyl (R)-4-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)morpholine-3-carboxylate (4.37 g, 11.7 mmol) in MeOH (55 mL) in RT, and stir the mix in RT for 4.5 hours. Remove volatiles under vacuum, neutralize the aqueous residue with 2 M HCl aqueous solution, and extract by DCM (3x). Combine the organic layers, dry (Na2SO4), filter, and evaporate under vacuum to obtain the title compound as a white solid. LC-MS B:t R =0.86min;[M+H] + =359.49.

[0465] Table C-2 below lists the component C that is manufactured from the corresponding starting material in the same way as the two-step sequence described above for C-2.1.

[0466] [Table 15]

[0467] [Table 16]

[0468] 6-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-6-azaspiro[2.5]octane-5-carboxylic acid (C-2.13) Step 1: Add a solution of (trimethylsilyl)diazomethane (2.0 M, 0.75 mL, 1.49 mmol in hex) to a solution of commercially available 6-azaspiro[2.5]octane-5-carboxylate hydrochloride in MeOH (2 mL) at 0°C. Warm this RM to RT and stir for 30 minutes. Concentrate this mix to obtain rac-6-azaspiro[2.5]octane-5-carboxylate methyl ester, which is used directly in the next step. LC-MS I:t R =0.66min;[M+H] + = 170.18.

[0469] Steps 2 and 3: The title compound is prepared from rac-6-aza-spiro[2.5]octane-5-carboxylic acid methyl ester according to the two-step procedure described in C-2.1. LC-MS I:t R =1.27min;[M+H] + = 397.34.

[0470] O-benzyl-N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methylserine(C-2.14) Step 1: Add thionyl chloride to a 0°C solution of O-benzyl-N-methyl-DL-serine (3.10 g, 14.8 mmol) in DCM (20 mL), and stir with RM at 60°C for 16 hours. Pour this mix into ice water and extract with DCM (3x). Combine the organic layers, wash with brine, dry (MgSO4), filter, and concentrate under vacuum. Purify with FC (elution with 0%-20% ELISA in hept) to obtain methyl O-benzyl-N-methyl serinate as a colorless oil. LC-MS B:t R =0.53min;[M+H] + = 224.04.

[0471] Steps 2 and 3: The title compound is prepared from methyl O-benzyl-N-methyl selinate according to the two-step procedure described in C-2.1. LC-MS B:t R =1.01min;[M+H] + = 437.30.

[0472] General method 3 for the synthesis of component C (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-methylpiperazine-2-carboxylic acid (C-3.1) Step 1: Sodium acetate (3.36 g, 41 mmol), then TFA (0.63 mL, 8.2 mmol) and 37% formaldehyde aqueous solution (2.92 mL, 39 mmol) Add 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (2.0 g, 8.2 mmol) to a solution of RT in MeOH (40 mL), and stir the resulting mix for 30 min. After cooling this mix to 0°C, gradually add NaBH3CN (1.74 g, 26.3 mmol). Warm the mix to RT, stir for 5 hours, and then concentrate. Fractionate the residue between ELISA and 1 M NaOH aqueous solution and extract. Separate the layers, and re-extract the aqueous layer with ELISA (2x). Combine the organic extracts, wash with brine, dry (Na2SO4), filter, and evaporate to obtain 1-(tert-butyl) 2-methyl (R)-4-methylpiperazine-1,2-dicarboxylate as a colorless oil. LC-MS I:t R =0.81min;[M+H] + = 259.22.

[0473] Step 2: Methyl (R)-4-methylpiperazine-2-carboxylate dicarboxylate is prepared from 1-(tert-butyl)2-methyl (R)-4-methylpiperazine-1,2-dicarboxylate in the same manner as described in C-1.1, Step 2. LC-MS I:t R =0.34min;[M+H] + = 159.16.

[0474] Steps 3 and 4: The title compound is prepared from Boc-N-methyl-L-leucine and methyl (R)-4-methylpiperazine-2-carboxylate dihydrochloride according to the two-step reaction sequence described in C-2.1. LC-MS B:t R =0.67min;[M+H] + = 372.51.

[0475] Table C-3 below lists the component C that is manufactured from the corresponding starting material in the same way as the four-step sequence described above for C-3.1.

[0476] [Table 17]

[0477] (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-cyclopropylpiperazine-2-carboxylic acid (HCl salt)(C-3.7) Step 1: Add (1-ethoxycyclopropoxy)trimethylsilane (2.6 mL, 12.80 mmol), NaBH3CN (0.66 g, 9.98 mmol), and AcOH (0.5 mL, 8.74 mmol) to a solution of methyl (R)-1-Boc-piperazine-2-carboxylate (1.54 g, 6.30 mmol) in MeOH (30 mL) and THF (30 mL), and heat the resulting mix at 60°C for 16 hours. Add water (5 mL), then 1 M NaOH aqueous solution (10 mL), to the cooled mix, stir for 15 minutes, and remove volatiles under reduced pressure. The residue was extracted by DCM (2x), the organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and evaporated to obtain 1-(tert-butyl)2-methyl(R)-4-cyclopropylpiperazine-1,2-dicarboxylate as a colorless oil. LC-MS B:t R =0.58min;[M+H] + = 285.31.

[0478] Steps 2-4: The title compound is prepared from 1-(tert-butyl)2-methyl(R)-4-cyclopropylpiperazine-1,2-dicarboxylate according to the three-step sequence described in C-3.1, Steps 2-4. LC-MS B:t R =0.73min;[M+H] + = 398.43.

[0479] General method 4 for the synthesis of component C N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-(chroman-3-ylmethyl)glycine(C-4.1) Step 1: Add HATU (219 mg, 0.58 mmol) to a solution of RT in DMF (2 mL) containing Boc-N-methyl-L-leucine (135 mg, 0.55 mmol), IM-1.3 (155 mg, 0.5 mmol), and DIPEA (0.34 mL, 2 mmol), and stir the resulting mix for 1 hour. Purify this RM directly by prep.HPLC (basic) to obtain benzyl N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-((chroman-3-yl)methyl)glycinate (218 mg, 81%). LC-MS I:t R =1.35min;[M+H] + = 539.23.

[0480] Step 2: Add LiOH (52.9 mg, 1.26 mmol) to a solution of benzyl N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-((chroman-3-yl)methyl)glycinate (218 mg, 0.4 mmol) in THF / H2O (2:1) (2 mL) in RT, and stir the mix overnight in RT. Remove volatiles under vacuum, acidify the aqueous residue with 2 M HCl aqueous solution, and extract with siRNA (3x). Combine the organic layers, dry (MgSO4), filter, and evaporate to obtain the title compound C-4.1 (200 mg, 71%) as a white solid. LC-MS I:t R =0.62min;[M+H] + = 449.25.

[0481] Table C-4 below lists the component C that is manufactured from the corresponding starting material in the same way as the two-step sequence described above for C-4.1.

[0482] [Table 18]

[0483] General method 5 for the synthesis of component C (S)-2-(2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamide)-2,3-dihydro-1H-indene-2-carboxylic acid (C-5.1) Step 1: Add HATU (1.24 g, 3.25 mmol) to a solution of Boc-N-methyl-L-leucine (800 mg, 3.25 mmol), methyl 2-amino-indan-2-carboxylate HCl (764 mg, 3.25 mmol), and DIPEA (2.23 mL, 13 mmol) in DMF (8 mL) with RT. Stir RM in RT for 1 hour, then dilute with water (20 mL) and DCM (50 mL). Separate the layers and extract the aqueous layer with DCM (2 x 50 mL). Combine the organic layers, wash with brine (20 mL), dry (MgSO4), filter, and concentrate. Elute FC (20%~55% siRNA in hept, siRNA at siRNA / hept 3:7) f= Purified with 0.34), methyl (S)-2-(2-((tert-butoxycarbonyl)amino)-4-methylpentanamide)-2,3-dihydro-1H-indene-2-carboxylate (1.07g, 79%) is obtained as a colorless oil. LC-MS B:t R =1.07min;[M+H] + = 419.17.

[0484] Step 2: Add NaH (36.6 mg, 0.956 mmol) to a solution of methyl (S)-2-(2-((tert-butoxycarbonyl)amino)-4-methylpentanamide)-2,3-dihydro-1H-indene-2-carboxylate (200 mg, 0.478 mmol) in DMF (6 mL) at 0°C. After stirring for 10 min, add MeI (60 Add μL (0.96 mmol) and remove the ice bath. Stir this mix in RT for 1 hour, then fractionate RM between 2N HCl (6 mL) and DCM (75 mL) and separate the layers. Re-extract the aqueous layer with DCM (2 x 75 mL), combine the organic layers, wash with brine (30 mL), dry (Na2SO4), filter, and evaporate. Purify the crude product by FC (eluting with 35%~80% ELISA in hept) to obtain methyl (S)-2-(2-((tert-butoxycarbonyl)amino)-N,4-dimethylpentanamide)-2,3-dihydro-1H-indene-2-carboxylate as a colorless oil. LC-MS B:t R =1.11min;[M+H] + = 433.07.

[0485] Step 3: Add 21 mL (83.2 mmol) of 4 M NaOH solution to the solution of methyl (S)-2-(2-((tert-butoxycarbonyl)amino)-N,4-dimethylpentanamide)-2,3-dihydro-1H-indene-2-carboxylate (90 mg, 2.08 mmol) in MeOH (30 mL) of RT, and stir RM at 50°C for 4 hours. Cool this RM to RT, then dilute this mix with DCM (100 mL) and acidify with 2 M HCl solution (10 mL). Separate the layers and extract the aqueous layer with DCM (2 x 75 mL). Combine the organic layers, wash with brine (30 mL), dry (MgSO4), filter, and concentrate to obtain the title compound C-5.1 (796 mg, 91%) as a white foam, which is used directly in the next step. LC-MS B:t R =1.01min;[M+H] + = 419.09.

[0486] Table C-5 below lists the component C that is manufactured from the corresponding starting material in the same way as the three-step sequence described above for C-5.1.

[0487] [Table 19]

[0488] General method for the synthesis of component C 6 (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-(3-hydroxypropyl)piperazine-2-carboxylic acid HCl salt (C-6.1) Step 1: Add K2CO3 (1.66 g, 12 mmol) to a solution of 1-(tert-butyl)2-methyl(R)-piperazine-1,2-dicarboxylate (1.0 g, 4.01 mmol) and benzyl 3-bromopropyl ether (0.95 mL, 5.22 mmol) in MeCN (10 mL) of RT, and stir the resulting mix at 60°C for 17 hours. Add water (20 mL) and DCM (75 mL) to this RM, then separate the two layers, and extract the aqueous layer with DCM (2 x 50 mL). Combine the organic extracts, wash with brine (50 mL), dry (MgSO4), filter, and concentrate. FC (5%~25% in hept) Purified by elution with ethyl acetate, (R)-4-(3-benzyloxypropyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.58 g, 100%) is obtained as a colorless oil. LC-MS B:t R =0.75min;[M+H] + = 393.43.

[0489] Step 2: Add 4M HCl (5 mL, 20 mmol) in dioxane to a solution of (R)-4-(3-benzyloxypropyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.57 g, 4 mmol) in dioxane (7 mL) in RT, and stir the resulting mix at 50°C for 2 hours. Cool this RM to RT, then dilute with DCM (100 mL), and add saturated K2CO3 aqueous solution (20 mL). Separate the layers, and extract the aqueous layer with DCM (2 x 75 mL). Combine the organic layers, wash with brine (100 mL), dry (MgSO4), filter, and concentrate to obtain (R)-4-(3-benzyloxypropyl)-piperazine-2-carboxylic acid methyl ester (1.06 g, 91%) as a colorless oil, which is used directly in the next step. LC-MS B:t R =0.53min;[M+H] + = 293.32.

[0490] Step 3: Add HATU (1.36 g, 3.58 mmol) to a solution of Boc-N-methyl-L-leucine (880 mg, 3.58 mmol), (R)-4-(3-benzyloxypropyl)-piperazine-2-carboxylic acid methyl ester (1.05 g, 3.58 mmol), and DIPEA (1.84 mL, 10.7 mmol) in RT (11 mL) of DMF. Stir the resulting mix in RT for 1 hour, and dilute this RM with DCM (100 mL) and water (10 mL). Separate the layers and extract the aqueous layer with DCM (2 x 75 mL). Combine the organic layers, wash with brine (50 mL), dry (MgSO4), filter, and concentrate. Purified by FC (eluted with 15%-42% ethyl acetate in hept), methyl (R)-4-(3-(benzyloxy)propyl)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)piperazine-2-carboxylate (1.67 g, 90%) is obtained as a colorless oil. LC-MS B:t R =0.90min;[M+H] + = 520.39.

[0491] Step 4: Add a 2M NaOH solution (32 mL, 63.9 mmol) to the RT solution of methyl (R)-4-(3-(benzyloxy)propyl)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)piperazine-2-carboxylate (1.66 g, 3.19 mmol) in MeOH (60 mL), and stir the RM at 50°C for 1 hour. Cool the RM to RT, dilute the RM with DCM (100 mL), and acidify with 25% HCl aqueous solution (10 mL). Separate the layers and extract the aqueous layer with DCM (2 x 75 mL). The organic layers are combined, washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to obtain (R)-4-(3-benzyloxypropyl)-1-[(S)-2-(tert-butoxycarbonylmethylamino)-4-methylpentanoyl]-piperazine-2-carboxylic acid (1.47 g, 85%) as a white solid, which is used directly in the next step. LC-MS B:t R =0.84min;[M+H] + = 506.36.

[0492] Step 5: The solution of (R)-4-(3-benzyloxypropyl)-1-[(S)-2-(tert-butoxycarbonylmethylamino)-4-methylpentanoyl]-piperazine-2-carboxylic acid (1.74 g, 3.21 mmol) in EtOH (20 mL) is inactivated (3x) under N2 / vacuum, and then 10% Pd / C (171 mg, 0.16 mmol) is added. After further inactivation three times, an H2 balloon is attached and the RM is stirred under RT for 18 hours. This mix is ​​concentrated, rinsed with EtOH using a Celite plug, and filtered. The filtrate is concentrated to obtain the title compound C-6.1 (1.14 g, 79%) as a white solid. LC-MS B:t R =0.67min;[M+H] + = 416.34.

[0493] (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-(2-hydroxyethyl)piperazine-2-carboxylic acid HCl salt (C-6.2) The title compound is prepared in step 1 using benzyl 2-bromoethyl ether instead of benzyl 3-bromopropyl ether, following the five-step sequence described in C-6.1. LC-MS B:t R =0.67min;[M+H] + = 402.07.

[0494] (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-(2-methoxyethyl)piperazine-2-carboxylate HCl salt (C-6.3) Step 1: Add 1-bromo-2-methoxyethane (4.31 mL, 44.9 mmol) to a solution of 1-(tert-butyl) 2-methyl (R)-piperazine-1,2-dicarboxylate (4.00 g, 16 mmol) and DIPEA (8.41 mL, 48.1 mmol) in MeCN (87 mL) with RT. Stir the resulting mix at 80°C for 18 hours. Concentrate the mix and fractionate the residue between water (10 mL) and DCM (50 mL). Separate the layers and re-extract the aqueous layer with DCM (2 x 75 mL). Combine the organic extracts, wash with brine (50 mL), dry (MgSO4), filter, and evaporate to obtain (R)-4-(2-methoxy-ethyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as an orange oil. LC-MS B:t R =0.54min;[M+H] + = 303.36.

[0495] Steps 2-4: The title compound is prepared from (R)-4-(2-methoxy-ethyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester according to the reaction sequence described in C-6.1, Steps 2-4. LC-MS B:t R =0.71min;[M+H] + = 416.36.

[0496] (S)-1-(2-((tert-butoxycarbonyl)(methyl)amino)-N-(3-methoxypropyl)-4-methylpentanamide)cyclopropane-1-carboxylic acid (C-6.4) Step 1: 1-(3-methoxypropylamino)-cyclopropanecarboxylic acid methyl ester is prepared from methyl 1-aminocyclopropane carboxylate and 1-bromo-3-methoxypropane according to the reaction described in C-6.3, Step 1. LC-MS B:t R =0.39min;[M+H] + = 188.43.

[0497] Steps 2 and 3: The title compound is prepared from 1-(3-methoxy-propylamino)-cyclopropanecarboxylic acid methyl ester according to the reaction sequence described in C-6.1, Steps 3 and 4. LC-MS B:t R =0.91min;[M+H] + = 401.30.

[0498] General method for the synthesis of component C 7 (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-((2,2,2-trichloroethoxy)carbonyl)piperazine-2-carboxylic acid (C-7.1) Step 1: Add 2,2,2-trichloroethyl chloroformate (1.2 mL, 8.54 mmol) to a solution of 1-(tert-butyl) 2-methyl (R)-piperazine-1,2-dicarboxylate (2.0 g, 8.02 mmol) and DIPEA (2.88 mL, 16.5 mmol) in RT (40 mL) of DCM. Stir the resulting mix in RT for 45 min. Dilute this RM with DCM (100 mL) and water (20 mL). Separate the layers and extract the aqueous layer with DCM (2 x 75 mL). Combine the organic layers, wash with brine (50 mL), dry (MgSO4), filter, and concentrate. FC (20%~60 in hept) Elution with % toluene, R at toluene / hept 1:1 fPurified with 0.3), 1-(tert-butyl) 2-methyl 4-(2,2,2-trichloroethyl) (R)-piperazine-1,2,4-tricarboxylate (2.90 g, 74%) is obtained as a white solid. LC-MS B:t R =1.13min;[M+H] + = 545.75.

[0499] Steps 2-4: The title compound is prepared from 1-(tert-butyl) 2-methyl 4-(2,2,2-trichloroethyl) (R)-piperazine-1,2,4-tricarboxylate according to the reaction sequence described in C-6.1, Steps 2-4. LC-MS B:t R =1.03min;[M+H] + = 531.98.

[0500] General method for the synthesis of component C 8 (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-phenylpiperazine-2-carboxylic acid (C-8.1) Step 1: Add Cu(OAc)2 (749 mg, 6.2 mmol) to a solution of 1-(tert-butyl) 2-methyl (R)-piperazine-1,2-dicarboxylate (1.00 g, 4.01 mmol) and phenylboronic acid (749 mg, 4.01 mmol) in RT in DCM (20 mL), and stir the resulting mix overnight in RT. Dilute this RM in DCM and wash with cold water (20 mL) and brine (20 mL). Dry the organic layer (MgSO4), filter, and evaporate. Purify by prep.HPLC (basic) to obtain (R)-4-phenyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (337 mg, 26%) as a colorless oil. LC-MS B:t R =1.02min;[M+H] + = 321.13.

[0501] Step 2: Add TFA (0.8 mL, 10.6 mmol) to a solution of (R)-4-phenyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (337 mg, 1.06 mmol) in DCM (40 mL), and stir the resulting mix for 24 hours. Dilute this RM with DCM (10 mL) and neutralize with saturated NaHCO3 aqueous solution (30 mL). Separate the layers and re-extract the aqueous layer with DCM (20 mL). Combine the organic extracts, dry (Na2SO4), filter, and concentrate to obtain (R)-4-phenyl-piperazine-2-carboxylic acid methyl ester (232 mg, 100%) as a yellowish oil. LC-MS B:t R =0.52min;[M+H] + = 221.32.

[0502] Steps 3 and 4: The title compound is prepared from Boc-N-methyl-L-leucine and (R)-4-phenyl-piperazine-2-carboxylic acid methyl ester according to the reaction sequence described in C-2.1. LC-MS B:t R =1.03min;[M+H] + = 433.9.

[0503] (RS)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-(5-fluoropyridine-2-yl)piperazine-2-carboxylic acid (C-8.2) Step 1: A mixture of 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (2500 mg, 10 mmol), 2-bromo-5-fluoropyridine (2161 mg, 12 mmol), tris(dibenzylideneacetone)dipalladium(0) (473 mg, 0.501 mmol), and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (426 mg, 1 mmol) in toluene (30 mL) is degassed and inactivated with argon. This RM is then heated to 100 °C for 4 h 30 to complete the conversion (monitored by LC-MS). This solution is recooled to RT and filtered through a glass fiber filter. Water is added to the obtained filtrate, the organic layer is collected, and then the inorganic phase is converted to Et Further extraction with OAc (2x). The organic phase is collected and sequentially washed with saturated NH4Cl aqueous solution, saturated NaHCO3 aqueous solution, and brine, dried over MgSO4, and then concentrated under reduced pressure. The crude product is purified with FC (0%~30% ethyl acetate in hept) to obtain 1-(tert-butyl) 2-methyl (R)-4-(5-fluoropyridine-2-yl)piperazine-1,2-dicarboxylate as a yellow oil (2.21 g). LC-MS B:t R =0.92min;[M+H] + =340.16.

[0504] Steps 2-4: The title compound is prepared from boc-N-methyl-L-leucine and 1-(tert-butyl)2-methyl(R)-4-(5-fluoropyridine-2-yl)piperazine-1,2-dicarboxylate according to reaction sequences 2-4 described in C-8.1. Strong epimerization is observed at the piperazine chiral center at the end of the 4-step sequence. LC-MS B:t R =0.96min;[M+H] + = 453.37.

[0505] General method for the synthesis of component C 9 (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-(pyridine-3-ylsulfonyl)piperazine-2-carboxylic acid (C-9.1) Step 1: Add pyridine-3-sulfonyl chloride (2.33 g, 12.8 mmol) to a solution of 1-(tert-butyl) 2-methyl (R)-piperazine-1,2-dicarboxylate (2.00 g, 8.02 mmol) and TEA (3.37 mL, 24.1 mmol) in RT (80 mL) of DCM, and stir the resulting mix in RT for 1 hour. Dilute this RM with DCM (75 mL) and water (10 mL). Separate the layers and extract the aqueous layer with DCM (2 x 75 mL). Combine the organic layers, wash with brine (50 mL), dry (MgSO4), filter, and concentrate. Elute with 80%-85% ethyl in FC (hept), and ethyl in ethyl / hept 7:3 R fPurified with (R)-4-(pyridine-3-sulfonyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.06 g, 99%) as a white foam. LC-MS B:t R =0.89min;[M+H] + = 386.16.

[0506] Step 2: Add 4M HCl (9.73 mL, 38.9 mmol) in dioxane to a solution of (R)-4-(pyridine-3-sulfonyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.0 g, 7.78 mmol) in dioxane (10 mL) with RT. Stir the resulting mix at 50°C for 2 hours. Filter the suspension and rinse the solid with TBME (20 mL) to obtain methyl (R)-4-(pyridine-3-ylsulfonyl)piperazine-2-carboxylate dihydrochloride (3.12 g, 112%) as a white solid. LC-MS B:t R =0.44min;[M+H] + = 286.15.

[0507] Steps 3 and 4: The title compound is prepared from Boc-N-methyl-L-leucine and (methyl (R)-4-(pyridine-3-ylsulfonyl)piperazine-2-carboxylate dihydrochloride according to the reaction sequence described in C-2.1. LC-MS B:t R =0.93min;[M+H] + = 499.27.

[0508] (R)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-4-((5-methoxypyridine-3-yl)sulfonyl)piperazine-2-carboxylic acid (C-9.2) The title compound is prepared in step 1 using 5-methoxypyridine-3-sulfonyl chloride instead of pyridine-3-sulfonyl chloride, following the four-step reaction sequence described in C-9.1. LC-MS B:t R =0.96min;[M+H]+ = 529.10.

[0509] General method for the synthesis of component C 10 Table C-10 below lists component C, which is manufactured from the corresponding starting material in the same sequence as described above for steps C-1.1, 3 and 4.

[0510] [Table 20]

[0511] [Table 21]

[0512] General method for the synthesis of component C 11 (S)-1-(2-((tert-butoxycarbonyl)(methyl)amino)-3-cyclopentyl-N-methylpropanamide)cyclopropane-1-carboxylic acid (C-11.1) Step 1: Add benzyl chloroformate (4.6 mL, 30.6 mmol) to a solution of methyl 1-aminocyclopropane carboxylate (3.25 g, 27.7 mmol) and NaHCO3 (9.64 g, 115 mmol) in DCM (30 mL) and RT in H2O (30 mL). Stir the resulting mix in RT. After 2 hours, separate the two layers and extract the aqueous layer with DCM (2 x 30 mL). Combine the organic extracts and concentrate to obtain 1-benzyloxycarbonylaminocyclopropanecarboxylic acid methyl ester (7.28 g, 106%) as a yellow solid. LC-MS B:t R =0.79min;[M+H] + = 250.37.

[0513] Step 2: Add the solution of NaH (1.85 g, 46.3 mmol), then 1-benzyloxycarbonylaminocyclopropanecarboxylic acid methyl ester (7.28 g, 29.2 mmol) in DMF (30 mL) to a 0°C solution of DMF (45 mL). After 45 min, add MeI (5.5 mL, 87.5 mmol) and warm the mix in RT overnight. Fractionate this RM between H2O (50 mL) and siRNA (150 mL) and separate the layers. Re-extract the aqueous layer with siRNA (2 x 75 mL), combine the organic layers, wash with brine (40 mL), dry (MgSO4), filter, and evaporate to obtain 1-(benzyloxycarbonylaminocyclopropanecarboxylic acid methyl ester). Rubonyl-methyl-amino)cyclopropanecarboxylic acid methyl ester (7.70 g, 100%) is obtained as an orange liquid and used as is in the next step. LC-MS B:t R =0.88min;[M+H] + = 264.33.

[0514] Step 3: A solution of 1-(benzyloxycarbonyl-methyl-amino)-cyclopropanecarboxylic acid methyl ester (4.00 g, 11.4 mmol) in MeOH (18 mL) is inactivated (3x) under N2 / vacuum, and then 10% Pd / C (606 mg, 0.57 mmol) is added. After further inactivation three times, an H2 balloon is attached and the RM is stirred for 18 hours. This mix is ​​concentrated, rinsed with EtOH using a Celite plug, and filtered. The filtrate is concentrated (note: the product is volatile) to obtain 1-methylamino-cyclopropanecarboxylic acid methyl ester (653 mg, 44%). LC-MS B:t R =0.26min;[M+H] + = 130.24.

[0515] Steps 4 and 5: The title compound is prepared from D2-1.1 and 1-methylaminocyclopropanecarboxylic acid methyl ester according to the two-step sequence described for C-2.1. LC-MS B:t R =0.92min;[M+H] + = 369.29.

[0516] General method for the synthesis of component C 12 N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-(3-methoxypropyl)-D-alanine(C-12.1) Step 1: Add NaH3BCN (398 mg, 6.02 mmol) to a solution of D-alanine methyl ester HCl (600 mg, 4.3 mmol), 3-methoxy-propionaldehyde (429 mg, 4.73 mmol), molecular sieve 3A (450 mg), and AcOH (0.295 mL, 5.16 mmol) in MeOH (19 mL) with RT. Stir the resulting mix with RT for 35 min. Concentrate this mix and add DCM to the residue. Wash the organic layer with sat.NaHCO3 and re-extract the aqueous layer with DCM. Combine the organic extracts, wash with brine, dry with (MgSO4), filter, and concentrate to obtain (R)-2-(3-methoxy-propylamino)-propionic acid methyl ester (615 mg, 82%) as a colorless oil. LC-MS B:t R =0.33;[M+H] + = 176.50.

[0517] Steps 2 and 3: The title compound is prepared from (R)-2-(3-methoxypropylamino)-propionic acid methyl ester according to the two-step sequence described in C-2.1. LC-MS B:t R =0.91min;[M+H] + = 389.42.

[0518] General method for the synthesis of component C 13 (S)-1-(2-((tert-butoxycarbonyl)(methyl)amino)-N-(2-methoxyethyl)-4-methylpentanamide)cyclopropane-1-carboxylic acid (C-13.1) Step 1: Add benzyl bromide (4.41 mL, 36.4 mmol) to a suspension of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (7.00 g, 33.0 mmol) and K2CO3 (6.92 g, 49.6 mmol) in MeCN (320 mL). Heat the resulting mix at 60°C for 15 hours. Concentrate the RM and add ELISA and water to the residue. Separate the organic layer, wash with brine, dry (MgSO4), filter, and concentrate to obtain 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid benzyl ester (9.97 g, 104%) as a white solid. LC-MS B:t R =0.95min;[M+H] + = 292.31.

[0519] Step 2: Add 4M HCl (84.0 mL, 336 mmol) in dioxane to a suspension of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid benzyl ester (9.97 g, 33.0 mmol) in DCM (20 mL) of RT, and stir the resulting mix in RT for 1.5 hours. Concentrate the RM and co-evaporate with DCM under HV to obtain 1-amino-cyclopropanecarboxylic acid benzyl ester HCl (7.93 g, 105%) as a white solid. LC-MS B:t R =0.50min;[M+H] + = 192.34.

[0520] Step 3: Gradually add 2-nitrobenzenesulfonyl chloride (8.30 g, 36.4 mmol) to a 0°C suspension of 1-amino-cyclopropanecarboxylic acid benzyl ester HCl (7.93 g, 33.0 mmol) and TEA (13.9 mL, 99.1 mmol) in DCM (70 mL). After 30 min, remove the ice bath and stir the mix in RT for 1.5 hours. Fractionate this RM between sat. NaHCO3 and DCM and separate the layers. Re-extract the aqueous layer with DCM, combine the organic layers, wash with brine (40 mL), dry (MgSO4), filter, and concentrate. FC (siRNA / hept 3:7~1:1, siRNA / hept 3:7) f=Purified using 0.21), 1-(2-nitro-benzenesulfonylamino)-cyclopropanecarboxylic acid benzyl ester (12.05 g, 97%) is obtained as an orange oil. LC-MS B:t R =0.96min;[M+H] + = 377.29.

[0521] Step 4: Add DIAD (2.1 mL, 10.2 mmol) dropwise to a solution of 1-(2-nitro-benzenesulfonylamino)-cyclopropanecarboxylic acid benzyl ester (2.00 g, 5.31 mmol), 2-methoxy-ethanol (0.635 mL, 7.97 mmol), and PPh3 (2.83 g, 10.2 mmol) in TH...

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, * X is -CR Ｘ１ R Ｘ２ It represents; (- R Ｘ１ and R Ｘ２ Together with the carbon atoms to which they bond: -- C ３－６ -Cycloalkane-1,1-diyl; -- C condensed on a benzene ring ５－６ -Cycloalkane-1,1-diyl; -- C ３－６ -cycloalkan-1,1-diyl, where one C １－３ -alkoxy, fluoro or hydroxy; or two fluoro independently substituted C ３－６ -cycloalkan-1,1-diyl group; -- C ４－６ - Heterocycloalkanediyl, and the C ４－６ - When a heterocycloalkane-diyl has one ring nitrogen atom and that nitrogen has a free valence, the nitrogen is either unsubstituted or substituted with one substituent, and the substituent is C １－４ -a Lukil and -COO-C １－３ - C, independently selected from alkyl groups. ４－６ - Heterocycloalkane-diyl; Or, -- C ４－６ - Heterocycloalkane-diyl having one ring oxygen atom C ４－６ - Heterocycloalkane-diyl; Does it form a ring? - R Ｘ１ and R Ｘ２ All of them are independently C １－４ - Does it represent alkyl? Or, - R Ｘ１ represents hydrogen, and, R Ｘ２ teeth, -- Hydrogen; -- C １－６ - Alkyl; -- C １－４ - Fluoroalkyl; -- C ３－６ - Cycloalkyl; -- C １－３ - Alkyl, one --- Hydroxyl; --- C １－４ - Alkoxy; --- -L Ｘ１ -C ３－６ -Cycloalkyl (the C ３－６ - The cycloalkyl group is either unsubstituted or substituted with two fluorocarbons; L Ｘ１ (These independently represent direct bonds or oxygen atoms.) --- C ４－６ - A heterocycloalkyl group having one ring oxygen atom. ４－６ - Heterocycloalkyl; --- NR Ｎ１ R Ｎ２ (R Ｎ１ and R Ｎ２ Together with the above nitrogen, it forms a 4-6 membered carbon ring containing this nitrogen atom, and the ring is substituted with one or two fluorocarbons. 【Chemistry 2】 A partially aromatic bicyclic ring; The C replaced by １－３ - Alkyl; or, -- -L Ｘ２ -Ar Ｘ２ (--- L Ｘ２ These are independently, directly bonded, C １－３ -Alkilen, -C １－３ -Alkilen-O- ＊ or -C １－３ -Alkylene-O-C １－２ -Alkilen- ＊ The asterisk represents the base Ar Ｘ２ It shows a bond that connects to; --- Ar Ｘ２ Each independently represents an aryl or a 5- to 10-membered heteroaryl group; the group Ar Ｘ２ These are independently unsubstituted or substituted with one or two substituents, and the substituents are ---- C １－４ - Alkyl; ---- C １－３ - Alkoxy; ---- Halogen; ---- C ３－６ - Cycloalkyl; ---- C １－３ - Fluoroalkyl; and ---- Ar Ｘ３ (Ar Ｘ３ The group Ar independently represents phenyl or a 5- or 6-membered heteroaryl; the group Ar Ｘ３ These are independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－３ - Alkyl, C １－３ - Alkoxy, C １－３ -Alkoxy-C ２－３ - Alkyl, C ３－５ - Cycloalkyl, C １－３ - Independently selected from fluoroalkyls and halogens. Selected independently from; It represents; and, R １ Independently, - Hydrogen; --C １－８ - Alkyl; --C ２－６ - Alkyl, with one hydroxyl or C １－４ - The C substituted with alkoxy ２－６ - Alkyl; --C １－６ - Alkyl, with one R １１ Replaced by; R １１ However, independently, -- a 5 or 6-membered saturated heterocycloalkyl having one or two ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen and oxygen, and the 5 or 6-membered heterocycloalkyl is independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - A 5- or 6-membered heterocycloalkyl group independently selected from alkyl, halogen, and benzyl; -- C ３－６ - Cycloalkyl, unsubstituted or with one C １－４ - The C substituted with alkoxy ３－６ - Cycloalkyl; -- Phenyl or 5- or 6-membered heteroaryl compounds, independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - A phenyl or 5- or 6-membered heteroaryl independently selected from fluoroalkoxys, halogens, cyanos, and morpholine-4-yl; -- Benzyl oxy; 【Transformation 3】 spiro ring fragment; 【Chemistry 4】 A saturated bicyclic ring; Or, 【Transformation 5】 A partially aromatic bicyclic ring; The C that represents １－６ - Alkyl; Does it represent; * Or, fragment 【Transformation 6】 (R Ｘ teeth, - Hydrogen; - C １－４ - Alkyl; - C ３－６ - Cycloalkyl; - C １－４ - Alkyl, with one C ３－４ - The C substituted with cycloalkyl １－４ - Alkyl; - C ２－４ - Alkyl, with one hydroxyl or C １－３ - The C substituted with alkoxy ２－４ - Alkyl; - phenyl or a 5- or 6-membered heteroaryl, independently unsubstituted or substituted by 1 or 2 substituents, said substituents being selected independently from C １－４ - alkyl, C １－３ - alkoxy, C １－３ - fluoroalkyl, C １－３ - fluoroalkoxy, cyano or halogen; said phenyl or 5- or 6-membered heteroaryl 【Transformation 7】 (R ＳＸ１ is hydrogen or -CO-O-C １－４ - Represents alkyl. --CO-R ＯＸ１ or -SO ２ -R ＯＸ１ ; (R ＯＸ１ is, independently, -- C １－４ - Alkyl; -- C １－３ - Alkyl, with one C １－３ -alkoxy, tetrahydropyranyl, morpholine-4-yl, phenyl, 10-membered heteroaryl or -NR ＯＮＸ１ R ＯＮＸ２ (R ＯＮＸ１ and R ＯＮＸ２ These are independently hydrogen or C １－３ - Represents alkyl.) The C substituted by １－３ - Alkyl; -- Tetrahydropyranil; -- Phenyl or 5- or 6-membered heteroaryl compounds, independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－３ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - A phenyl or 5- or 6-membered heteroaryl independently selected from fluoroalkoxy, cyano, or halogen; or, -- Structure (R Ｘ－Ａ ) the basis: 【Transformation 8】 (wherein (A) represents a 5 or 6-membered non-aromatic ring condensed to the phenyl group, and ring (A) comprises two heteroatoms independently selected from oxygen and nitrogen; ring (A) is independently unsubstituted or substituted with one substituent, the substituent being oxo and C) １－３ - Independently selected from alkyl groups. It represents. ); or, - -C-O-R ＯＸ２ ;(R ＯＸ２ は、 -- C １－４ - Alkyl; -- 2,2,2-trichloroethyl; Or, -- Tetrahydropyranil; (This represents...) (This represents...) This represents a complex algebra; R ２ is C １－４ - Represents alkyl; R ３ is hydrogen; C １－６ -Alkyl; -CH ２ -C ３－６ -Cycloalkyl; or C ２－４ - Represents Alkinnil; R ４ is the base-CO-NH-R ４１ Represents; R ４１ teeth, - C ２－６ - Alkyl, with one C １－４ - Alkoxy, C １－４ -C substituted with fluoroalkoxy or hydroxyl ２－６ - Alkyl; - C １－３ -Alkoxy-C ２－３ -Alkylene-O-CH ２ -CH ２ -; - -CH ２ -CH ２ -C ５－６ - A heterocycloalkyl having one ring oxygen atom, and the C ５－６ - The heterocyclyl is unsubstituted or has one or two C １－４ - The C substituted with alkyl ５－６ - Heterocycloalkyl; - -L １ -Aryl; (L １ is, -CH ２ -CH ２ -ien-CH ２ -CH ２ -O- ＊ ien-CH ２ -CF ２ - ＊ ien-CH ２ - (Cyclopropane-1,1-diyl) - ＊ , -CH(CH ２ -OH)-CH ２ - ＊ or -CH ２ -CH(OH)- ＊ It represents; the asterisk is L １ This indicates a bond to the above aryl; the aryl represents phenyl or naphthyl; the aryl is unsubstituted or substituted with one, two, or three substituents, the substituents independently being C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ -Fluoroalkoxy, halogen, cyano, C ３－６ - Cycloalkyl, C ３－６ -Cycloalkyl-methyl, C １－３ -Alkoxy-C １－３ -Alkyl, hydroxy-C １－３ - Alkyl, C ２－３ -Alkinyl, Morpholine-4-yl, C １－３ -alkyl-SO ２ -, 5 or 6-membered heteroaryl or -NR Ｎ４１ R Ｎ４２ (Independently, R Ｎ４１ is hydrogen or C １－４ - Alkyl, R Ｎ４２ is hydrogen or C １－４ -It is alkyl.) - -L ２ -HET; (L ２ is, -CH ２ -CH ２ -ien-CH ２ -CH ２ -O- ＊ ien-CH ２ -CF ２ - ＊ ien-CH ２ - (Cyclopropane-1,1-diyl) - ＊ , -CH(CH ２ -OH)-CH ２ - ＊ or -CH ２ -CH(OH)- ＊ It represents; the asterisk is L ２ This shows a bond that connects to HET; HET represents a 5-10 member heteroaryl, which is independently unsubstituted or substituted with 1, 2, or 3 substituents, and the substituents are independently C １－４ - Alkyl; C １－４ - Alkoxy; C １－３ - Fluoroalkyl; C １－３ -Fluoroalkoxy; Halogen; Cyano; C ３－６ -Cycloalkyl; C ３ －６ -Cycloalkyl-methyl; C １－３ -Alkoxy-C １－３ -Alkyl;Hydroxy-C １－３ - Alkyl; C ２－３ -Alkynyl; benzyl; or phenyl, which is unsubstituted or substituted with one or two substituents, wherein the substituents are independently C １－４ - Alkyl, C １－４ - Alkoxy or C １－４ - Phenylen is a fluoroalkoxy; - -CH ２ -CH ２ -HCy １ (HCy １ This represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a 5-7 member saturated heterocycle having one or two heteroatoms independently selected from oxygen and nitrogen, wherein if nitrogen is present and has free valence, the nitrogen is unsubstituted or has one carbon atom. １－４ - Substituted with alkyl; the phenyl ring of the partially aromatic bicyclic ring system is unsubstituted or substituted with 1, 2, or 3 substituents, the substituents independently being C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ -It is a fluoroalkoxy, halogen, or cyano(-). - -CH ２ -CH ２ -HCy ２ (HCy ２ This represents a partially aromatic bicyclic ring system consisting of a 5-membered heteroaryl fused to a 5- to 7-membered saturated carbon ring. ); or, - -L ３ -HCy ３ (L ３ is a direct bond or -CH ２ - represents; HCy ３ L represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a saturated heterocycle with 5 to 7 members and one oxygen atom; ３ In the 5-7 member saturated heterocycle portion, the group HCl is present at the carbon atom. ３ Bonded to; the phenyl ring of the partially aromatic bicyclic ring system is unsubstituted or has one C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - Substituted with fluoroalkoxy, halogen, or cyano(s); It represents; Ar １ teeth, - Five or six-membered heteroarylenes, which are unsubstituted; - Phenylene or a 5- or 6-membered heteroarylene, independently substituted with 1, 2, or 3 substituents, wherein the substituents are C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - Phenylene or 5- or 6-membered heteroarylene independently selected from fluoroalkoxy, cyano, and halogen; - Phenylene condensed to a 5- or 6-membered saturated heterocycle having one or two oxygen atoms, wherein the 5- or 6-membered saturated heterocycle is independently unsubstituted or substituted with two fluorocarbons; or, - A bicyclic aromatic ring selected from naphthylene and 8-10 membered bicyclic heteroarylenes, which is independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－３ - Fluoroalkyl, C １－４ - Alkoxy, C １－３ - The bicyclic aromatic ring independently selected from fluoroalkoxy, cyano, and halogen; Or, - Quinoline-diyl, wherein the quinoline-diyl exists in the form of each N-oxide; the quinoline-diyl N-oxide is unsubstituted or the quinoline-diyl N-oxide is substituted with one methyl or fluoro group; It represents; Ar ２ teeth, - Phenyl or naphthyl, independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－３ - Fluoroalkyl, halogen, cyano, C １－６ - Alkoxy and C １－３ - A phenyl or naphthyl selected independently from fluoroalkoxys; - A 5- or 6-membered heteroaryl compound, independently unsubstituted or substituted with one substituent, wherein the substituent is C １－４ - Alkyl, C １－３ - Fluoroalkyl, halogen, cyano, C １－６ - Alkoxy and C １－３ - A 5- or 6-membered heteroaryl selected independently from fluoroalkoxys; Or, - 9 or 10-membered heteroaryls; (This represents...)

2. Equation (I Ｅ A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, which is also a compound of: 【Chemistry 9】

3. * X is -CR Ｘ１ R Ｘ２ It represents; (- R Ｘ１ and R Ｘ２ Together with the carbon atoms to which they bond: -- C ３－６ -Cycloalkane-1,1-diyl-; -- C condensed on a benzene ring ５－６ -Cycloalkane-1,1-diyl-; Or, -- C ３－６ -Cycloalkane-1,1-diyl-, with one C １－３ - The C substituted with an alkoxy or two fluorocarbons ３－６ -Cycloalkane-1,1-diyl group; Does it form a ring? - R Ｘ１ and R Ｘ２ All of them are independently C １－４ - Does it represent alkyl? Or, - R Ｘ１ represents hydrogen, and, R Ｘ２ teeth, -- Hydrogen; -- C １－６ - Alkyl; -- C １－４ - Fluoroalkyl; -- C ３－６ - Cycloalkyl; -- C １－３ - Alkyl, one --- Hydroxyl; --- C １－４ - Alkoxy; --- -L Ｘ１ -C ３－６ -Cycloalkyl (the C ３－６ - The cycloalkyl group is either unsubstituted or substituted with two fluorocarbons; L Ｘ１ (These independently represent direct bonds or oxygen atoms.) --- C ４－６ - A heterocycloalkyl group having one ring oxygen atom. ４－６ - Heterocycloalkyl; --- NR Ｎ１ R Ｎ２ (R Ｎ１ and R Ｎ２ Together with the above nitrogen, it forms a 4-6 membered carbon ring containing this nitrogen atom, and the ring is substituted with one or two fluorocarbons. The C replaced by １－３ - Alkyl; -- -L Ｘ２ -Ar Ｘ２ (--- L Ｘ２ These are independently, directly bonded, C １－３ -Alkilen, -C １－３ -Alkilen-O- ＊ or -C １－３ -Alkylene-O-C １－２ -Alkilen- ＊ The asterisk represents the base Ar Ｘ２ It shows a bond that connects to; --- Ar Ｘ２ Each independently represents an aryl or a 5- to 10-membered heteroaryl; the group Ar Ｘ２ These are independently unsubstituted or substituted with one or two substituents, and the substituents are ---- C １－４ - Alkyl; ---- C １－３ - Alkoxy; ---- Halogen; ---- Cyano; ---- C ３－６ - Cycloalkyl; ---- C １－３ - Fluoroalkyl; and ---- Ar Ｘ３ (Ar Ｘ３ The group Ar independently represents phenyl or a 5- or 6-membered heteroaryl; the group Ar Ｘ３ These are independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－３ - Alkyl, C １－３ - Alkoxy, C １－３ -Alkoxy-C ２－３ - Alkyl, C ３－５ - Cycloalkyl, C １－３ - Independently selected from fluoroalkyls and halogens. Selected independently from; It represents; and, R １ However, independently, hydrogen or -C １－３ - Does it represent alkyl? Or, * X is -CR Ｘ１ R Ｘ２ It represents; (- R Ｘ１ represents hydrogen, and, R Ｘ２ Does this represent hydrogen or methyl? Or, - R Ｘ１ and R Ｘ２ C ３－５ It forms a ring that is a cycloalkane-1,1-diyl; and, R １ However, independently, --C ４－６ - Alkyl; --C ２－６ - Alkyl, with one C １－４ - The C substituted with alkoxy ２－６ - Alkyl; --C ３－６ - Alkyl, and the C is substituted with one phenyl or benzyloxy molecule. ３－６ - Alkyl; --(CH ２ ) ｍ -R １１ (m represents an integer 1 or 2; R １１ Independently, -- A 5- or 6-membered saturated heterocycloalkyl having one or two ring oxygen atoms, independently unsubstituted or having one or two C １－４ - A 5- or 6-membered heterocycloalkyl group substituted with alkyl; -- C ３－６ - Cycloalkyl, unsubstituted or with one C １－４ - The C substituted with alkoxy ３－６ - Cycloalkyl; -- Phenyl or 5- or 6-membered heteroaryl compounds, independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - A phenyl or 5- or 6-membered heteroaryl, independently selected from fluoroalkoxy, cyano, or halogen; 【Chemistry 10】 spiro ring fragment; 【Chemistry 11】 A saturated bicyclic ring; Or, 【Chemistry 12】 A partially aromatic bicyclic ring; (This represents...) Does it represent; * Or, fragment, 【Chemistry 13】 (R Ｘ teeth, - Hydrogen; - C １－４ - Alkyl; - C ３－４ - Cycloalkyl; - C １－４ - Alkyl, with one C ３－４ - The C substituted with cycloalkyl １－４ - Alkyl; - C ２－４ - Alkyl, with one hydroxyl or C １－３ - The C substituted with alkoxy ２－４ - Alkyl; - Phenyl or 5- or 6-membered heteroaryl compounds, independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－３ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - A phenyl or 5- or 6-membered heteroaryl, independently selected from fluoroalkoxy, cyano, or halogen; 【Chemistry 14】 (R ＳＸ１ is hydrogen or -CO-O-C １－４ - Represents alkyl. - CO-R ＯＸ１ or -SO ２ -R ＯＸ１ ; (R ＯＸ１ Independently, -- C １－４ - Alkyl; -- C １－３ - Alkyl, with one C １－３ -alkoxy, tetrahydropyranyl, morpholine-4-yl, phenyl, 10-membered heteroaryl or -NR ＯＮＸ１ R ＯＮＸ２ (R ＯＮＸ１ and R ＯＮＸ２ These are independently hydrogen or C １－３ - Represents alkyl.) The C substituted by １－３ - Alkyl; -- Tetrahydropyranil; -- Phenyl or 5- or 6-membered heteroaryl compounds, independently unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－３ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - A phenyl or 5- or 6-membered heteroaryl independently selected from fluoroalkoxy, cyano, or halogen; or, -- Structure (R Ｘ－Ａ ) the basis: 【Chemistry 15】 (wherein (A) represents a 5 or 6-membered non-aromatic ring condensed to a phenyl group, ring (A) comprising two heteroatoms independently selected from oxygen and nitrogen; ring (A) independently being unsubstituted or substituted with one substituent, the substituent being oxo and C) １－３ - Selected independently from alkyl groups. It represents. ); or, - -C-O-R ＯＸ２ ;(R ＯＸ２ は、 -- C １－４ - Alkyl; -- 2,2,2-trichloroethyl; Or, -- Tetrahydropyranil; (This represents...) (This represents...) Represents a complex algebra; The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. fragment 【Chemistry 16】 but: 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 (R Ｘ teeth, - C １－４ - Alkyl; - C ３－４ - Cycloalkyl; - C １－４ - Alkyl, with one C ３－４ - The C substituted with cycloalkyl １－４ - Alkyl; - C １－４ - Alkyl, with one hydroxyl or C １－３ - The C substituted with alkoxy １－４ - Alkyl; - Phenyl; - A six-membered heteroaryl, which is either unsubstituted or substituted with one halogen; 【Chemistry 21】 (R ＳＸ１ Ha-CO-O-C １－４ - Represents alkyl. - CO-R ＯＸ１ or -SO ２ -R ＯＸ１ ; (R ＯＸ１ , independently, -- C １－４ - Alkyl; -- C １－３ - Alkyl, with one C １－３ -alkoxy, tetrahydropyranyl, morpholine-4-yl, phenyl, 10-membered heteroaryl or -NR ＯＮＸ１ R ＯＮＸ２ (R ＯＮＸ１ and R ＯＮＸ２ These are independently hydrogen or C １－３ - Represents alkyl.) The C substituted by １－３ - Alkyl; -- Tetrahydropyranil; -- Phenyl, which is unsubstituted or substituted with one or two substituents, wherein the substituents are independently C １－３ - Alkoxy, C １－３ - Phenyls that are fluoroalkoxy or halogens; -- Five or six-membered heteroaryl compounds, independently unsubstituted or with one C １－３ - A 5 or 6-membered heteroaryl substituted with an alkoxy; or, -- Structure (R Ｘ－Ａ ) is based on: 【Chemistry 22】 (wherein (A) represents a 5 or 6-membered non-aromatic ring condensed to the phenyl group, ring (A) comprising two heteroatoms independently selected from oxygen and nitrogen; ring (A) independently being unsubstituted or substituted with one substituent, the substituent being oxo and C) １－３ - Selected independently from alkyl groups. It represents. ); or, - -C-O-R ＯＸ２ ;(R ＯＸ２ は、 -- C １－４ - Alkyl; -- 2,2,2-trichloroethyl; or, -- Tetrahydropyranil; (This represents...) (This represents...) 【Chemistry 23】 Represents a group selected from; the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

5. R ２ is a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R ３ isobutyl; the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R ４ The base - CO-NH-R ４１ Represents; R ４１ but, - C ２－６ - Alkyl, with one C １－４ - Alkoxy or C １－４ -C substituted with fluoroalkoxy ２－６ - Alkyl; - C １－３ -Alkoxy-C ２－３ -Alkylene-O-CH ２ -CH ２ -; - -CH ２ -CH ２ -C ５－６ - A heterocycloalkyl having one ring oxygen atom, and the C ５－６ - The heterocyclyl is unsubstituted or has one or two C １－４ - The C substituted with alkyl ５－６ - Heterocycloalkyl; - -L １ -Aryl; (L １ is, -CH ２ -CH ２ -ien-CH ２ -CH ２ -O- ＊ or -CH ２ -CF ２ - ＊ ien-CH ２ - (Cyclopropane-1,1-diyl) - ＊ , -CH(CH ２ -OH)-CH ２ - ＊ or -CH ２ -CH(OH)- ＊ It represents; the asterisk is L １ This indicates a bond that connects to the above aryl; aryl represents phenyl; the aryl is independently unsubstituted or substituted with one, two, or three substituents, and the substituents are independently C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ -Fluoroalkoxy, halogen, cyano, hydroxy-C １－３ - Alkyl, C ２－３ -Alkinyl, Morpholine-4-yl, C １－３ -alkyl-SO ２ -, 5 or 6-membered heteroaryl, or -NR Ｎ４１ R Ｎ４２ (Independently, R Ｎ４１ is hydrogen or C １－４ - Alkyl, R Ｎ４２ is hydrogen or C １－４ -It is alkyl.) - -L ２ - HET １ ; (L ２ is, -CH ２ -CH ２ -ien-CH ２ -CF ２ - ＊ ien-CH ２ - (Cyclopropane-1,1-diyl) - ＊ or -CH ２ -CH(OH)- ＊ It represents; the asterisk is L ２ to HET １ This indicates a bond to be attached to; HET １ represents a 5- or 6-membered heteroaryl, which is independently unsubstituted or substituted with one or two substituents, and which substituents are independently C １－４ - Alkyl; C １－４ - Alkoxy; C １－３ -Fluoroalkyl;halogen;C ３－６ -Cycloalkyl; C ３－６ -Cycloalkyl-methyl; C １－３ -Alkoxy-C １－３ - Alkyl; C ２－３ - Alkynyl, benzyl; or phenyl, which is unsubstituted or substituted with one or two substituents, wherein the substituents are independently C １－４ - Alkyl, C １－４ - Alkoxy or C １－４ - Phenylen is a fluoroalkoxy; - -CH ２ -CH ２ - HET ２ (HET ２ HET represents a 9 or 10-membered bicyclic heteroaryl, and the HET ２ (This is unsubstituted.) - -CH ２ -CH ２ -HCy １ (HCy １ This represents a partially aromatic bicyclic ring system consisting of a phenyl ring fused to a 5-7 member saturated heterocycle having one or two heteroatoms independently selected from oxygen and nitrogen, wherein if nitrogen is present and has free valence, the nitrogen is unsubstituted or has one carbon atom. １－４ - Substituted with alkyl; the phenyl ring of the partially aromatic bicyclic ring system is unsubstituted or substituted with one or two substituents, the substituents independently being C １－４ - Alkyl, C １－４ -It is an alkoxy or halogen.); or, - -CH ２ -CH ２ -HCy ２ (HCy ２ This represents a partially aromatic bicyclic ring system consisting of a 5-membered heteroaryl fused to a 5- to 7-membered saturated carbon ring. Represents; the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. Ar ２ is a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. Ar １ but, - Phenylene or a 5- or 6-membered heteroarylene, independently substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－４ - Phenylene or 5- or 6-membered heteroarylene independently selected from alkoxy and halogen; - Phenylene condensed to a 5- or 6-membered saturated heterocycle having one or two oxygen atoms, wherein the 5- or 6-membered saturated heterocycle is independently unsubstituted; or, - A bicyclic aromatic ring selected from naphthylene and 8-10 membered bicyclic heteroarylenes; independently, unsubstituted or substituted with one substituent, wherein the substituent is C １－４ - A bicyclic aromatic ring independently selected from alkyl and halogen; Represents; the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. The compound in question is one of the compounds listed in the table below. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Table 71 Table 72 Table 73 Table 74 Table 75 Table 76 Table 77 Table 78 A compound selected from the compounds described in claim 1, or a pharmaceutically acceptable salt thereof.

11. The compound in question is (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadesino[16,17-f]quinoline-3-carboxamide; 【Chemistry 24】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. A therapeutic agent for CFTR-related diseases and disorders, including cystic fibrosis, comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient: 【Chemistry 25】 (In the formula, X, R １ , R ２ , R ３ , R ４ Ar ２ This is defined as for the compound of formula (I) described in claim 1; Ar １ teeth, - Phenylene, specifically unsubstituted phenylene; - Five or six-membered heteroarylenes, which are unsubstituted; - Phenylene or a 5- or 6-membered heteroarylene; independently substituted with 1, 2, or 3 substituents, wherein the substituents are C １－４ - Alkyl, C １－４ - Alkoxy, C １－３ - Fluoroalkyl, C １－３ - Phenylene or 5- or 6-membered heteroarylene independently selected from fluoroalkoxy, cyano, and halogen; - Phenylene condensed to a 5- or 6-membered saturated heterocycle having one or two oxygen atoms, wherein the 5- or 6-membered saturated heterocycle is independently unsubstituted or substituted with two fluorocarbons; or, - A bicyclic ring selected from naphthylene and 8-10 membered bicyclic heteroarylenes. independently, unsubstituted or substituted with one or two substituents, wherein the substituents are C １－４ - Alkyl, C １－３ - Fluoroalkyl, C １－４ - Alkoxy, C １－３ - The bicyclic ring independently selected from fluoroalkoxy, cyano, and halogen; or, - Quinoline-diyl, wherein the quinoline-diyl exists in the form of each N-oxide; the quinoline-diyl N-oxide is unsubstituted or substituted with one methyl or fluoro molecule; (This represents...)

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

14. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

15. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the treatment of CFTR-related diseases and disorders, including cystic fibrosis.

16. A therapeutic agent for CFTR-related diseases and disorders, including cystic fibrosis, comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

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