Macrocyclic kif18a inhibitors and uses thereof

Abstract

The present invention provides novel compounds having the general formula (I), wherein L1, L2, L3, R 1 , R 2 , R 3 , A1, A2, A3, B1, B2, B3, n1 and n2 are as described herein, or a pharmaceutically acceptable salt thereof; compositions including the compounds; and methods of using the compounds.(I)

Description

Technical Field

[0001] This invention relates to organic compounds that can be used to treat cancers in mammals, and particularly to KIF18A (kinin family member 18A) inhibitors. Specifically, this invention relates to macrocyclic compounds having KIF18A inhibitory activity; their preparation; pharmaceutical compositions containing them; and their potential uses as medicines. Background Technology

[0002] KIF18A is a mitotic kinetic protein with ATPase activity. It is thought to regulate the dynamics of the kinetochore microtubule tip during cell mitosis for proper chromosome positioning (Rath and Kozielsky. Nat. Rev. Cancer. 2012, 12(8)). The motor domain of KIF18A mediates the directional sliding of the tip in an ATP-dependent manner and undergoes a conformational change upon ATP hydrolysis. Furthermore, the accumulation of KIF18A at the microtubule tip requires a C-terminal tail domain. Genetic evidence has demonstrated that KIF18A plays a dual role in chromosome alignment and microtubule depolymerization / stabilization. Depletion of KIF18A leads to spindle abnormalities, chromosome misalignment, and activation of the spindle assembly checkpoint (SAC). KIF18A depolymerizes longer microtubules more rapidly than shorter microtubules. Genetic excision of KIF18A produces long microtubules (Mayr et al., Curr. Biol. 2007, 17(6)).

[0003] Mounting evidence suggests that KIF18A is involved in cancer progression, as its overexpression is generally associated with poor prognosis in various tumor types, such as liver cancer, colorectal cancer, kidney cancer, and pancreatic cancer. Several independent studies have demonstrated that KIF18A is a synthetic lethal partner for various forms of genomic instability, such as whole-genome doubling (WGD), aneuploidy, and chromosomal instability (CIN) (Quinton et al. Nature. 2021, 590(7846); Cohen-Sharir et al. Nature. 2021, 590(7846); Marquis et al. Nat. Commun. 2021, 12(1)). KIF18A depletion selectively induces mitotic arrest, lagging chromosomes, micronucleus formation, cell cycle arrest, and apoptosis in CIN-prone tumor cells, but has negligible effects on diploid cells. Similarly, the pharmacological inhibition phenotype of KIF18A mimics KIF18A loss, thereby causing sustained SAC activation, mitotic prolongation, chromosome misalignment, and apoptosis in WGD+ cancer cells. Summary of the Invention

[0004] The object of this invention is novel compounds of formula (I); their preparation; pharmaceuticals based on the compounds according to the invention; their production; and the use of compounds of formula (I) as KIF18A inhibitors for the treatment of cancer. Compounds of formula (I) exhibit excellent KIF18A inhibitory activity, particularly time-dependent inhibition. Furthermore, compounds of formula (I) also exhibit good safety and a favorable PK profile, for example, good microsomal stability, solubility, hepatic clearance, and safety margin.

[0005] One aspect of the present invention relates to compounds of formula (I), in Each of A1, A2, and A3 is independently selected from N and CR. a , where R a H, halogen or C 1-6 alkyl; R 1 Selected from H, halogen, cyano, OH, NO2, CON(R) b1 (R) b2 ), NR b1 SO2R b2 , 、N(R b1 (R) b2 SO2R b1 SO2(R) b1 (R) b2 OR b1 -N=SO(R) b1 (R) b2 ), -PO(R b1 (R) b2 ) and C, optionally substituted with one, two or three independent substituents selected from halogens and OH. 1-6 alkyl, R b1 and R b2 Each of them is independently selected from H and C. 3-10 Cycloalkyl groups and C groups optionally substituted with one, two, or three independent substituents selected from halogens and OH. 1-6 alkyl; L1 is selected from CONH, NHCO, and , Each of B1, B2, and B3 is independently selected from N and CR. 2 ; R 2 Selected from H, halogens, C1-6 Alkyl and C 1-6 Alkoxy; L2 is selected from , SO2NR d And O, Y is N, Z1 is O or CH2. Z2 is CH. Each of m1 and m2 is independently 0, 1, or 2. R c Appears once or twice and is independently selected from H, halogen, or halogenated C. 1-6 alkyl, R d For H, C 1-6 Alkyl or halogenated C 1-6 alkyl; L3 is an optional location R e Substituted (CH2) q1 (CH2) q2 NH or -(CH2) r -O-(CH2) s -, q is 2, 3, 4, 5, or 6. r is 0, 1, or 2. s is 0, 1, or 2. R e Halogen, C 3-10 cycloalkyl or C 1-6 alkyl; Each of n1 and n2 is independently 0 or 1; R 3 For those that are absent or selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl; Or its pharmaceutically acceptable salt.

[0006] Another aspect of the invention relates to a method for preparing a compound of formula (I), and a compound of formula (I) or a pharmaceutically acceptable salt thereof prepared according to the method.

[0007] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] Another aspect of the invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, which are used as therapeutically active substances.

[0009] Another aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0010] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0011] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the inhibition of KIF18A.

[0012] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

[0013] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting KIF18A.

[0014] Another aspect of the invention relates to a method for treating cancer, the method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0015] definition Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of various terms used to describe this invention.

[0016] Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC system nomenclature.

[0017] The term “one or more compounds of the present invention” refers to compounds of formula (I) and their stereoisomers, solvates and salts (e.g., pharmaceutically acceptable salts).

[0018] The term "substituent" refers to an atom or group that replaces a hydrogen atom on a parent molecule.

[0019] As used in this article, the term "C" 1-6 "Alkyl" refers, alone or in combination, to a saturated, straight-chain or branched alkyl group containing 1 to 6, specifically 2 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. Specifically, "C..." 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, or isopentyl.

[0020] Term "C" 1-6 "Alkoxy" indicates C 1-6Alkyl-O-.

[0021] Term "C" 3-10 "Cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group with 3 to 10 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more common carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclic [1.1.0]butyl, bicyclic [2.2.1]heptyl, bicyclic [1.1.1]pentyl, or bicyclic [2.2.2]octyl.

[0022] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine.

[0023] The term "halogenated C" 1-6 "Alkyl" indicates an alkyl group in which at least one hydrogen atom is replaced by the same or different halogen atoms, specifically fluorine atoms. Halogenated C 1-6 Examples of alkyl groups include monochloro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as difluoromethyl.

[0024] The compounds according to the invention can exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a conventional acid addition salt or base addition salt formed from a suitable, non-toxic organic or inorganic acid or base, retaining the biological efficacy and properties of the compound of formula (I). Acid addition salts include, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid, and salts derived from organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, formic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Base addition salts include salts derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. The chemical modification of pharmaceutical compounds into salts to obtain improved physical and chemical stability, hygroscopicity, flowability, and solubility is a well-known technique among medicinal chemists. This technique is described, for example, in Bastin RJ, et al., Organic Process Research & Development 2000, 4, 427-435. Specifically, the sodium salt of compound (I).

[0025] The term "therapeutic effective amount" refers to the amount of a compound or molecule of the present invention, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. Therapeutic effective amount depends on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0026] The term "pharmaceutical composition" refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient for administration together to a mammal (e.g., a human) in need of such treatment.

[0027] KIF18A inhibitors This invention relates to (i) a compound of formula (I), in Each of A1, A2, and A3 is independently selected from N and CR. a , where R a H, halogen or C 1-6 alkyl; R 1 Selected from H, halogen, cyano, OH, NO2, CON(R) b1 (R) b2 ), NR b1 SO2R b2 , 、N(R b1 (R) b2 SO2R b1 SO2(R) b1 (R) b2 OR b1 -N=SO(R) b1 (R) b2 ), -PO(R b1 (R) b2 ) and C, optionally substituted with one, two or three independent substituents selected from halogens and OH. 1-6 alkyl, R b1 and R b2 Each of them is independently selected from H and C. 3-10 Cycloalkyl groups and C groups optionally substituted with one, two, or three independent substituents selected from halogens and OH. 1-6 alkyl; L1 is selected from CONH, NHCO, and , Each of B1, B2, and B3 is independently selected from N and CR. 2 ; R 2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; L2 is selected from , SO2NR d And O, Y is N, Z1 is O or CH2. Z2 is CH. Each of m1 and m2 is independently 0, 1, or 2. R c Appears once or twice and is independently selected from H, halogen, or halogenated C. 1-6 alkyl, R d For H, C 1-6 Alkyl or halogenated C 1-6 alkyl; L3 is an optional location R e Substituted (CH2) q1 (CH2) q2 NH or -(CH2) r -O-(CH2) s -, q is 2, 3, 4, 5, or 6. r is 0, 1, or 2. s is 0, 1, or 2. R e Halogen, C 3-10 cycloalkyl or C 1-6 alkyl; Each of n1 and n2 is independently 0 or 1; R 3 For those that are absent or selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl; Or its pharmaceutically acceptable salt.

[0028] A further embodiment of the present invention is (ii) the compound according to embodiment (i), wherein... A1 is N or CH; A2 is N or CH; A3 is N or CR a , where Ra It can be H, fluorine, or methyl.

[0029] A further embodiment of the present invention is (iii) the compound according to embodiment (i) or embodiment (ii), wherein... Each of A1 and A2 is CH, and A3 is CR. a , where R a It can be H or methyl.

[0030] A further embodiment of the present invention is (iv) the compound according to any one of embodiments (i) to (iii), wherein... R 1 For NR b1 SO2R b2 or , R b1 For H, R b2 C that is optionally substituted with OH 1-6 alkyl.

[0031] A further embodiment of the present invention is (v) the compound according to any one of Examples (i) to (iv), wherein... R 1 For NR b1 SO2R b2 , R b1 For H, R b2 Selected from methyl, ethyl and hydroxyethyl.

[0032] A further embodiment of the present invention is (vi) the compound according to any one of Examples (i) to (v), wherein... L1 is selected from CONH, NHCO and .

[0033] A further embodiment of the present invention is (vii) the compound according to any one of embodiments (i) to (vi), wherein R 2 Selected from H, fluorine, methyl and methoxy.

[0034] A further embodiment of the present invention is (viii) the compound according to any one of Examples (i) to (v), wherein... B1 is N or CH. B2 is N, B3 is N or CR 2 , R 2 For H or C 1-6 alkyl.

[0035] A further embodiment of the present invention is (ix) the compound according to any one of embodiments (i) to (viii), wherein R 2 It can be H or methyl.

[0036] Another embodiment of the invention is (x) the compound according to any one of (i) to (ix), wherein m1 is 1 or 2. m2 is 0 or 1. R c It appears once or twice, and for each R c Independently selected from H, fluorine, and difluoromethyl. R d It can be H, methyl, or difluoroethyl.

[0037] A further embodiment of the present invention is (xi) the compound according to any one of embodiments (i) to (ix), wherein L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1. Each R c It is independently selected from H and halogens.

[0038] A further embodiment of the present invention is (xii) the compound according to any one of embodiments (i) to (ix), wherein L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1; R c It is H or fluorine.

[0039] A further embodiment of the present invention is (xiii) the compound according to any one of embodiments (i) to (xii), wherein... L3 is an optional location Re Substituted (CH2) q1 (CH2) q2 NH or -(CH2) r -O-(CH2) s -, q1 is 3, 4, 5, or 6. q2 is 2, r is 0 s is 2, R e It is either fluorine or methyl.

[0040] A further embodiment of the present invention is (xiv) the compound according to any one of Examples (i) to (xii), wherein... L3 is (CH2) q1 Or -(CH2) r -O-(CH2) s -, q1 is 3. r is 0 s is 2.

[0041] A further embodiment of the present invention is (xv) the compound according to any one of Examples (i) to (xiv), wherein... Each of n1 and n2 is 1.

[0042] A further embodiment of the present invention is (xvi) the compound according to any one of Examples (i) to (xv), wherein... R 3 It is either absent or selected from fluorine, methyl, ethyl, difluoromethyl and trifluoromethyl.

[0043] A further embodiment of the present invention is (xvii) the compound according to embodiment (i), wherein... Each of A1 and A2 is CH. A3 is CR a , where R a For H or C 1-6 alkyl; R 1 For NR b1 SO2R b2 , R b1 For H, R b2 Hydroxyl C 1-6 alkyl; L1 is NHCO. B1 is N or CH; B2 is N; B3 is N or CR 2 ; R 2 For H or C 1-6 alkyl; L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1. Each R c Independently selected from H and halogens; L3 is (CH2) q1 Or -(CH2) r -O-(CH2) s -, q1 is 3. r is 0 s is 2; Each of n1 and n2 is 1; R 3 For those that are absent or selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl.

[0044] A further embodiment of the present invention is (xviii) the compound according to embodiment (xvii), wherein... Each of A1 and A2 is CH. A3 is CR a , where R a It is H or methyl; R 1 For NR b1 SO2R b2 , R b1 For H, R b2 It is hydroxyethyl; L1 is NHCO. B1 is N or CH; B2 is N; B3 is N or CR 2 ; R 2 It is H or methyl; L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1. R c It is H or fluorine; L3 is (CH2) q1 Or -(CH2) r -O-(CH2) s -, q1 is 3. r is 0 s is 2; Each of n1 and n2 is 1; R 3 It is either absent or selected from fluorine, methyl, ethyl and difluoromethyl.

[0045] Further embodiments of the present invention are (xix) compounds selected from the following: 2-Hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .12,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(8-oxo-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(8-oxo-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9(14),10,12-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide, N-(8-oxo-1,7,13,15,29-pentaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(22-fluoro-8-oxo-1,7,11,15,29-pentaazapentane[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9(14),10,12-hexene-12-yl)ethanesulfonamide,] N-(20-fluoro-8-oxo-1,7,13,15,29-pentaazapentane[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy-N-(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .12,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] N-(24-fluoro-1,8,9,10,17,32-hexaazahexacyclo[22.2.2.2]) 17,20 .1 2,6 .1 7,10 .0 11,16 [32-C2(32),3,5,7(31),8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide,] N-(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15, 18 .1 2,6 .0 9,14 [29-hexane-12-yl]ethanesulfonamide, N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexaden-8-one, N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14[29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-hexane-12-yl]-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15, 19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10, 14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10, 14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N-[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6.0 9,14 [29-hexane-12-yl]-2-hydroxy-ethanesulfonamide, N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28-tetraazapentacyclo[20.2.2.1]) 10,14 .1 15, 18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(18S)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28-tetraazapentacyclo[20.2.2.1] 10,14 .1 15,18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(18R)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28-tetraazapentacyclo[20.2.2.1] 10,14 .1 15,18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexane-4-yl]ethanesulfonamide, N-(18,18-difluoro-8-oxo-1,9,13,15,29-pentaazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15 ,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-(18,18,23-trifluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15 ,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexene-4-yl)ethanesulfonamide,] 2-Hydroxy-N-[(19S)-18,18,23-trifluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10 ,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-18,18,23-trifluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10 ,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10, 14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexene-4-yl]-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N-(18,18-difluoro-8-oxo-1,5,9,15,29-pentaazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,5,9,15,29-pentazapentacyclo[21.2.2.1] 10 ,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl]-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15, 19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N-(18,18-difluoro-8-oxo-1,9,13,15-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .02,7 [29-carbon-2,4,6,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-8-oxo-1,3,9,15,29-pentaazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15 ,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexene-4-yl)ethanesulfonamide,] N-(18,18-difluoro-8-oxo-1,9,15,29-tetraazahexacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 .0 17,19 [29-carbon-2,4,6,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-(8-oxo-18-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexene-4-yl)ethanesulfonamide,] N-(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15 ,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)methanesulfonamide,] N-(17,17-difluoro-8-oxo-1,9,15,28-tetraazapentacyclo[20.2.2.1]) 10,14 .1 15,18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N-(18,22-difluoro-8-oxo-1,3,7,15,29-pentaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] N-(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2, 6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy-N-(7-oxo-1,8,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N-(8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N-(8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)methanesulfonamide, N-(8,15,15-trioxo-15λ) 6-Thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptadec-2(7),3,5,10(27),11,13-hexaden-4-yl)ethanesulfonamide, N-(17-methyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N-(21-methyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N-[16-(2,2-difluoroethyl)-8,15,15-trioxo-15λ] 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl]ethanesulfonamide, N-(16-methyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N-(16,21-dimethyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-(8-oxo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1]) 10,14 .0 2,7 [27-hexadecimal-2(7),3,5,10,12,14(27)-hexene-4-yl)ethanesulfonamide, N-(18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N-(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N-(23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N-(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy-N-[(19S)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy-N-[(19R)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, Or its pharmaceutically acceptable salt.

[0046] A further embodiment of the present invention is (xx) a method for preparing compounds having structures of formula (Ia), (Ib), (Ic), or (Id). (Ia) (Ib) (Ic) (Id) The method includes one of the following steps: (a) To make compound III (III) With NH2SO2R b2 A substitution reaction is carried out in a solvent in the presence of a base to provide a compound of formula (Ia). Where Q is fluorine, the base is preferably TEA, DIPEA, K2CO3 or Cs2CO3, and the solvent is preferably DMF, DMSO, dioxane or CH3CN; (b) To make compounds of formula IIb (IIb) A reduction reaction is carried out in a solvent in the presence of a reducing agent to provide a compound of formula (Ib). The reducing agent is preferably LiAlH4 or LiBH4, and the solvent is preferably DCM or THF; (c) To make compounds of formula IIc (IIc) With NH2SO2R b2 A compound of formula (Ic) is provided by reacting an inorganic base in an organic solvent in the presence of CuI and MNPMO. The organic solvent is preferably DMF or DMSO, and the inorganic base is preferably potassium tripolyphosphate; (d) Make IId compounds (IId) With NH2SO2R b2 The reaction is carried out in an organic solvent using an inorganic base in the presence of CuI and MNPMO. The organic solvent is preferably DMF or DMSO, and the inorganic base is preferably potassium tripolyphosphate; Among them, L3, R 2 R 3 R b2 R c R dA1, A2, A3, B1, B2, B3, Y, Z1, Z2, n1, n2, m1, m2 are as defined in any of embodiments (i) to (xix).

[0047] A further embodiment of the present invention is (xxi) a compound or pharmaceutically acceptable salt according to any one of Examples (i) to (xix), which is prepared according to the method described in Example (xx).

[0048] Pharmaceutical composition and administration Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents, or excipients, and methods for preparing such compositions and medicaments using the compounds of the present invention. In one example, the compound of formula (I) can be formulated into a galenical form by mixing it with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used) at ambient temperature, at an appropriate pH, and with the desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0049] The composition is formulated, administered, and applied in accordance with good medical practice. Factors considered in this context include the specific condition being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the condition, the site of delivery, the method of administration, the timing of administration, and other factors known to the medical practitioner. The "effective amount" of the compound to be administered will be influenced by these considerations and is the minimum amount necessary to inhibit KIF18A. For example, this amount may be below what would be toxic to normal cells or the mammal as a whole.

[0050] In one example, the effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg / kg of patient body weight per day, alternatively in the range of about 0.1 to 20 mg / kg of patient body weight per day, with the initial range of the compound typically being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 100 (e.g., 25 to 100) mg of the compound of the invention.

[0051] The compounds of this invention can be administered by any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, as well as (if necessary for local treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0052] The compounds of the present invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

[0053] Typical formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, by Ansel, Howard C. et al. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems .Philadelphia:Lippincott, Williams&Wilkins, 2004;Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy .Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, humectants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, flavorings, diluents, and other known additives to provide an aesthetically pleasing presentation of the medicine (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (i.e., a drug).

[0054] Examples of suitable oral dosage forms are tablets containing about 1 to 1000 mg (e.g., 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg) of the compound of the present invention, which is compounded with about 1 to 1000 (e.g., 90 to 30) mg of anhydrous lactose, about 1 to 1000 (e.g., 5 to 40) mg of croscarmellose sodium, about 1 to 1000 (e.g., 5 to 30) mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 (e.g., 1 to 10) mg of magnesium stearate. The powdered ingredients are first mixed together, and then mixed with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving the compounds of the present invention (e.g., 1 to 1000 (e.g., 5 to 400 mg)) in a suitable buffer solution (e.g., phosphate buffer), with the addition of a permeabilizing agent (e.g., a salt such as sodium chloride) if desired. The solution can be filtered, for example, using a 0.2-micron filter to remove impurities and contaminants.

[0055] Therefore, one embodiment includes a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition comprises a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0056] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer.

[0057] The following examples illustrate typical compositions of the present invention, but are only representative of them.

[0058] Composition A The compounds of the present invention can be used as active ingredients in a manner known per se to produce tablets having the following composition: Composition B The compounds of the present invention can be used as active ingredients in a manner known per se to produce capsules having the following composition: Indications and treatment methods The compounds of this invention capture KIF18A in a microtubule-bound state, thereby inhibiting KIF18A ATPase activity. Therefore, the compounds of this invention can be used to induce mitotic arrest, micronucleus formation, and apoptosis in specific cancer cells. The compounds of this invention can be used to trigger synthetic lethal susceptibility in cancer cells with high levels of chromosomal instability, such as high-grade serous ovarian cancer, triple-negative breast cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer, and endometrial cancer.

[0059] Another embodiment includes a method of treating cancer in a mammal requiring such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), its stereoisomers, tautomers, prodrugs, or pharmaceutically acceptable salts. Cancers include, but are not limited to, ovarian cancer (e.g., high-grade serous ovarian cancer), breast cancer (e.g., triple-negative breast cancer), lung cancer (e.g., non-small cell lung cancer), gastric cancer, esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer, and endometrial cancer.

[0060] A further embodiment of the present invention is (xxiii) a compound of the present invention used as a therapeutically active substance.

[0061] Further embodiments of the present invention are (xxiv) the compounds of the present invention for use in the treatment or in cancer.

[0062] A further embodiment of the present invention is (xxv) the use of the compounds of the present invention for the treatment of cancer.

[0063] A further embodiment of the present invention is (xxvi) the use of the compounds of the present invention for inhibiting KIF18A.

[0064] Further embodiments of the present invention are (xxvii) the use of the compounds of the present invention in the preparation of a medicament for treating cancer.

[0065] Further embodiments of the present invention are (xxviii) the use of the compounds of the present invention in the preparation of a medicament for inhibiting KIF18A.

[0066] A further embodiment of the present invention is (xxix) a method for treating cancer, the method comprising administering an effective amount of the compound of the present invention.

[0067] Further embodiments of the present invention are (xxx) the use according to any one of embodiments (xxv) to (xxviii) or the method according to embodiment (xxix), wherein the cancer is ovarian cancer (e.g., high-grade serous ovarian cancer), breast cancer (e.g., triple-negative breast cancer), lung cancer (e.g., non-small cell lung cancer), gastric cancer, esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer, or endometrial cancer.

[0068] synthesis The compounds of this invention can be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise stated, all substituents, especially L1, L2, L3, R... 1 R 2 R 3 R a R b1 R b2 R c R d R e A1, A2, A3, B1, B2, B3, Y, Z1, Z2, n1, n2, m1, m2, q1, q2, r, and s are as defined above. Furthermore, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings well-known to those skilled in the art of organic chemistry.

[0069] The general synthetic route for preparing compound (I) is shown below.

[0070] Option 1 Where Q is F or NO2, PG is a protecting group (such as Boc or Cbz), and X is Cl or Br.

[0071] Compound of formula (Ia) Ia It can be prepared according to the synthetic route outlined in Scheme 1: a) Compound of Formula VI VI Compound X X Compounds of Formula IX IX It is prepared by substitution reaction in solvents such as DMF, DMSO, dioxane, or CH3CN in the presence of a base (such as TEA, DIPEA, or K2CO3); b) Compound V V Compound VI can be used VI With compound of formula VIIIa VIIIa It is prepared by amidation reaction in solvents (such as DMF, CH3CN, THF, DCM, or pyridine) in the presence of NMI / TCFH, EDCI / pyridine, or HATU / DIPEA. Alternatively, compounds of formula V can also be derived from compounds of formula VII. VII With compound of formula VIIIb VIIIb It is obtained by cross-coupling in solvents (such as DMF, CH3CN, THF, DCM, pyridine, or 1,4-dioxane) in the presence of a Pd catalyst (such as Pd2dba3 / xantphos) and a base (such as TEA, DIPEA, or Cs2CO3). Compounds of formula VII can be obtained by amidation of compounds of formula VI in solvents (such as DMF, CH3CN, THF, DCM or pyridine) in the presence of ammonium chloride in NMI / TCFH, EDCI / pyridine or HATU / DIPEA. c) Compounds of Formula IV IV Compound V can be prepared by deprotecting it in the presence of a strong acid (such as HCl or TFA) in a solvent such as DCM or dioxane, or by using TFA via a pure reaction without any solvent. d) Compounds of Formula III III It can be prepared by intramolecular coupling reaction of compound of formula IV with Pd-PEPPSi-IPent in the presence of a base (such as K2CO3, Cs2CO3 or t-BuONa) in a solvent (such as 1,4-dioxane, t-BuOH or toluene). e) Compound Ia can be reacted with NH2SO2R via formula IIIa (Q = F). b2 It is prepared by substitution reaction in a solvent (such as DMF, DMSO, dioxane, or CH3CN) in the presence of a base (such as TEA, DIPEA, K2CO3, or Cs2CO3).

[0072] Compounds of formula (Ib, Ic) Ib It can be prepared according to the synthetic route outlined in Scheme 1: f) Compound of formula IIa IIa It can be obtained by the reduction reaction of compound of formula III (Q = NO2) in solvents (such as DMF, MeOH, DCM or THF) in the presence of Pd / C-H2 or B2(OH)4 / 4,4'-bipyridine; g) To make IIb compounds IIb It can be prepared by coupling compound of formula IIa with ClSO2CH2COOEt in the presence of an organic base (such as TEA, DIEPA or DMAP) in a solvent such as (THF, EtOAc, DMF or DCM); h) Compounds of formula Ib can be prepared by reducing compounds of formula IIb in a solvent (such as DCM or THF) in the presence of a reducing agent (such as LiAlH4 or LiBH4).

[0073] Option 2 Where PG is H or a protecting group (such as Boc or Cbz), and X is Cl or Br.

[0074] Va compounds Va It is possible to use compounds of formula X and compounds of formula XIa. XIa It is prepared by substitution reaction in a solvent (such as DMF, DMSO, dioxane, or CH3CN) in the presence of a base (such as TEA, DIPEA, or K2CO3).

[0075] Option 3 Compound IIIc IIIc It can be prepared according to the synthetic route outlined in Scheme 3: a1) Compound XIVb XIVb Compounds of formula XIb XIb Compounds of formula XVa, XVa It is prepared by substitution reaction in solvents such as DMF, DMSO, dioxane or CH3CN in the presence of a base (such as TEA or DIPEA); b1) Compound XIII XIII Compounds of formula XIVb and XVb can be used together. XVb It is prepared by cross-coupling reaction in a solvent (such as 1,4-dioxane or t-BuOH) in the presence of a Pd catalyst (such as Pd2dba3 / xantphos or Pd-PEPPSi-Ipent) and an inorganic base (such as Cs2CO3 or K2CO3). a2) Alternatively, compounds of formula XIVa XIVa It can be prepared by crosslinking compound of formula XIb with compound of formula XVb in a solvent (such as 1,4-dioxane or t-BuOH) in the presence of a Pd catalyst (such as Pd2dba3 / xantphos or Pd-PEPPSi-Ipent) and an inorganic base (such as Cs2CO3 or K2CO3). b2) Compound XIII can be prepared by substitution reaction of compound XIVa with compound XVa in a solvent (such as DMF, DMSO, dioxane or CH3CN) in the presence of a base (such as TEA or DIPEA); c) Compound XII XII It can be prepared by a ring-closure metathesis reaction in a solvent (such as DCM, DCE or toluene) in the presence of a second-generation Grubbs catalyst or a Hoveyda-grubbs catalyst. d) Compound IIIc IIIc It can be prepared by hydrogenation of the compound of formula XII in a solvent such as (THF, MeOH or DCM) in the presence of Pd / C.

[0076] Option 4 Formula Ic compound Ic It can be prepared according to the synthetic route outlined in Scheme 4: a) Formula Vc compound Vc Compounds of formula XIc XIc Compounds of formula XVc, XVc It is prepared by a substitution reaction under microwave irradiation in a solvent (such as DMF, DMSO, dioxane, or CH3CN) in the presence of a base (such as TEA or DIPEA). b) Compounds of formula IIc IIc It can be prepared by the intramolecular Mitsunobu reaction of the Vc compound in the presence of CMBP in a solvent (such as THF, toluene, or a mixture of THF and toluene); c) Compound Ic can react with amine NH2SO2R via compound IIc. b2It is prepared by reacting an inorganic base (such as potassium tripolyphosphate) in an organic solvent (such as DMF, DMSO) in the presence of CuI and MNPMO.

[0077] Formula Id compound Id It can be prepared according to the synthetic route outlined in Scheme 4: d) Compounds of formula IId IId Compounds of formula IIc can react with SO2R b2 OH is prepared by the Mitsunobu reaction in a solvent (such as THF, toluene, or a mixture of THF and toluene) in the presence of CMBP; e) Compounds of formula Id can react with NH2SO2R via compounds of formula IId. b2 It is prepared by reacting an inorganic base (such as potassium tripolyphosphate) in an organic solvent (such as DMF or DMSO) in the presence of CuI and MNPMO.

[0078] Examples The invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the invention.

[0079] abbreviation The invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the invention.

[0080] The abbreviations used in this article are as follows: General experimental conditions Purify intermediates and final compounds using rapid chromatography with one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module; ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS Registry Number: Silica Gel: 63231-67-4, particle size: 47-60 µm silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0081] Intermediates and final compounds were obtained by preparative HPLC using XBridge on a reversed-phase column. TM Preparative-C18 (5 µm, OBD™ 30 × 100 mm) column, SunFire TM Preparative-C18 (5 µm, OBD) TM 30 × 100 mm) column, Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 µm, 25 × 150 mm); Waters AutoP purification system (sample manager 2767, pump 2525, detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water); or Gilson-281 purification system (pump 322, detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA). A solution in water; or acetonitrile and water).

[0082] For chiral separation of SFC, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm), or AD (10 µm, 30 × 250 mm), using a Mettler Toledo Multigram III system SFC, a Waters 80Q preparative SFC, or a Thar 80 preparative SFC. The solvent system was CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3∙H2O in MeOH). The back pressure was 100 bar, and the detection UV was 254 nm or 220 nm.

[0083] Using LC / MS (Waters) TMThe LC / MS spectra of the compounds were obtained using an Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 minutes): Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile; Acidic conditions II: A: 0.0375% TFA solution in H2O; B: 0.01875% TFA solution in acetonitrile; Alkaline conditions I: A: 0.1% NH3·H2O solution in H2O; B: Acetonitrile; Alkaline conditions II: A: 0.025% NH3·H2O solution in H2O; B: Acetonitrile; Neutral conditions: A: H2O; B: Acetonitrile.

[0084] Mass spectrometry (MS): Typically only ions representing the parent mass are reported, and unless otherwise specified, the mass ions cited are positive mass ions (MH). + .

[0085] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0086] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Unless otherwise specified, reagents were purchased as is from commercial suppliers without further purification.

[0087] Preparation Examples Intermediate-1: 4-fluoro-4-[3-(4-piperidinyl)propyl]piperidine-1-carboxylic acid tert-butyl ester Int-1 Step (a): Preparation of benzyl 4-(3-hydroxypropyl)piperidine-1-carboxylate Int-1a N-(benzyloxycarbonyloxy)succinimide (26.1 g, 104.73 mmol) was added to a solution of 3-(4-piperidinyl)propane-1-ol in methanol (150 mL) at 20 °C. After stirring at 20 °C for 12 hours, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (5% to 30% EA in PE) to give benzyl 4-(3-hydroxypropyl)piperidin-1-carboxylate (Int-1a, 26.0 g, 93.74 mmol). MS determination (ESI) + )[(M+H) + ]:278.1.

[0088] Step (b): Preparation of benzyl 4-(3-iodopropyl)piperidine-1-carboxylate Int-1b Iodine (27.78 g, 109.44 mmol) was added to a mixture of imidazole (8.06 g, 118.33 mmol) and triphenylphosphine (27.78 g, 105.91 mmol) in DCM (200 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. Then, a solution of 4-(3-hydroxypropyl)piperidin-1-carboxylic acid benzyl ester (Int-1a, 25.0 g, 90.14 mmol) in DCM (60 mL) was added at 0 °C. After stirring at 20 °C for 12 hours, the reaction mixture was diluted with DCM (200 mL) and washed with Na₂SO₃ (500 mL) and brine (200 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was then purified by silica gel column chromatography (10% to 20% EA in PE) to give benzyl 4-(3-iodopropyl)piperidine-1-carboxylate (Int-1b, 30.0 g, 77.47 mmol). MS determination (ESI) + )[(M+H) + ]: 388.0.

[0089] Step (c): Preparation of 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]piperidine-1,4-dicarboxylic acid O1-tert-butyl O4-methyl ester Int-1c LDA (8.39 mL, 16.78 mmol) was added dropwise to a solution of N-BOC-piperidine-4-carboxylate (3.77 g, 15.49 mmol) in THF (50 mL) at -60 °C. The mixture was stirred at -60 °C for 1 hour. Then, benzyl 4-(3-iodopropyl)piperidine-1-carboxylate (Int-1b, 5.0 g, 12.91 mmol) in THF (5 mL) was added dropwise to the mixture at -60 °C. After stirring at 20 °C for 12 hours, the mixture was poured into H2O (100 mL) and extracted three times with EA (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (0% to 15% EA in PE) to give 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]piperidine-1,4-dicarboxylic acid O1-tert-butyl ester O4-methyl ester (Int-1c, 5.6 g, 11.14 mmol). MS determination (ESI) + )[(M+Na) + ]: 525.3.

[0090] Step (d): Preparation of 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-1-tert-butoxycarbonyl-piperidin-4-carboxylic acid Int-1d A mixture of 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]piperidin-1,4-dicarboxylic acid O1-tert-butyl O4-methyl ester (Int-1c, 5.60 g, 11.14 mmol), NaOH (4.45 g, 111.41 mmol), and methanol (50 mL) was stirred at 70 °C for 6 hours. The mixture was concentrated under vacuum. The residue was acidified to pH = 6 with 1.0 N HCl and extracted three times with DCM (50 mL). The organic layer was concentrated under vacuum. The residue was purified by reverse-phase rapid (0.1% FA) to give 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-1-tert-butoxycarbonyl-piperidin-4-carboxylic acid (Int-1d, 3.0 g, 6.14 mmol). MS measured value (ESI) + )[(M+Na) + ]: 511.3.

[0091] Step (e): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid Int-1e A mixture of 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-1-tert-butoxycarbonyl-piperidin-4-carboxylic acid (Int-1d, 3.00 g, 6.14 mmol), AgNO3 (1.59 g, 9.36 mmol), and Selectfluor (4.35 g, 12.28 mmol) (CAS: 140681-55-6, PharmaBlock) in acetone (40 mL) and water (40 mL) was degassed three times under N2. The mixture was stirred at 20 °C under N2 for 12 hours. The mixture was diluted with H2O (100 mL) and extracted three times with EA (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10% to 30% EA in PE) to give tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylate (Int-1e, 2.40 g, 5.19 mmol) as a yellow oil. MS values ​​(ESI) + )[(M+Na) + ]: 485.3.

[0092] Step (f): Preparation of tert-butyl 4-fluoro-4-[3-(4-piperidinyl)propyl]piperidine-1-carboxylate Int-1 A solution of 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-1e, 2.40 g, 5.19 mmol) in EtOAc (100 mL) was degassed three times under N2, and then Pd / C (600.0 mg, 10%, loaded on activated carbon) was added to the mixture under N2. The mixture was degassed and purged three times with H2, and stirred at 20 °C under an H2 balloon (15 psi) for 12 h. The mixture was filtered through diatomaceous earth and washed with MeOH (30 mL). The filtrate was concentrated under vacuum to give 4-fluoro-4-[3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-1, 1.40 g, 4.26 mmol). MS values ​​(ESI)+ [(M+H) + ].): 329.2 Intermediate 2: 4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]piperidine-1-carboxylic acid tert-butyl ester Int-2 Step (a): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-formyl-piperidin-1-carboxylic acid Int-2a At 0 °C, t-BuOK (28.13 mL, 28.13 mmol, 1.0 M, in THF) and 4-(3-iodopropyl)piperidin-1-carboxylic acid benzyl ester (Int-1b, 7.26 g, 18.75 mmol) in DMF (10 mL) were added dropwise to a solution of 1-BOC-4-piperidinecarboxaldehyde (4.00 g, 18.75 mmol) in DMF (50 mL). After stirring at 25 °C for 12 hours, the mixture was quenched with H2O (100 mL) and extracted with EA (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (5% to 30% EA in PE) to give tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-formyl-piperidin-1-carboxylic acid (Int-2a, 2.40 g, 5.08 mmol). MS determination (ESI) + )[(M+Na) + ]: 495.3.

[0093] Step (b): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-(difluoromethyl)piperidine-1-carboxylic acid Int-2b BAST (3.37 g, 15.23 mmol) (CAS: 202289-38-1, Shanghai Haohong Pharmaceutical Co., Ltd) was added to a solution of 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-formyl-piperidin-1-carboxylic acid tert-butyl ester (Int-2a, 2.40 g, 5.08 mmol) in DCM (50 mL) at 20 °C. After stirring at 45 °C for 4 hours, the mixture was poured into saturated NaHCO3 (100 mL) and extracted three times with EA (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (5% to 20% EA in PE) and concentrated under vacuum to give tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-(difluoromethyl)piperidin-1-carboxylate (Int-2b, 1.50 g, 3.03 mmol). MS determination (ESI) + )[(M-Boc+H) + ]: 395.3.

[0094] Step (c): Preparation of tert-butyl 4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]piperidine-1-carboxylate Int-2 Similar to intermediate 1 in step (f), 4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-1e) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-(difluoromethyl)piperidin-1-carboxylic acid tert-butyl ester (Int-2b). 4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-2, 570.0 mg, 1.58 mmol) was obtained. MS values ​​(ESI) + ) [(M+H) + ]: 361.2.

[0095] Intermediate 3: 4-Methyl-4-[3-(4-piperidinyl)propyl]piperidine-1-carboxylic acid tert-butyl ester Int-3 Step (a): Preparation of tert-butyl 4-formyl-4-methyl-piperidine-1-carboxylate Int-3a t-BuOK (52.61 g, 468.89 mmol) and iodomethane (29.32 mL, 468.89 mmol) were added to a solution of 1-BOC-4-piperidinecarboxaldehyde (50.0 g, 234.44 mmol) in DMF (500 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with H2O (400 mL) and extracted three times with EA (400 m). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (5% to 10% EA in PE) to give tert-butyl 4-formyl-4-methyl-piperidine-1-carboxylate (Int-3a, 30.0 g, 131.98 mmol). MS results (ESI) + ) [(M-C4H8+H) + ]: 128.2.

[0096] Step (b): Preparation of tert-butyl 4-[(Z)-2-methoxyvinyl]-4-methyl-piperidine-1-carboxylate Int-3b Under an N2 balloon, t-BuOK solution (70.39 mL, 70.39 mmol) was added dropwise to a solution of (methoxymethyl)triphenylphosphine chloride (20.51 g, 59.83 mmol) in THF (60 mL), and the reaction mixture was stirred at 25 °C for 30 min. Subsequently, a solution of tert-butyl 4-formyl-4-methylpiperidin-1-carboxylate (Int-3a, 8.0 g, 35.2 mmol) in THF (20 mL) was added. The reaction mixture was stirred at 25 °C for 12 h. It was diluted with H2O (100 mL) and extracted three times with EA (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10% to 30% EA in PE) to give tert-butyl 4-[(Z)-2-methoxyvinyl]-4-methyl-piperidine-1-carboxylate (Int-3b, 6.2 g, 24.28 mmol). MS determination (ESI) + ) [(M-Boc+H) + ]: 156.2.

[0097] Step (c): Preparation of tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate Int-3c A solution of TsOH (13.76 g, 79.89 mmol) in water (25 mL) was added to a solution of 4-[(Z)-2-methoxyvinyl]-4-methylpiperidin-1-carboxylic acid tert-butyl ester (Int-3b, 6.8 g, 26.63 mmol) in acetone (50 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H₂O (50 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give 4-methyl-4-(2-oxoethyl)piperidin-1-carboxylic acid tert-butyl ester (Int-3c, 6.0 g, 24.86 mmol), which was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ = 9.87 (t,J= 3.2 Hz, 1H), 3.57 - 3.51 (m, 2H), 3.33 - 3.27 (m,2H), 2.36 (d,J= 2.8 Hz, 2H), 1.58 - 1.51 (m, 3H), 1.49 - 1.46 (m, 10H), 1.16 (s, 3H).

[0098] Step (d): Preparation of tert-butyl 4-methyl-4-prop-2-ynyl-piperidine-1-carboxylate Int-3d A mixture of dimethyl (1-diazo-2-oxopropyl)phosphonate (5.73 g, 29.83 mmol), K₂CO₃ (10.31 g, 74.59 mmol), and tert-butyl 4-methyl-4-(2-oxoethyl)piperidin-1-carboxylate (Int-3c, 6.0 g, 24.86 mmol) in methanol (50 mL) was stirred at 25 °C under N₂ for 12 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (5% to 10% EA in PE) to give tert-butyl 4-methyl-4-prop-2-ynyl-piperidin-1-carboxylate (Int-3d, 4.0 g, 16.85 mmol). MS results (ESI)+ ) [(M-C4H8+H) + ]:182.3 Step (e): Preparation of tert-butyl 4-methyl-4-[3-(4-pyridyl)prop-2-ynyl]piperidine-1-carboxylate Int-3e 4-Methyl-4-prop-2-ynyl-piperidin-1-carboxylic acid tert-butyl ester (Int-3d, 2.93 g, 12.34 mmol) was added to a mixture of 4-iodopyridine (2.3 g, 11.22 mmol), CuI (213.78 mg, 1.12 mmol), Pd(PPh3)2Cl2 (787.5 mg, 1.12 mmol) (CAS: 13965-03-2, Wuhan LPBchemTechnology Co., Ltd), and TEA (15.65 mL, 112.2 mmol) in DMF (10 mL) at 20 °C under N2. The mixture was degassed three times under N2. The suspension was stirred at 80 °C for 2 hours under N2. The reaction mixture was filtered through a diatomaceous earth mat. It was diluted with H2O (40 mL) and extracted three times with EA (40 mL). The combined organic layers were concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (5% to 10% EA in PE) to give tert-butyl 4-methyl-4-[3-(4-pyridyl)prop-2-ynyl]piperidine-1-carboxylate (Int-3e, 3.1 g, 9.86 mmol). MS determination (ESI) + ) [(M+H) + ]: 315.2.

[0099] Step (f): Preparation of tert-butyl 4-methyl-4-[3-(4-piperidinyl)propyl]piperidine-1-carboxylate Int-3 A solution of tert-butyl 4-methyl-4-[3-(4-pyridyl)prop-2-ynyl]piperidine-1-carboxylate (Int-3e, 3.1 g, 9.86 mmol) and HOAc (710.45 mg, 11.83 mmol) in IPA (20 mL) and THF (20 mL) was stirred at 20 °C until a clear solution was obtained. The H2 back pressure regulator was adjusted to 2.5 MPa, the H2 flow rate was adjusted to 30 mL / min, and the fixed bed (5% Ru / Al2O3, 5 mL, 2.5 g) was heated to 100 °C. The solution was then pumped into the reactor at a flow rate of 0.3 mL / min. After the reaction was complete, the tube was washed with 100 mL of MeOH, and all the reaction solution was collected and concentrated under vacuum to give tert-butyl 4-methyl-4-[3-(4-piperidinyl)propyl]piperidine-1-carboxylate (Int-3, 3.1 g, 9.55 mmol). MS measured (ESI) + ) [(M+H) + ]: 325.2.

[0100] Intermediate 4: 4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid benzyl ester Int-4 Step (a): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-formyl-piperidin-1-carboxylic acid Int-4a At 0 °C, t-BuOK (28.13 mL, 28.13 mmol, 1.0 M, in THF) and 4-(3-iodopropyl)piperidin-1-carboxylic acid benzyl ester (Int-1b, 7.26 g, 18.75 mmol) in DMF (10 mL) were added dropwise to a solution of 1-BOC-4-piperidinecarboxaldehyde (4.00 g, 18.75 mmol) in DMF (50 mL). After stirring at 25 °C for 12 hours, the mixture was quenched with H2O (100 mL) and extracted with EA (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-formyl-piperidin-1-methyl tert-butyl ester (Int-4a, 2.40 g). MS determination (ESI) +) [M+Na + ]: 495.3.

[0101] Step (b): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-(difluoromethyl)piperidine-1-carboxylic acid Int-4b BAST (3.37 g, 15.23 mmol) was added to a solution of 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-formyl-piperidin-1-carboxylic acid tert-butyl ester (Int-4a, 2.40 g, 5.08 mmol) in DCM (50 mL) at 20 °C. After stirring at 45 °C for 4 hours, the mixture was poured into saturated NaHCO3 (100 mL) and extracted three times with EA (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-(difluoromethyl)piperidin-1-carboxylic acid tert-butyl ester (Int-4b, 1.50 g). MS values ​​(ESI) + )[(M-Boc+H) + ]: 395.3.

[0102] Step (c): Preparation of benzyl 4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]piperidine-1-carboxylate Int-4 A solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-(difluoromethyl)piperidin-1-carboxylate (Int-4b, 900.0 mg, 1.82 mmol) in TFA (2.0 mL) and DCM (10 mL) was stirred at 20 °C for 2 hours. The mixture was poured into saturated NaHCO3 (100 mL) and extracted three times with EA (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to give benzyl 4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]piperidin-1-carboxylate (Int-4, 700.0 mg). MS values ​​(ESI) + )[(M+H) + ]: 395.2.

[0103] Intermediate 5: 4-[2-[[4-(trifluoromethyl)-4-piperidinyl]amino]ethyl]piperidin-1-carboxylic acid tert-butyl ester Int-5 Step (a): 4-(trifluoromethyl)piperidin-4-amine Int-5a TFA (8.0 mL, 11.89 mmol) was added to a solution of tert-butyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate (3.19 g, 11.89 mmol) in DCM (40 mL). The mixture was stirred at 20 °C for 2 hours. The resulting mixture was concentrated under vacuum to give 4-(trifluoromethyl)piperidine-4-amine (Int-5a, 3.36.0 g, 11.89 mmol), which was used directly in the next step without further purification.

[0104] Step (b): Benzyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate Int-5b A solution of K₂CO₃ (6572.32 mg, 47.56 mmol) in water (20 mL) was added to a solution of 4-(trifluoromethyl)piperidin-4-amine (Int-5a, 3.355 g, 11.89 mmol) in THF (20 mL), followed by the addition of N-(benzyloxycarbonyloxy)succinimide (2963.01 mg, 11.89 mmol). After stirring at 25 °C for 12 hours, the mixture was diluted with EA (200 mL), washed with saturated K₂CO₃ (200 mL) and brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (20% EA in PE). Benzyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate (Int-5b, 3.32 g, 10.98 mmol) was obtained. MS determination (ESI) + ) [(M+H) + ]: 303.3 Step (c): 4-[[2-(1-tert-butoxycarbonyl-4-piperidinyl)acetyl]amino]-4-(trifluoromethyl)piperidin-1-carboxylic acid benzyl ester Int-5c Phosphorus oxychloride (2.05 mL, 21.96 mmol) was added dropwise to a solution of 4-amino-4-(trifluoromethyl)piperidine-1-carboxylic acid benzyl ester (Int-5b, 3.32 g, 10.98 mmol) and 1-BOC-4-piperidinylacetic acid (2.94 g, 12.08 mmol) in pyridine (30 mL) at 0 °C. The mixture was heated to 20 °C and stirred at 20 °C for 2 hours. The mixture was quenched with H2O (30 mL). The mixture was extracted three times with EA (100 mL). The combined organic layers were washed three times with 1N HCl (250 mL) and brine (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The crude product was subjected to reverse rapid (Welch Ultimate XB_C) 18 Purification was performed at 20–40 μm; 120 A, water (0.1% FA)-ACN, 56%, 100 mL / min to give benzyl 4-[[2-(1-tert-butoxycarbonyl-4-piperidinyl)acetyl]amino]-4-(trifluoromethyl)piperidin-1-carboxylate (Int-5c, 3610.0 mg, 6.84 mmol). MS results (ESI) + ) [(M-Boc+H) + ]: 428.2 Step (d): 4-[2-(1-tert-butoxycarbonyl-4-piperidinyl)ethylamino]-4-(trifluoromethyl)piperidin-1-carboxylic acid benzyl ester Int-5d The BH3 / THF solution (16.11 mL, 16.11 mmol) was cooled to 0°C. At 0°C, a solution of 4-[[2-(1-tert-butoxycarbonyl-4-piperidinyl)acetyl]amino]-4-(trifluoromethyl)piperidin-1-carboxylic acid benzyl ester (Int-5c, 1.70 g, 3.22 mmol) in THF (5 mL) was added dropwise to the mixture. The mixture was warmed to 25°C and stirred at 25°C for 72 hours. The mixture was quenched at 0°C with MeOH (20 mL). After stirring at 70°C for 3 hours, the mixture was concentrated under vacuum. The crude product was subjected to reverse rapid (Welch Ultimate XB_C) 18Purified by concentration at 20–40 μm; 120 A, water (0.1% FA)-ACN, 100%, 100 mL / min to give 4-[2-(1-tert-butoxycarbonyl-4-piperidinyl)ethylamino]-4-(trifluoromethyl)piperidin-1-carboxylic acid benzyl ester (Int-5d, 1.228 g, 2.39 mmol). MS determination (ESI) + ) [(M-Boc+H) + ]: 414.3.

[0105] Step (e): 4-[2-[[4-(trifluoromethyl)-4-piperidinyl]amino]ethyl]piperidin-1-carboxylic acid tert-butyl ester Int-5 Similar to intermediate 1 in step (f), 4-[2-[[4-(trifluoromethyl)-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-5d) with 4-[2-(1-tert-butoxycarbonyl-4-piperidinyl)ethylamino]-4-(trifluoromethyl)piperidin-1-carboxylic acid benzyl ester (Int-5d). 4-[2-[[4-(trifluoromethyl)-4-piperidinyl]amino]ethyl]piperidin-1-carboxylic acid tert-butyl ester (Int-5, 848.0 mg, 2.23 mmol) was obtained. MS values ​​(ESI) + ) [(M+H) + ]: 380.2.

[0106] Intermediate 7: 4-Fluoro-1-methyl-4-[3-(4-methyl-4-piperidinyl)propyl]piperidine Int-7 Step (a): Preparation of tert-butyl 4-(3-methoxy-3-oxopropyl)-4-methyl-piperidine-1-carboxylate Int-7a t-BuOK (87.99 mL, 87.99 mmol, 1.0 M, in THF) was added dropwise to a solution of trimethyl phosphonoacetate (13.62 g, 74.79 mmol) in THF (60 mL) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 30 min, followed by the dropwise addition of a solution of tert-butyl 4-formyl-4-methyl-piperidin-1-carboxylate (10.0 g, 43.99 mmol) in THF (60 mL) at 0 °C. After stirring at 25 °C for 12 hours, the mixture was diluted with H2O (200 mL) and extracted three times with EA (300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (5% to 10% EA in PE) and concentrated under vacuum to give tert-butyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1-carboxylate (Int-7a, 10.0 g, 35.29 mmol). 1 H NMR (400 MHz, CDCl3) δ = 6.94 (d,J=16.0 Hz, 1H), 5.80 (d,J= 16.0 Hz, 1H), 3.74 (s, 3H), 3.53 - 3.44 (m, 2H),3.38 - 3.27 (m, 2H), 1.71 - 1.58 (m, 4H), 1.45 (s, 9H), 1.10 (s, 3H).

[0107] Step (b): Preparation of tert-butyl 4-(3-methoxy-3-oxopropyl)-4-methyl-piperidine-1-carboxylate Int-7b Pd / C (5.0 g, 10%, supported on activated carbon) was added to a solution of 4-[(E)-3-methoxy-3-oxo-propyl-1-enyl]-4-methyl-piperidin-1-carboxylic acid tert-butyl ester (Int-7a, 10.0 g, 35.29 mmol) in methanol (100 mL) under N2. The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 25 °C for 2 h under an H2 balloon. The mixture was filtered through diatomaceous earth and washed with DCM (200 mL). The filtrate was concentrated under vacuum to give 4-(3-methoxy-3-oxo-propyl)-4-methyl-piperidin-1-carboxylic acid tert-butyl ester (Int-7b, 9.1 g, 31.89 mmol). 1 H NMR (400 MHz, CDCl3) δ = 3.68 (s, 3H), 3.62 - 3.53 (m, 2H), 3.24 - 3.14 (m, 2H), 2.33 - 2.24 (m, 2H), 1.71 - 1.55 (m, 6H), 1.45 (s, 9H),0.93 (s, 3H).

[0108] Step (c): Preparation of tert-butyl 4-(3-iodopropyl)-4-methylpiperidine-1-carboxylate Int-7c LiAlH4 (1.86 g, 49.06 mmol) was added to a solution of tert-butyl 4-(3-methoxy-3-oxopropyl)-4-methylpiperidin-1-carboxylate (Int-7b, 7.0 g, 24.53 mmol) in THF (70 mL) at 0 °C. The reaction mixture was stirred at 25 °C under an N2 balloon for 2 hours. The suspension was then incubated at 0 °C with Na2SO4. . Quenching was performed in batches with 10H₂O (10 g). After stirring at 25 °C for 2 hours, the suspension was filtered. The filtrate was concentrated under vacuum to give tert-butyl 4-(3-hydroxypropyl)-4-methylpiperidin-1-carboxylate (Int-7c, 5.8 g, 22.54 mmol), which was used directly in the next step without further purification. MS results (ESI) + )[(M-Bu+H) + ]: 202.2.

[0109] Step (d): Preparation of tert-butyl 4-(3-iodopropyl)-4-methylpiperidine-1-carboxylate Int-7d Iodine (6.94 g, 27.36 mmol) was added to a mixture of imidazole (2.01 g, 29.58 mmol) and triphenylphosphine (6.94 g, 26.48 mmol) in DCM (60 mL) at 25 °C. The mixture was stirred at 25 °C under N2 for 1 hour, and then a solution of tert-butyl 4-(3-hydroxypropyl)-4-methylpiperidin-1-carboxylate (Int-7c, 5.8 g, 22.54 mmol) in DCM (50 mL) was added to the mixture at 25 °C under N2. After stirring at 25 °C under N2 for 12 hours, the reaction mixture was diluted with DCM (100 mL) and washed with Na2SO3 (100 mL) and brine (100 mL). The organic matter was dried (MgSO4) and concentrated under vacuum. The crude product was purified by silica gel column chromatography (5% to 10% EA in PE) to give tert-butyl 4-(3-iodopropyl)-4-methylpiperidin-1-carboxylate (Int-7d, 5.0 g, 13.61 mmol). MS determination (ESI) + )[(M-Bu+H) + ]: 312.0.

[0110] Step (e): Preparation of 4-[3-(1-tert-butoxycarbonyl-4-methyl-4-piperidinyl)propyl]piperidine-1,4-dicarboxylic acid O1-benzyl ester O4-methyl ester Int-7e LiHMDS (12.87 mL, 1.0 M, in THF) was added dropwise to a solution of N-Cbz-4-piperidinecarboxylate (3.17 g, 11.44 mmol) in THF (50 mL) at -60 °C. The mixture was stirred at -60 °C for 1 hour. Then, tert-butyl 4-(3-iodopropyl)-4-methylpiperidine-1-carboxylate (Int-7d, 3.5 g, 9.53 mmol) in THF (10 mL) was added dropwise to the mixture at -60 °C. After stirring at 20 °C for 12 hours, the mixture was poured into H2O (100 mL) and extracted three times with EA (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (5% to 20% EA in PE) to give 4-[3-(1-tert-butoxycarbonyl-4-methyl-4-piperidinyl)propyl]piperidin-1,4-dicarboxylic acid O1-benzyl ester O4-methyl ester (Int-7e, 2.00 g, 3.87 mmol). MS determination (ESI) + )[(M+Na) + ]: 539.3.

[0111] Step (f): Preparation of 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4-methyl-4-piperidinyl)propyl]piperidine-4-carboxylic acid Int-7f A mixture of 4-[3-(1-tert-butoxycarbonyl-4-methyl-4-piperidinyl)propyl]piperidine-1,4-dicarboxylic acid O1-benzyl ester O4-methyl ester (Int-7e, 1.50 g, 2.9 mmol) and NaOH (1.16 g, 29.03 mmol) in ethanol (20 mL) and water (20 mL) was stirred at 70 °C for 6 hours. The mixture was diluted with H2O (100 mL) and extracted with EA (200 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was rapidly purified by reverse-phase (0.1% FA) to give 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4-methyl-4-piperidinyl)propyl]piperidin-4-carboxylic acid (Int-7f, 1.20 g, 2.39 mmol). MS determination (ESI) + )[(M-Boc+H) + ]: 503.3.

[0112] Step (g): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidinyl)propyl]-4-methyl-piperidin-1-carboxylic acid Int-7g A mixture of 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4-methyl-4-piperidinyl)propyl]piperidin-4-carboxylic acid (Int-7f, 1.20 g, 2.39 mmol), AgNO3 (811.08 mg, 4.77 mmol), and Selectfluor (2018.05 mg, 5.7 mmol) in acetone (10 mL) and water (10 mL) was degassed and purged three times with N2. After stirring at 20 °C under N2 for 12 hours, the mixture was diluted with H2O (30 mL) and extracted three times with DCM (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% to 40% EA in PE) to give 4-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidinyl)propyl]-4-methyl-piperidin-1-carboxylic acid tert-butyl ester (Int-7g, 800.0 mg, 1.68 mmol. MS measured (ESI)). + )[(M+Na) + ]: 499.3.

[0113] Step (h): Preparation of benzyl 4-fluoro-4-[3-(4-methyl-4-piperidinyl)propyl]piperidine-1-carboxylate Int-7 A solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidinyl)propyl]-4-methyl-piperidin-1-carboxylate (Int-7 g, 600.0 mg, 1.26 mmol) in TFA (3.0 mL) and DCM (10 mL) was stirred at 20 °C for 2 h. The mixture was diluted with H2O (30 mL), alkalized to pH = 8 with solid NaHCO3, and extracted three times with DCM (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to give benzyl 4-fluoro-4-[3-(4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylate (Int-7, 450.0 mg, 1.2 mmol). MS determination (ESI) + )[(M+H) + ]: 377.3.

[0114] Intermediate 15: tert-butyl 4,4-difluoro-3-[3-(4-piperidinyl)propyl]piperidin-1-carboxylate Int-15 Step (a): Preparation of 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-oxo-piperidin-1,3-dicarboxylic acid O1-tert-butyl ester O3-methyl ester Int-15a K₂CO₃ (5.91 g, 42.75 mmol) and 4-(3-iodopropyl)piperidin-1,3-dicarboxylic acid O₁-tert-butyl ester O₃-methyl ester (5.5 g, 21.38 mmol) were added to a solution of 4-oxopiperidinium-1,3-dicarboxylic acid O₁-tert-butyl ester O₃-methyl ester (Int-1b, 9.93 g, 25.65 mmol) in DMF (50 mL) at 0 °C. After stirring at 50 °C for 16 hours, the mixture was poured into water (200 mL) and extracted three times with EA (150 mL). The combined organic phases were washed twice with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (60% EA in PE) to give 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-oxo-piperidin-1,3-dicarboxylic acid O1-tert-butyl ester O3-methyl ester (Int-15a, 9100.0 mg, 17.61 mmol). MS determination (ESI) + ) [(M-Boc+H) +]: 417.4.

[0115] Step (b): Preparation of tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-oxo-piperidin-1-carboxylic acid Int-15b LiCl (4.28 g, 101.04 mmol) was added to a solution of 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-oxo-piperidin-1,3-dicarboxylic acid O1-tert-butyl ester O3-methyl ester (Int-15a, 8.7 g, 16.84 mmol) in NMP (90 mL). After stirring at 150 °C for 2 hours, the mixture was poured into water (150 mL) and extracted twice with EA (120 mL). The combined organic phases were washed three times with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (35% EA in PE) to give tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-oxo-piperidin-1-carboxylic acid (Int-15b, 5.1 g, 11.12 mmol). MS determination (ESI) + ) [(M-Boc+H) + ]: 359.1.

[0116] Step (c): Preparation of tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid Int-15c DAST (13.64 mL, 111.21 mmol) was added to a solution of 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-oxo-piperidin-1-carboxylic acid tert-butyl ester (Int-15b, 5.1 g, 11.12 mmol) in DCM (60 mL) at 0 °C. After stirring at 25 °C for 12 hours, the mixture was poured into saturated NaHCO3 (200 mL) at 0 °C and extracted twice with DCM (80 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (25% EA in PE) to give 3-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-15c, 4.2 g, 8.74 mmol). MS measured value (ESI) + )[(M-Boc+H) + ]: 381.2.

[0117] Step (d): Preparation of tert-butyl 4,4-difluoro-3-[3-(4-piperidinyl)propyl]piperidine-1-carboxylate Int-15 Similar to intermediate 1 in step (f), 4,4-difluoro-3-[3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-15) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-15c). 4,4-difluoro-3-[3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-15b, 2.8 g, 8.08 mmol) was obtained. MS results (ESI) + ) [(M+H) + ]: 347.2.

[0118] Intermediate-16: tert-butyl 4,4-difluoro-3-[2-(4-piperidinyl)ethoxy]piperidine-1-carboxylate Int-16 Step (a): Preparation of benzyl 4-(2-iodoethyl)piperidine-1-carboxylate (Int-16a) Int-16a Iodine (3.51 g, 13.83 mmol) was added to a solution of imidazole (1.02 g, 14.96 mmol) and triphenylphosphine (3.51 g, 13.39 mmol) in DCM (40 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour, and then a solution of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid benzyl ester (3.0 g, 11.39 mmol) in DCM (2 mL) was added. After stirring at 25 °C for 3 hours, the mixture was poured into a saturated aqueous solution of Na₂SO₃ (150 mL) and extracted three times with DCM (150 mL). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO; 80 g SepaFlash silica rapid column, gradient: 5% to 35% EA eluent in PE, 120 mL / min) to give benzyl 4-(2-iodoethyl)piperidine-1-carboxylate (Int-16a, 3800.0 mg, 10.18 mmol). MS determination (ESI) + ) [(M+H) + ]: 374.0.

[0119] Step (b): Preparation of tert-butyl 3-[2-(1-benzyloxycarbonyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (Int-16b) Int-16b Sodium hydride (674.39 mg, 16.86 mmol) was added to a solution of tert-butyl 4,4-difluoro-3-hydroxy-piperidine-1-carboxylate (1000.0 mg, 4.21 mmol) and benzyl 4-(2-iodoethyl)piperidine-1-carboxylate (Int-16a, 1887.78 mg, 5.06 mmol) in NMP (20 mL) at 0 °C. The mixture was evacuated and backfilled three times with N2. After stirring at 25 °C under N2 for 2 hours, the mixture was poured into saturated NH4Cl (150 mL) and extracted three times with EA (150 mL). The combined organic phases were washed twice with brine (400 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was passed through rapid silica gel chromatography (ISCO; 40 g SepaFlash silica rapid column, gradient: 30% to 60% EA in PE, 80 mL / min) to give tert-butyl 3-[2-(1-benzyloxycarbonyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (Int-16b, 1400.0 mg, 2.9 mmol). MS determination (ESI) + ) [(M+Na) + ]: 505.2.

[0120] Step (c): Preparation of tert-butyl 4,4-difluoro-3-[2-(4-piperidinyl)ethoxy]piperidine-1-carboxylate (Int-16) Int-16 Similar to intermediate 1 in step (f), 4,4-difluoro-3-[2-(4-piperidinyl)ethoxy]piperidin-1-carboxylic acid tert-butyl ester (Int-16) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-16b). 4,4-Difluoro-3-[2-(4-piperidinyl)ethoxy]piperidin-1-carboxylic acid tert-butyl ester (Int-16, 1130.0 mg, 3.24 mmol) was obtained, which was used directly in the next step without further purification.

[0121] Intermediate-17: tert-butyl 3,3-difluoro-4-[2-(4-piperidinyl)ethoxy]pyrrolidine-1-carboxylate Int-17 Step (a): tert-butyl 3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate Int-17a At 25 °C, NaHCO3 (1316.28 mg, 15.67 mmol) and tert-butyl 3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate (1399.0 mg, 6.27 mmol) were added to 4,4-difluoropyrrolidine-3-ol hydrochloride (1000.0 mg, 6.27 mmol) in THF (5 mL) and water (5 mL). After stirring at 25 °C for 12 hours, the mixture was poured into water (30 mL) and extracted three times with EA (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate (Int-17a, 1399.0 mg, 6.27 mmol), which was used directly in the next step without further purification.

[0122] 1 H NMR (400 MHz, DMSO-d6) δ = 6.08 (s, 1H), 4.18 (s, 1H), 3.65 - 3.50 (m, 3H), 3.21 (d,J= 10.0 Hz, 1 H), 1.47 (s, 2H), 1.40 (s, 9H).

[0123] Step (b): 4-[2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidine-3-yl)oxyethyl]piperidine-1-carboxylic acid benzyl ester Int-17b NaH (401.4 mg, 10.03 mmol) was added to a solution of tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (Int-17a, 560.0 mg, 2.51 mmol) in NMP (5 mL) at 0 °C. The suspension was stirred at 0 °C for 0.5 h. A solution of benzyl 4-[2-(p-toluenesulfonyloxy)ethyl]piperidine-1-carboxylate (1047.45 mg, 2.51 mmol) in NMP (5 mL) was added to the suspension at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 5.5 h. The suspension was quenched at 0 °C with saturated NH4Cl (5 mL) under N2. The mixture was extracted three times with EA (70 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by reverse-phase rapid chromatography (80 g Welch Ultimate XB_C18 rapid column 20–40 μm; 120 A, water (0.1% FA)-ACN, 100%, 100 mL / min) to give 4-[2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidine-3-yl)oxyethyl]piperidine-1-carboxylic acid benzyl ester (Int-17b, 869.0 mg, 1.85 mmol). MS results (ESI) + )[(M+Na) + ]: 491.2.

[0124] Step (c): tert-butyl 3,3-difluoro-4-[2-(4-piperidinyl)ethoxy]pyrrolidine-1-carboxylate Int-17 Similar to intermediate 1 in step (f), 3,3-difluoro-4-[2-(4-piperidinyl)ethoxy]pyrrolidine-1-carboxylic acid tert-butyl ester (Int-17, 610.0 mg, 1.82 mmol) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-17b) with 4-[2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidine-3-yl)oxyethyl]piperidin-1-carboxylic acid benzyl ester (Int-17b). MS measured (ESI) + ) [(M+H) + ]: 335.3.

[0125] Intermediate 18: 4,4-difluoro-3-[3-(4-fluoro-4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester Int-18 Step (a): tert-butyl 3-allyl-4-oxo-piperidine-1-carboxylate Int-18a Under N2 at -78°C, 1-BOC-4-piperidinone (20.0 g, 100.38 mmol) in THF (50 mL) was added to a solution of LDA (56.0 mL, 112.0 mmol) in THF (50 mL). The mixture was stirred at -78°C for 2 hours, and then allyl bromide (12.75 g, 105.4 mmol) was added to the mixture at -78°C. The solution was stirred at -78°C for 1 hour and warmed to 20°C and stirred at 20°C for 12 hours. After the reaction was complete, the temperature was cooled to 0°C, and 300 mL of saturated NH4Cl was added dropwise to quench the reaction at 0°C and the mixture was extracted twice with EA (150 mL). The organic phases were combined, and the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (8% EA in PE). 3-Allyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (Int-18a, 5.48 g, 22.9 mmol) was obtained. MS determination (ESI) + ) [(M-tBu +H) + ]: 184.1.

[0126] Step (b): tert-butyl 3-allyl-4,4-difluoropiperidine-1-carboxylate Int-18b BAST (50.66 g, 228.98 mmol) was added dropwise to a solution of tert-butyl 3-allyl-4-oxo-piperidine-1-carboxylate (Int-18a, 5.48 g, 22.9 mmol) in DCM (300 mL) at 25 °C under N2. The mixture was heated to 45 °C and stirred at 4 °C for 2 h. The mixture was cooled to 25 °C and quenched to pH 7-8 with a saturated aqueous solution of NaHCO3. The mixture was extracted three times with DCM (150 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (4% EA in PE). 3-allyl-4,4-difluoro-piperidine-1-carboxylate (Int-18b, 4686.0 mg, 17.93 mmol) was obtained by MS analysis (ESI). + )[(M tBu +H) + ]: 206.1.

[0127] Step (c): tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)piperidine-1-carboxylate Int-18c Compounds are synthesized via flow chemistry. Conditions: Solution A: (tert-butyl 3-allyl-4,4-difluoro-piperidine-1-carboxylate (Int-18b, 2.2g), THF (10V, 22mL) Solution B: BH3 . THF (2 eq., 1M, 18 mL) Solution C: H₂O₂ (3 eq., 50%, 0.4 g) and NaOH (3 eq., 3M, 9 mL), Set the bath temperature to 25℃ ± 2℃, and set pump A = 2.4 mL / min, pump B = 2.0 mL / min, and pump C = 1.5 mL / min. Time = 0, start pumps A and B. Time = 5 minutes, start pump C Time = 10-15 minutes, sample collection and TLC. Quenching: Transfer FLR2 to Na2SO3 (10%, 2 eq.) at 0-5℃ via continuous flow. The combined collected phases were extracted twice with EA (150 mL). The organic phases were combined, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)piperidine-1-carboxylate (Int-18c, 2358.0 mg, 8.44 mmol).

[0128] Step (d): tert-butyl 4,4-difluoro-3-(3-iodopropyl)piperidine-1-carboxylate Int-18d Iodine (2.6 g, 10.25 mmol) was added to a solution of imidazole (0.75 g, 11.08 mmol) and triphenylphosphine (2.6 g, 9.92 mmol) in DCM (200 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 hour, and then a solution of tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)piperidine-1-carboxylate (Int-18c, 2358.0 mg, 8.44 mmol) in DCM (40 mL) was added to the mixture under N2. After stirring at 20 °C under N2 for 12 hours, the mixture was poured into saturated Na2SO3 (250 mL) and extracted three times with DCM (200 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product was then purified by rapid column chromatography, eluting with 8% EA in isohexane. The desired fraction was concentrated under vacuum to give tert-butyl 4,4-difluoro-3-(3-iodopropyl)piperidine-1-carboxylate (Int-18d, 1800.0 mg, 4.62 mmol). MS determination (ESI) + ) [(M-C4H9+H) + ]: 344.0.

[0129] Step (e): 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-18e t-BuOK (2.47 mL, 2.47 mmol) and tert-butyl 4,4-difluoro-3-(3-iodopropyl)piperidine-1-carboxylate (Int-18d, 944.39 mg, 2.43 mmol) were added dropwise to a solution of 4-formyl-N-CBZ-piperidine (600.0 mg, 2.43 mmol) in DMF (15 mL) at 0 °C. After stirring at 25 °C for 5 hours, the mixture was poured into water (70 mL) and extracted three times with EA (60 mL). The combined organic phases were washed twice with brine (80 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product was subjected to preparative HPLC (conditions: Phenomenex luna C18 150). 40mm Purified with 15 μm water (FA)-ACN, 40%–80%, and then extracted three times with EA (50 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give tert-butyl 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidinyl)propyl]-4,4-difluoropiperidin-1-carboxylic acid (Int-18e, 440.0 mg, 0.87 mmol). MS determination (ESI) + ) [(M+Na) + ]: 531.2 Step (f): 1-Benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]piperidin-4-carboxylic acid Int-18f At 25°C, a solution of sodium hypochlorite (234.72 mg, 2.6 mmol) in water (1.6 mL) was supplemented with tert-butyl 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylate (Int-18e, 440.0 mg, 0.87 mmol), sodium dihydrogen phosphate hydrate (358.15 mg, 2.6 mmol), and 2-methyl-but-2-ene (606.7 mg, 8.65 mmol) in THF (2.4 mL), t-BuOH (4.0 mL, 0.87 mmol), and water (0.800 mL). After stirring at 25°C for 0.5 hours, the mixture was quenched with H₂O (20 mL) and extracted three times with EA (15 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain a crude product. The crude product was purified by reverse-phase rapid chromatography (120 g Welch Ultimate XB_C18 20–40 μm; 120 A, water (0.1% FA)-ACN, 76%, 80 mL / min). 1-Benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]piperidin-4-carboxylic acid (Int-18f, 355.0 mg, 0.68 mmol). MS values ​​(ESI) + )[(M-Boc+H) + ]: 425.3.

[0130] Step (g): 3-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-18g AgNO3 (181.46 mg, 1.07 mmol) was added to a mixture of 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]piperidin-4-carboxylic acid (Int-18f, 350.0 mg, 0.67 mmol) and Selectfluor (472.7 mg, 1.33 mmol) in acetone (6 mL) and water (6 mL) under N2. The mixture was degassed three times under N2. After stirring at 20 °C under N2 for 3 hours, the mixture was diluted with H2O (40 mL) and extracted three times with EA (20 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (18% EA in PE). 3-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-18 g, 189.0 mg, 0.38 mmol) was obtained. MS determination (ESI) + ) [(M+Na) + ]: 521.2 Step (h): 4,4-Difluoro-3-[3-(4-fluoro-4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester Int-18 Similar to intermediate 1 in step (f), 4,4-difluoro-3-[3-(4-fluoro-4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-1e) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidinyl)propyl]-4,4-difluoropiperidin-1-carboxylic acid tert-butyl ester (Int-18g). 4,4-difluoro-3-[3-(4-fluoro-4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-18, 138.0 mg, 0.38 mmol) was obtained, which was used directly in the next step without further purification. MS results (ESI) + ) [(M+H) + ]: 365.3.

[0131] Intermediate 19: 4,4-Difluoro-3-[3-(4-methyl-4-piperidinyl)propyl]piperidine-1-carboxylic acid tert-butyl ester Int-19 Step (a): 3-[3-[1-benzyloxycarbonyl-4-(difluoromethyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-19a Add (0.54 mL, 2.95 mmol) to a solution of 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-18e, 150.0 mg, 0.29 mmol) in DCM (6 mL) at 0 °C. After stirring at 45 °C for 16 hours, the mixture was poured into NaHCO3 (30 mL) at 0 °C and extracted twice with EA (30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was then purified by rapid column chromatography (20% EA in isohexane). The desired fraction was concentrated to dryness under vacuum to give tert-butyl 3-[3-[1-benzyloxycarbonyl-4-(difluoromethyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid (Int-19a, 150.0 mg, 0.28 mmol). MS determination (ESI) + )[(M+H) + ]: 531.2.

[0132] Step (b): tert-butyl 3-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid Int-19 Similar to intermediate 1 in step (f), tert-butyl 4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylate (Int-1e) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-(difluoromethyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylate (Int-19a).

[0133] Intermediate 20: 6,6-difluoro-1-[3-(4-piperidinyl)propyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester Int-20 Step (a): 4-[3-(1-tert-butoxycarbonyl-2,5-dihydropyrrole-3-yl)propyl]piperidine-1-carboxylic acid benzyl ester Int-20a Cs₂CO₃ (7572.12 mg, 23.24 mmol) and Cy₃P-Pd-G₃ (503.67 mg, 0.77 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid (2744.11 mg, 9.3 mmol) were added to a solution of 4-(3-iodopropyl)piperidine-1-carboxylic acid benzyl ester (Int-1b, 3.0 g, 7.75 mmol) in DMF (50 mL) and water (10 mL). The reaction mixture was stirred at 90 °C for 12 hours under N₂. The crude mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum. The mixture was diluted with EA (160 mL), washed three times with water (90 mL) and brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was then subjected to preparative HPLC (column: Phenomenex luna C18 150). 40mm 15 μm; Conditions: Water (TFA)-ACN; B%: 60%-90%; Flow rate (mL / min): 60) Purification. The fraction was adjusted to pH = 9 with saturated NaHCO3 aqueous solution and concentrated under vacuum to remove MeCN, and extracted twice with EA (80 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give 4-[3-(1-tert-butoxycarbonyl-2,5-dihydropyrrole-3-yl)propyl]piperidine-1-carboxylic acid benzyl ester (Int-20a, 700.0 mg, 1.63 mmol). MS determination (ESI) + ) [(M-Boc+H) + ]: 329.2 Step (b): 1-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester Int-20b To a solution of 4-[3-(1-tert-butoxycarbonyl-2,5-dihydropyrrolo-3-yl)propyl]piperidine-1-carboxylic acid benzyl ester (Int-20a, 350.0 mg, 0.82 mmol) in THF (3 mL), NaI (73.45 mg, 0.49 mmol) and trifluoromethyltrimethylsilane (1509.7 mg, 10.62 mmol) were added. The reaction mixture was stirred at 66 °C for 5 hours under N2. The mixture was concentrated under vacuum. The residue was purified by column chromatography (30% EA in PE) to give 1-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Int-20b, 1509.7 mg, 10.62 mmol). MS measured value (ESI) + ) [(M-Boc+H) + ]: 379.2.

[0134] Step (c): 6,6-Difluoro-1-[3-(4-piperidinyl)propyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester Int-20 Similar to intermediate 1 in step (f), 6,6-difluoro-1-[3-(4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-1e) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Int-20b) with 1-[3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Int-20, 287.0 mg, 0.83 mmol).

[0135] Intermediate 21: 2-[3-(4-piperidinyl)propyl]morpholine-4-carboxylic acid tert-butyl ester Int-21 Step (a): tert-butyl 2-formylmorpholine-4-carboxylate Int-21a Add (COCl)₂ (2.36 mL, 27.62 mmol) and DCM (30 mL) to a 500 mL three-necked round-bottom flask and maintain an inert nitrogen atmosphere. Then, add DMSO (4.9 mL, 69.04 mmol) at -78 °C. The mixture is then stirred at -78 °C for 1 hour. Add dropwise a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (3000.0 mg, 13.81 mmol) in DCM (10 mL) at -78 °C, and stir the mixture for 30 minutes. Then, add TEA (9.6 mL, 69.04 mmol) at -78 °C. After stirring at -78 °C for 2 hours, pour the mixture into water (150 mL) and extract three times with EA (150 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain tert-butyl 2-formylmorpholine-4-carboxylate (Int-21a, 3.2 g, 14.87 mmol).

[0136] 1 H NMR (400 MHz, DMSO-d6) δ = 9.56 (s, 1H), 4.07 (dd,J= 4.0, 9.2 Hz,1H), 3.88 - 3.84 (m, 3H), 3.57 (m, 1H), 3.10 - 3.07 (m, 2H), 1.40 (s, 9H) Step (b): 2-[1-hydroxy-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylic acid tert-butyl ester Int-21b n-BuLi (5.57 mL, 13.94 mmol) was added to a solution of 4-ethynylpyridine (1317.44 mg, 12.78 mmol) in THF (25 mL) at -60 °C under N2. The reaction mixture was stirred further for 6 min, and then a solution of 2-formylmorpholine-4-carboxylic acid tert-butyl ester (Int-21a, 2.5 g, 11.61 mmol) in THF (5 mL) was added to the mixture under N2. After stirring at -60 °C under N2 for 2 hours, the mixture was poured into saturated NH4Cl (150 mL) and extracted three times with EA (100 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO; 80 g SepaFlash silica rapid column, gradient: 80% to 100% EA eluent in PE, 120 mL / min). The desired fraction was concentrated under vacuum to give tert-butyl 2-[1-hydroxy-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate (Int-21b, 1300.0 mg, 4.08 mmol). MS determination (ESI) + )[(M+H) + ]:319.3.

[0137] Step (c): 2-[1-(imidazol-1-thiocarbonyloxy)-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylic acid tert-butyl ester Int-21c To a solution of 2-[1-hydroxy-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylic acid tert-butyl ester (Int-21b, 1.3 g, 4.08 mmol) in DCM (13 mL), 1,1'-thiocarbonyldiimidazole (873.22 mg, 4.9 mmol) was added. After stirring at 25 °C for 16 hours, the mixture was concentrated under vacuum. The crude product was analyzed by preparative HPLC (conditions: Phenomenex luna C18 150). 40mm Purified with water (FA)-ACN, 30%–60% at 15 μm to give tert-butyl [2-[1-(imidazol-1-thiocarbonyloxy)-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylic acid (Int-21c, 400.0 mg, 0.93 mmol). MS results (ESI)+ )[(M+H) + ]: 429.2.

[0138] Step (d): 2-[3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylic acid tert-butyl ester Int-21d Bu3SnH (0.5 mL, 1.87 mmol) was added to a solution of tert-butyl 2-[1-(imidazol-1-thiocarbonyloxy)-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate (Int-21c, 400.0 mg, 0.93 mmol) and AIBN (15.33 mg, 0.09 mmol) in toluene (8 mL). The mixture was evacuated and backfilled three times with N2. After stirring at 80 °C under N2 for 1.5 hours, the mixture was poured into saturated CsF (100 mL) and extracted three times with EA (60 mL). The combined organic phases were washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (ISCO; 12 g SepaFlash silica rapid column, gradient: 20% to 50% EA eluent in PE, 45 mL / min) to give tert-butyl 2-[3-(4-pyridyl)prop-2-ynyl]morpholino-4-carboxylate (Int-21d, 200.0 mg, 0.66 mmol). MS determination (ESI) + )[(M+H) + ]: 303.2.

[0139] Step (e): 2-[3-(4-piperidinyl)propyl]morpholine-4-carboxylic acid tert-butyl ester Int-21 A solution of tert-butyl 2-[3-(4-pyridyl)prop-2-ynyl]morpholino-4-carboxylate (Int-21d, 200.0 mg, 0.66 mmol) in THF (20 mL) was stirred at 25 °C until a clear solution was obtained. The H2 back pressure regulator was adjusted to 2.5 MPa, the H2 flow rate was adjusted to 30 mL / min, and the fixed bed (10% Ru / SiO2, 3 g) was heated to 90 °C. The solution was then pumped into the reactor at a flow rate of 0.3 mL / min. After the reaction was complete, the tube was washed with 50 mL of MeOH, and all the reaction solution was collected for analysis. After the reaction was complete, the reaction solution was concentrated under vacuum to obtain tert-butyl 2-[3-(4-piperidinyl)propyl]morpholino-4-carboxylate (Int-21, 180.0 mg, 0.58 mmol). MS values ​​(ESI) + )[(M+H) + ]: 313.2.

[0140] Intermediate 22: 4,4-Difluoro-3-[3-(4-methyl-4-piperidinyl)propyl]piperidine-1-carboxylic acid tert-butyl ester Int-22 Step (a): Benzyl 4-formyl-4-methyl-piperidine-1-carboxylate Int-22a t-BuOK (24.51 g, 202.19 mmol) and iodomethane (12.64 mL, 202.19 mmol) were added to a solution of 4-formyl-N-CBZ-piperidine (25.0 g, 101.1 mmol) in DMF (500 mL) at 0 °C, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (500 mL) and extracted four times with EA (100 mL). The combined organic layers were washed twice with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (0% to 30% EA in SiO2, PE) and the desired fraction was concentrated under vacuum to give benzyl 4-formyl-4-methyl-piperidine-1-carboxylate (Int-22a, 14.5 g, 55.49 mmol). MS determination (ESI+) [(M+Na)] + ]:262.3 Step (b): 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1-carboxylic acid benzyl ester Int-22b t-BuOK (12.02 g, 107.15 mmol) was added dropwise to a solution of trimethyl phosphonoacetate (16.59 g, 91.08 mmol) in THF (100 mL) at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. Benzyl 4-formyl-4-methyl-piperidin-1-carboxylate (Int-22a, 14.0 g, 53.57 mmol) in THF (100 mL) was added dropwise to the mixture at 0 °C, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (300 mL) and extracted four times with EA (150 mL). The combined organic layers were washed twice with brine (200 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (0% to 30% EA in SiO₂, PE). The residue was purified by reversed-phase HPLC (0.1% FA conditions) and lyophilized to give benzyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1-carboxylate (Int-22b, 5.0 g, 15.75 mmol). 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.38–7.30 (m, 5H), 6.94 (d, J = 16.0 Hz, 1H), 5.80 (d, J = 16.0 Hz, 1H), 5.13 (s, 2H), 3.75 (s, 3H), 3.66–3.53 (m, 2H), 3.49–3.34 (m, 2H), 1.74–1.64 (m, 2H), 1.55–1.42 (m, 2H), 1.11 (s, 3H). MS measured values ​​(ESI+) [(M+Na)] + ]:318.2 Step (c): Preparation of methyl 3-(4-methyl-4-piperidinyl)propionate Int-22c Pd / C (500.0 mg) was added to a solution of 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidin-1-carboxylic acid benzyl ester (Int-22b, 5.0 g, 15.75 mmol) in methanol (20 mL) under N2 conditions. The mixture was then degassed and purged three times with H2, and stirred at 25 °C for 2 h. The reaction mixture was filtered to give methyl 3-(4-methyl-4-piperidinyl)propionate (Int-22c, 2.9 g, 15.56 mmol), which was used directly in the next step without further purification. MS results (ESI) + )[(M+H) +]:186.2.

[0141] Step (d): 4-(3-methoxy-3-oxopropyl)-4-methyl-piperidine-1-carboxylic acid benzyl ester Int-22d A solution of CbzOSu (3120.8 mg, 12.52 mmol) and methyl 3-(4-methyl-4-piperidinyl)propionate (Int-22c, 2.32 g, 12.52 mmol) in methanol (50 mL) was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under vacuum. The oil was diluted with water (50 mL) and extracted four times with EA (50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to give benzyl 4-(3-methoxy-3-oxopropyl)-4-methyl-piperidin-1-carboxylate (Int-22d, 3.94 g, 12.34 mmol). MS determination (ESI) + )[(M+H) + ]:320.2.

[0142] Step (e): Benzyl 4-(3-hydroxypropyl)-4-methyl-piperidine-1-carboxylate Int-22e NaBH4 (604.05 mg, 15.97 mmol) was added to a solution of 4-(3-methoxy-3-oxopropyl)-4-methyl-piperidin-1-carboxylate (Int-22d, 3.4 g, 7.98 mmol) in ethanol (35 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (120 mL) and extracted four times with EA (40 mL). The combined organic layers were washed twice with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (0% to 30% EA in SiO2, PE) and the organic layer was concentrated under vacuum to give 4-(3-hydroxypropyl)-4-methyl-piperidin-1-carboxylate (Int-22e, 1.58 g, 5.42 mmol). MS values ​​(ESI) + )[(M+Na) + ]:314.2.

[0143] Step (f): Benzyl 4-(3-iodopropyl)-4-methyl-piperidine-1-carboxylate Int-22f A mixture of imidazole (479.27 mg, 7.04 mmol), molecular iodine (1.65 g, 6.5 mmol), and PPh3 (1.66 g, 6.34 mmol) in DCM (12 mL) was stirred at 25 °C for 0.5 h. Then, benzyl 4-(3-hydroxypropyl)-4-methyl-piperidin-1-carboxylate (Int-22e, 1.58 g, 5.42 mmol) in DCM (10 mL) was added to the mixture, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with Na₂SO₃ (60 mL) and extracted four times with DCM (30 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (0% to 10% EA in SiO2, PE) and the organic layer was concentrated under vacuum to give benzyl 4-(3-iodopropyl)-4-methyl-piperidine-1-carboxylate (Int-22f, 2.01 g, 5.01 mmol). 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.41–7.28 (m, 5H), 5.13 (s, 2H), 3.74–3.56 (m, 2H), 3.39–3.23 (m, 2H), 3.17 (t, J = 6.8 Hz, 2H), 1.90–1.72 (m, 2H), 1.47–1.29 (m, 6H), 0.95 (s, 3H). MS measured values ​​(ESI) + )[(M+H) + ]: 402.1 Step (g): 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4-oxo-piperidin-1,3-dicarboxylic acid O1-tert-butyl ester O3-methyl ester Int-22g K₂CO₃ (1377.56 mg, 9.97 mmol) was added to a solution of 4-(3-iodopropyl)-4-methylpiperidin-1-carboxylate (2.0 g, 4.98 mmol) and 4-oxopiperidin-1,3-dicarboxylic acid O₁-tert-butyl ester O₃-methyl ester (Int-22f, 1282.31 mg, 4.98 mmol) in DMF (25 mL), and the mixture was stirred at 50 °C for 12 h. The reaction mixture was diluted with water (120 mL) and extracted four times with EA (40 mL). The combined organic layers were washed twice with brine (50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, 0% to 30% EA in PE) to give 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4-oxo-piperidin-1,3-dicarboxylic acid O1-tert-butyl ester O3-methyl ester (Int-22g, 1790.0mg, 3.37mmol). MS determination (ESI) + )[(M+Na) + ]:553.4.

[0144] Step (h): 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4-oxo-piperidin-1-carboxylic acid tert-butyl ester Int-22h LiCl (810.0 mg, 19.11 mmol) was added to a solution of 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4-oxo-piperidin-1,3-dicarboxylic acid O1-tert-butyl ester O3-methyl ester (Int-22 g, 1.69 g, 3.18 mmol) in NMP (17 mL). After stirring at 150 °C for 0.5 hours, the reaction mixture was diluted with water (120 mL) and extracted four times with EA (40 mL). The combined organic layers were washed twice with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, 0% to 30% EA in PE) to give tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4-oxo-piperidin-1-carboxylic acid (Int-22h, 1.32 g, 2.79 mmol). MS determination (ESI) + [M-C4H8+H] + : 473.3.

[0145] Step (i): 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4-oxo-piperidin-1-carboxylic acid tert-butyl ester Int-22i Add 4-(trifluoro-λ) to a solution of 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4-oxo-piperidin-1-carboxylic acid tert-butyl ester (Int-22h, 1200.0 mg, 2.54 mmol) in DCM (20 mL) at 0 °C. 4 3-Thio)morpholine (4446.78 mg, 25.39 mmol) was stirred at 30 °C for 16 h. The reaction mixture was diluted with water (120 mL) and extracted four times with EA (40 mL). The combined organic layers were washed twice with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to give 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4,4-difluoropiperidin-1-carboxylic acid tert-butyl ester (Int-22h, 780.0 mg, 1.58 mmol). MS determination (ESI) + [M+Na] + :495.3.

[0146] Step (j): 4,4-Difluoro-3-[3-(4-methyl-4-piperidinyl)propyl]piperidine-1-carboxylic acid tert-butyl ester Int-22 Similar to intermediate 1 in step (f), 4,4-difluoro-3-[3-(4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int 22, 524.0 mg, 1.45 mmol) was prepared by replacing 4-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Int 22) with 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int 22). MS measured values ​​(ESI) + [M+H] + : 361.3.

[0147] Intermediate 23: tert-butyl 4,4-difluoro-3-[2-(4-methyl-4-piperidinyl)ethoxy]piperidine-1-carboxylate Int-23 Step (a): Benzyl 4-(2-hydroxyethyl)-4-methyl-piperidine-1-carboxylate Int-23a A solution of tert-butyl 4-(2-hydroxyethyl)-4-methylpiperidin-1-carboxylate (2.0 g, 8.22 mmol) in TFA (3.0 mL, 8.22 mmol) was stirred at 25 °C for 10 hours. The residue was dissolved in THF (20 mL). Then, a solution of Na₂CO₃ (2.61 g, 24.66 mmol) in water (5 mL) was added dropwise to the mixture, followed by N-(benzyloxycarbonyloxy)succinimide (2.05 g, 8.22 mmol). After stirring at 25 °C for 12 hours, the reaction mixture was concentrated to dryness, and the residue was placed in EtOAc (50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated to give benzyl 4-(2-hydroxyethyl)-4-methylpiperidine-1-carboxylate (Int-23a, 3.20 g, 11.54 mmol) and used directly in the next step without further purification. MS results (ESI) + ) [(M+H) + ]: 278.1.

[0148] Step (b): 4-Methyl-4-[2-(p-toluenesulfonyloxy)ethyl]piperidine-1-carboxylic acid benzyl ester Int-23b TEA (1.81 g, 17.88 mmol) and p-toluenesulfonyl chloride (3.3 g, 17.31 mmol) were added to a solution of 4-(2-hydroxyethyl)-4-methyl-piperidine-1-carboxylate (3.2 g, 11.54 mmol, Int-23a) in DCM (35 mL) at 0 °C. The mixture was heated to 25 °C and stirred at 25 °C for 16 hours. The reaction mixture was then quenched with H2O (120 mL) and extracted twice with DCM (100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (30% EA in PE) to give 4-methyl-4-[2-(p-toluenesulfonyloxy)ethyl]piperidine-1-carboxylate (2.5 g, 5.79 mmol, Int-23b). MS measured value (ESI) + ) [(M+H) + ]: 432.1.

[0149] Step (c): 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-23c NaH (505.8 mg, 12.64 mmol) was added to a solution of tert-butyl 4,4-difluoro-3-hydroxy-piperidine-1-carboxylate (750.0 mg, 3.16 mmol) in NMP (15 mL) at 0 °C under N2. The suspension was stirred at 0 °C for 0.5 h. A solution of 4-methyl-4-[2-(p-toluenesulfonyloxy)ethyl]piperidine-1-carboxylate (1.23 g, 2.85 mmol, Int-23b) in NMP (5 mL) was added to the suspension at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C under N2 for 11.5 h. The suspension was quenched at 0 °C under N2 with a saturated aqueous solution of NH4Cl (80 mL). The reaction mixture was extracted twice with EA (50 mL). The combined organic layers were washed three times with brine (30 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (30% EA in PE) to give tert-butyl 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)ethoxy]-4,4-difluoropiperidin-1-carboxylic acid (1.0 g, 2.01 mmol, Int-23c). MS determination (ESI) + ) [(M-Boc+H) + ]: 397.3.

[0150] Step (d): 4,4-Difluoro-3-[2-(4-methyl-4-piperidinyl)ethoxy]piperidine-1-carboxylic acid tert-butyl ester Int-23 Pd / C (0.1 g, 10% purity, on carbon) and Pd(OH)₂ / C (0.1 g, 10% purity, on carbon) were added to a solution of 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (1.0 g, 2.01 mmol, Int-23c) in ethyl acetate (20 mL) under N₂. The suspension was degassed under vacuum and purged three times with H₂. The suspension was stirred at 25 °C under an H₂ balloon for 2 h. The crude mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum to give 4,4-difluoro-3-[2-(4-methyl-4-piperidinyl)ethoxy]piperidin-1-carboxylic acid tert-butyl ester (720.0 mg, 1.99 mmol, Int-23).

[0151] Intermediate 24: tert-butyl 3-[2-(4-ethyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid Int-24 Step (a): Benzyl 4-ethyl-4-formyl-piperidine-1-carboxylate Int-24a t-BuOK (36.3 g, 323.51 mmol) and iodoethane (25.88 mL, 323.51 mmol) were added to a solution of 4-formyl-N-CBZ-piperidine (40.0 g, 161.75 mmol) in DMF (500 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then diluted with H2O (1000 mL) and extracted three times with EA (400 mL). The combined organic layers were concentrated under vacuum. The residue was purified and concentrated by passing through a silica column (PE / EA = 20 / 1 to 10 / 1, Rf = 0.45) to give 4-ethyl-4-formyl-piperidine-1-carboxylic acid benzyl ester (20.0 g, 72.63 mmol, Int-24a). 1H NMR (400 MHz, CDCl3) δ = 9.71 - 9.18 (m, 1H), 7.47 -7.30 (m, 5H), 5.14 (s, 2H), 3.93 (s, 2H), 2.99 (s, 2H), 1.98 (d,J= 12.0 Hz,2H), 1.71 - 1.46 (m, 4H), 0.94 - 0.68 (m, 3H).

[0152] Step (b): Benzyl 4-ethyl-4-vinyl-piperidine-1-carboxylate Int-24b t-BuOK (21.56 g, 141.64 mmol) was added to a solution of methyltriphenylphosphine bromide (50.6 g, 141.64 mmol) in tetrahydrofuran (130 mL) at 0 °C, and the mixture was stirred at 40 °C for 1 h. Then, a solution of 4-ethyl-4-formyl-piperidin-1-carboxylic acid benzyl ester (13.0 g, 47.21 mmol, Int-24a) in THF (50 mL) was added, and the resulting mixture was stirred at 40 °C under N2 for 1 h. The mixture was quenched with water (400 mL) and extracted with EA (100 mL). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE: EA = 1 / 0 to 10 / 1), TLC (PE: EA = 3:1, PMA) and concentrated under vacuum to give benzyl 4-ethyl-4-vinyl-piperidine-1-carboxylate (10.3 g, 37.68 mmol, Int-24b). 1 H NMR (400 MHz, chloroform-d) δ = 7.42 - 7.28 (m,5H), 5.58 (dd,J= 11.2, 17.6 Hz, 1H), 5.25 - 5.17 (m, 1H), 5.13 (s, 2H), 4.96(dd,J= 0.8, 17.6 Hz, 1H), 3.76 (d,J= 12.8 Hz, 2H), 3.30 - 3.10 (m, 2H), 1.64 (d,J= 12.8 Hz, 2H), 1.49 - 1.39 (m, 2H), 1.35 (q,J= 7.6 Hz, 2H), 0.78 (t,J=7.6 Hz, 3H).

[0153] Step (c): Benzyl 4-ethyl-4-(2-hydroxyethyl)piperidine-1-carboxylate Int-24c Intermediate 24c was obtained via flow chemistry as follows: Solution 1: Benzyl 4-ethyl-4-vinyl-piperidine-1-carboxylate, 1 eq, 10 g in THF, 100 mL Solution 2: BH3·THF, 2 eq, 6.288 g (1M, 75 mL) Solution 3: H₂O₂, 3 eq, 3.733 g (50%, 7.5 g), in NaOH, 3 eq, 4.389 g (2 M, 55 mL) Solution 1 was pumped to flow reactor 1 (FLR1, PFA, coil reactor, 3.175 (1 / 8'') mm, 64.115 mL, 25°C) via pump 1 (S1, P1, 7.667 mL / min). Solution 2 was pumped to flow reactor 1 (FLR1, PFA, coil reactor, 3.175 (1 / 8'') mm, 64.115 mL, 25°C) via pump 2 (S2, P2, 5.156 mL / min). Solution 3 was pumped to flow reactor 2 (FLR2, GL, CSTR, 100 mL, 0℃) via pump 3 (S3, P3, 4.345 mL / min). The residence time in flow reactor 1 is FLR1, 5 minutes. The residence time of flow reactor 2 is FLR2, 5.825 minutes.

[0154] TLC (PE:EA = 3:1) showed that the starting material was completely consumed and the desired point was detected. The mixture was collected in a flask (containing 50 mL of 1M Na₂SO₃ aqueous solution). The mixture was extracted twice with EA (200 mL). The organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give benzyl 4-ethyl-4-(2-hydroxyethyl)piperidine-1-carboxylate (10.6 g, 36.38 mmol, 86.9% yield, Int-24c).

[0155] 1¹H NMR (400 MHz, chloroform) δ = 7.40 - 7.28 (m, 5H), 5.13 (s, 2H), 3.69 (t, J = 7.6 Hz, 2H), 3.59 - 3.31 (m, 4H), 1.63 (t, J = 8.0 Hz, 2H), 1.49 - 1.35 (m, 6H), 0.87 - 0.81 (m, 3H).

[0156] Step (d): Benzyl 4-ethyl-4-(2-iodoethyl)piperidine-1-carboxylate Int-24d Iodine (10.09 g, 39.75 mmol) was added to a solution of imidazole (2.93 g, 42.98 mmol) and triphenylphosphine (10.09 g, 38.47 mmol) in DCM (150 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour, and then a solution of 4-ethyl-4-(2-hydroxyethyl)piperidine-1-carboxylic acid benzyl ester (10.6 g, 32.74 mmol, Int-24c) in DCM (60 mL) was added. After stirring at 25 °C for 12 hours, the reaction mixture was diluted with water (300 mL) and extracted four times with EA (100 mL). The combined organic layers were washed twice with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE: EA = 1 / 0 to 10 / 1) to give benzyl 4-ethyl-4-(2-iodoethyl)piperidine-1-carboxylate (8.84 g, 22.03 mmol, Int-24d). MS determination (ESI) + ) [(M+H) + ]: 402.0.

[0157] Step (e): 4-Ethyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylic acid benzyl ester Int-24e Benzyl 4-ethyl-4-(2-iodoethyl)piperidine-1-carboxylate (3000.0 mg, 7.48 mmol, Int-24d) and p-tolylsulfonyloxysilver (6258.67 mg, 22.43 mmol) were dissolved in MeCN (40 mL) in the dark and stirred at 25 °C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted three times with EA (40 mL). The combined organic layers were washed twice with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE: EA = 1 / 0 to 3 / 1) to give benzyl 4-ethyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (1002.0 mg, 2.25 mmol, Int-24e). MS results (ESI) + ) [(M+H) + ]: 446. 2.

[0158] Step (f): 3-[2-(1-benzyloxycarbonyl-4-ethyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-24f Similar to intermediate 23, 3-[2-(1-benzyloxycarbonyl-4-ethyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (1030.0 mg, 2.02 mmol, Int-24f) was prepared by replacing 4-ethyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidin-1-carboxylic acid tert-butyl ester (Int-23b) with 4-methyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidin-1-carboxylic acid tert-butyl ester (Int-24e) (1070.49 mg, 2.4 mmol, Int-24e). MS measured values ​​(ESI) + ) [(M-Boc+H] + ) + ]: 411.2.

[0159] Step (g): tert-butyl 3-[2-(4-ethyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid Int-24 Similar to intermediate 23, 3-[2-(4-ethyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-24f) was prepared by replacing 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-24f). MS results (ESI) + )[(M+H) + ]: 377.3.

[0160] Intermediate 30: 3-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-30 Step (a): 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid Int-30a Similar to intermediate 31, 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-30a, 1048.0 mg, 2.16 mmol) was prepared by replacing 2,6-difluoronicotinic acid and 4-[3-(4-piperidinyl)propyl]piperidinyl-1-carboxylic acid (Int-15) with 4,6-difluoropyridine-3-carboxylic acid and 4,4-difluoro-3-[3-(4-piperidinyl)propyl]piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-30a, 1048.0 mg, 2.16 mmol) by MS determination (ESI). + ) [(M+H) + ]: 486.3.

[0161] Step (b): 3-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-30 Similar to intermediate 32, tert-butyl 3-[3-[1-(5-carbamoyl-2-fluoro-4-pyridinyl)propyl]-1-piperidinyl]-6-fluoro-pyridinyl-3-carboxylic acid (Int-30a) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridinyl-3-carboxylic acid (Int-30a). + ) [(M+Na) + ]: 507.2.

[0162] Intermediate 31: 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid Int-31 Step (a): Preparation of 6-fluoro-2-(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)nicotinic acid Int-31a DIPEA (1621.72 mg, 12.57 mmol) (7087-68-5, Sigma Aldrich China) and 2,6-difluoronicotinic acid (1000.0 mg, 6.29 mmol) were added to a solution of 4-[3-(4-piperidinyl)propyl]piperidine (2.64 g, 12.57 mmol) in MeCN (20 mL), and the reaction mixture was stirred at 20 °C for 16 h. The mixture was acidified to pH 6-7 with 1 N HCl (50 mL). A large amount of white precipitate formed. The solid was collected by filtration. The filter cake was ground with MeCN (50 mL) to give 6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxylic acid (Int-31a, 1.70 g, 4.86 mmol). 1H NMR (400 MHz, DMSO-d6) δ 9.61 (br s, 1H), 7.68- 7.58 (m, 1H), 6.21 - 6.11 (m, 1H), 4.04 - 3.94 (m, 2H), 3.23 - 3.16 (m,2H), 2.79 - 2.62 (m, 4H), 1.77 - 1.60 (m, 4H), 1.41 - 1.12 (m, 12H).

[0163] Step (b): Preparation of 2-(4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)piperidin-1-yl)-6-fluoronicotinic acid Int-31 Di-tert-butyl dicarbonate (936.86 mg, 4.29 mmol) was added to a solution of 6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxylic acid (Int-31a, 1500.0 mg, 4.29 mmol) in methanol (20 mL). The mixture was stirred at 20 °C for 2 h. The residue was purified by silica gel column chromatography (SiO2, 10% to 50% EA in PE) to give 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-31, 1.0 g, 2.22 mmol). MS results (ESI) + ) [(M+H) + ]: 450.2. 1 H NMR (400 MHz, DMSO-d6) δ = 12.93 (br s, 1H), 8.04 (t,J= 8.4 Hz, 1H), 6.45 - 6.32 (m, 1H), 3.96 - 3.85 (m, 2H), 3.80 - 3.71 (m, 2H), 2.95 - 2.85 (m, 2H), 2.76 - 2.62(m, 2H), 1.70 - 1.65 (m, 2H), 1.61 (br d, J = 12.3 Hz, 2H), 1.51 - 1.29 (m,15H), 1.23 - 1.18 (m, 4H), 0.99 - 0.87 (m, 2H).

[0164] Intermediate 32: N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide Int-32 EDCI (2600.0 mg, 13.56 mmol) (25952-53-8, AccelaChemBio) was added to a solution of 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-31, 2600.0 mg, 5.78 mmol) and ammonium chloride (928.07 mg, 17.35 mmol) in pyridine (26 mL) at 0 °C. After stirring at 36 °C for 12 hours, the mixture was concentrated under vacuum. The residue was purified by reverse-phase column chromatography (0.1% TFA in water, MeCN (55%–85%)). The fraction was concentrated under vacuum to give tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]propyl]piperidin-1-carboxylate (Int-32, 1.8 g, 4.01 mmol). MS determination (ESI) + ) [(M+H) + ]: 449.3.

[0165] Intermediate 33: 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-nitrobenzoic acid Int-33 Similar to intermediate 31, 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-nitrobenzoic acid (Int-33, 14.2 g, 29.8 mmol) was prepared by replacing 2,6-difluoronicotinic acid with 2-fluoro-4-nitrobenzoic acid. MS determination (ESI) + ) [(M-Boc+H) + ]: 376.1.

[0166] Intermediate 34: 4-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester Int-34 Similar to intermediate 32, 4-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]propyl]piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-34, 1.0 g, 2.11 mmol) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzoic acid (Int-33) with 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzoic acid. MS results (ESI) + ) [(M+H) + ]: 475.3.

[0167] Intermediate 35: 6-fluoro-4-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxylic acid Int-35 Similar to intermediate 31, 6-fluoro-4-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxylic acid (Int-35, 10.0 g, 22.25 mmol) was prepared by replacing 2,6-difluoronicotinic acid with 4,6-difluoropyridin-3-carboxylic acid. MS results (ESI) + ) [(M+H) + ]: 450.2. 1 H NMR (400 MHz, CDCl3) δ = 8.97- (s,1H), 6.81 (s, 1H), 4.15 - 4.08 (m, 2H), 3.25 (d,J= 11.6 Hz, 2H), 2.89 (t,J=11.6 Hz, 2H), 2.68 (t,J= 12.4 Hz, 2H), 1.94 (d,J= 10.4 Hz, 2H), 1.65 (d,J=12.0 Hz, 2H), 1.50 - 1.46 (m, 12H), 1.35 - 1.34 (m, 5H), 1.28 - 1.24 (m, 2H),1.21-1.07 (m, 2H).

[0168] Intermediate 36: 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester Int-36 Similar to intermediate 32, 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridinyl)-4-piperidinyl]propyl]piperidinyl]6-fluoro-pyridinyl-3-carboxylic acid (Int-36, 902 mg, 1.86 mmol) was prepared by replacing 2-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxylic acid (Int-35) with 6-fluoro-4-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperidinyl]propyl]piperidinyl-1-carboxylic acid tert-butyl ester (Int-36, 902 mg, 1.86 mmol). MS measured (ESI) + ) [(M+H) + ]:449.3.

[0169] Intermediate-37: 3-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-5-fluoro-pyridine-2-carboxylic acid Int-37 Similar to intermediate 31, 3-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-5-fluoro-pyridine-2-carboxylic acid (Int-37, 10.9 g, 24.25 mmol) was prepared by replacing 2,6-difluoronicotinic acid with 3,5-difluoropyridine-2-carboxylic acid. MS results (ESI) + ) [(M+H) + ]: 450.4. 1 H NMR (400 MHz, CDCl3) δ =8.47 (d,J= 2.0 Hz, 1H), 7.46 (dd,J= 2.4, 9.2 Hz, 1H), 4.17 - 3.98 (m, 2H), 3.24 (d,J= 11.6 Hz, 2H), 2.86 (t,J= 10.8 Hz, 2H), 2.67 (t,J= 12.4 Hz, 2H), 1.93 (d,J= 10.4 Hz, 2H), 1.65 (d,J= 12.8 Hz, 2H), 1.58 - 1.39 (m, 13H), 1.39- 1.32 (m, 4H), 1.28 - 1.21 (m, 2H), 1.15 - 1.01 (m, 2H).

[0170] Intermediate 38: 5-Fluoro-3-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperidinyl]pyridine-2-carboxamide Int-38 Similar to intermediate 32, 4-[3-[1-(2-carbamoyl-5-fluoro-3-pyridinyl)-4-piperidinyl]propyl]piperidinyl]-6-fluoro-pyridinyl-3-carboxylic acid (Int-38, 2.0 g, 4.46 mmol) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-5-fluoro-pyridinyl-2-carboxylic acid (Int-37) with 3-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]propyl]piperidinyl-1-carboxylic acid tert-butyl ester (Int-38, 2.0 g, 4.46 mmol). MS results (ESI) + ) [(M+H) + ]: 449.2.

[0171] Intermediate 39: 4-[4-[3-(1,4-dimethyl-4-piperidinyl)propyl]-1-piperidinyl]-6-methyl-pyridine-3-carboxamide Int-39 Step (a): Preparation of 4-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid Int-39a Similar to intermediate 31, 4-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-39a, 910 mg, 1.95 mmol) was prepared by replacing 2,6-difluoronicotinic acid with 4,6-difluoropyridine-3-carboxylic acid. MS results (ESI) + )[(M+H) + ]: 468.2.

[0172] Step (b): Preparation of tert-butyl 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid Int-39 Similar to Int-32, 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridinyl)propyl]-1-piperidinyl]-6-fluoro-pyridin-3-carboxylic acid (Int-39a) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridin-3-carboxylic acid (Int-39a). + )[(M+H) + ]: 467.3.

[0173] Intermediate 40: 2-[4-[2-fluoro-3-(1-methyl-4-piperidinyl)propyl]-1-piperidinyl]-6-methylpyridine-3-carboxamide Int-40 Step (a): Preparation of tert-butyl 4-[2-[methoxy(methyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate Int-40a T3P (30.63 g, 61.65 mmol) was added dropwise to a solution of O,N-dimethylhydroxylamine HCl (4.81 g, 49.32 mmol), DIEA (25.49 mL, 143.86 mmol), and 1-BOC-4-piperidinylacetic acid (10.0 g, 41.1 mmol) in EA (100 mL) at 0 °C. After stirring at 0°C for 2 hours, the mixture was diluted with EA (120 mL), washed with water (120 mL), saturated NaHCO3 aqueous solution (150 mL), 1N HCl (150 mL), and brine (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain tert-butyl 4-[2-[methoxy(methyl)amino]-2-oxo-ethyl]piperidine-1-carboxylic acid (Int-40a, 10.0 g, 34.92 mmol). MS determination (ESI) + ) [(M-Boc+H) + ]: 187.1.

[0174] Step (b): Preparation of tert-butyl 4-[2-oxo-3-(4-pyridyl)propyl]piperidine-1-carboxylate Int-40b n-BuLi (17.93 mL, 44.84 mmol) was added dropwise to a solution of 4-methylpyridine (4.36 mL, 44.84 mmol) in THF (110 mL) at -70 °C under N2. The mixture was stirred at -70 °C for 2 hours, and then tert-butyl 4-[2-[methoxy(methyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate (Int-40a, 10.7 g, 37.36 mmol) was added to the mixture at -70 °C. After stirring at -70 °C for 2 hours, the reaction mixture was poured into a saturated aqueous solution of NH4Cl (50 mL) and extracted three times with EA (60 mL). The combined organic phases were washed with brine (40 mL). The organic layer was then separated, dried, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (SiO2, 5% EA to 30% EA in PE) to give tert-butyl 4-[2-oxo-3-(4-pyridyl)propyl]piperidine-1-carboxylate (Int-40b, 7.8 g, 24.5 mmol). 1 H NMR (400 MHz, chloroform-d) δ = 8.58 - 8.56 (m, 2H),7.14 - 7.12 (m, 2H), 4.11-4.05 (m, 2H), 3.68 (s, 2H), 2.70 (t,J= 12.8 Hz,2H), 2.42 (d,J= 6.4 Hz, 2H), 2.00 - 1.97 (m, 1H), 1.62 (d,J= 13.6 Hz, 2H), 1.44 (s, 9H), 1.10-1.05 (m, 2H).

[0175] Step (c): Preparation of tert-butyl 4-[2-hydroxy-3-(4-piperidinyl)propyl]piperidine-1-carboxylate Int-40c A solution of tert-butyl 4-[2-oxo-3-(4-pyridinyl)propyl]piperidine-1-carboxylate (Int-40b, 9.2 g, 28.89 mmol) in methanol (90 mL) was stirred at 20 °C until transparent. The H2 back pressure regulator was adjusted to 2.5 MPa, the H2 flow rate to 30 mL / min, and the fixed bed (10% Ru / SiO2, 5 g) was heated to 100 °C. The solution was then pumped into the reactor at a flow rate of 0.3 mL / min. After the reaction was complete, the reaction solution was concentrated under vacuum to obtain crude tert-butyl 4-[2-hydroxy-3-(4-piperidine)propyl]piperidine-1-carboxylate (Int-40c, 1.7 g, 5.21 mmol). MS values ​​(ESI) + ) [(M+H) + ]: 327.2.

[0176] Step (d): Preparation of benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-hydroxypropyl]piperidine-1-carboxylate Int-40d N-(benzyloxycarbonyloxy)succinimide (2661.49 mg, 10.68 mmol) was added to a solution of 4-[2-oxo-3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-40c, 1650.0 mg, 5.09 mmol) in MeCN (100 mL) and stirred at 20 °C for 12 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO2, PE, 10% to 50% EA). After concentration, 4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-hydroxy-propyl]piperidin-1-carboxylic acid benzyl ester (Int-40d, 2000.0 mg, 4.34 mmol) was obtained. MS values ​​(ESI) + ) [(M+Na) + ]: 481.2. 1 H NMR (400 MHz, chloroform-d) δ = 7.37- 7.34 (m, 5H),5.12 (s, 2H), 4.19 - 4.05 (m, 4H), 2.85 - 2.72 (m, 4H), 2.33 - 2.31 (m, 4H),2.01-1.97 (m, 2H), 1.65 - 1.61 (m, 4H), 1.46 (s, 9H), 1.15-1.08 (m, 4H).

[0177] Step (e): Preparation of benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-fluoro-propyl]piperidine-1-carboxylate Int-40e DAST (0.52 mL, 3.91 mmol) (CAS: 38078-09-0, Shanghai Haohong Pharmaceutical Co., Ltd.) was added to a solution of 4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-hydroxypropyl]piperidine-1-carboxylic acid benzyl ester (Int-40d, 1200.0 mg, 2.61 mmol) in DCM (20 mL) at -10 °C. After stirring at -10 °C for 2 hours, the mixture was poured into a saturated aqueous solution of NaHCO3 (30 mL) and extracted twice with EA (20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase rapid purification (0.1% TFA in water, MeCN (60%-70%)) to obtain benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-fluoro-propyl]piperidin-1-carboxylate (Int-40e, 700.0 mg, 1.51 mmol). MS determination (ESI) + ) [(M-Boc+H) + ]: 363.3.

[0178] Step (f): Preparation of tert-butyl 4-[2-fluoro-3-(4-piperidinyl)propyl]piperidine-1-carboxylate Int-40f Pd / C (200.0 mg) was added to a solution of 4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-fluoro-propyl]piperidin-1-carboxylic acid benzyl ester (Int-40e, 700.0 mg, 1.51 mmol) in methanol (10 mL) under N2. The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 25 °C for 3 h under an H2 balloon. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum to give 4-[2-fluoro-3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-40f, 500.0 mg, 1.52 mmol), which was used directly in the next step without further purification.

[0179] Step (g): Preparation of 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-fluoro-propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid Int-40g Similar to intermediate 31, 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-fluoro-propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-40f, 360 mg) was prepared by replacing 4-[2-fluoro-3-(4-piperidinyl)propyl]piperidine. MS measured (ESI) + )[(M+H )+]: 468.3.

[0180] Step (h): Preparation of tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]-2-fluoro-propyl]piperidine-1-carboxylate Int-40 Similar to intermediate 32, 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridinyl)-4-piperidinyl]-1-piperidinyl]-6-fluoro-pyridin-3-carboxylic acid (Int-31) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)-2-fluoro-propyl]-1-piperidinyl]-6-fluoro-pyridin-3-carboxylic acid (Int-40f). 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]-2-fluoro-propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-40, 240 mg, 0.51 mmol) was obtained. MS determination (ESI) + ) [(M+H) + ]: 467.3.

[0181] Intermediate 41: 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-4-nitrobenzoic acid Int-41 Similar to intermediate 31, 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-4-nitrobenzoic acid (Int-41, 190 mg, 0.37 mmol) was prepared by replacing 2,6-difluoronicotinic acid and 4-[3-(4-piperidinyl)propyl]piperidinyl-1-carboxylic acid with 2-fluoro-4-nitrobenzoic acid and 4,4-difluoro-3-[3-(4-piperidinyl)propyl]piperidinyl-1-carboxylic acid (Int-15). MS measured values ​​(ESI) + ) [(M+H) + ]: 512.2.

[0182] Intermediate 42: 3-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-42 Similar to intermediate 32, tert-butyl 3-[3-[1-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-31) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzoic acid (Int-41) with 2-[4-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid (Int-42, 125 mg, 0.24 mmol) MS measured (ESI) + ) [(M+H) + ]: 511.3.

[0183] Intermediate 43: 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-iodobenzoic acid Int-43 Similar to intermediate 31, 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-iodobenzoic acid (Int-43, 650 mg, 1.12 mmol) was prepared by replacing 2,6-difluoronicotinic acid with 2-fluoro-4-iodobenzoic acid. MS measured (ESI) + ) [(M+H) + ]: 557.3. 1H NMR (400 MHz, CDCl3) δ = 7.99 (d,J=8.4 Hz, 1H), 7.82 - 7.67 (m, 2H), 4.15 - 3.99 (m, 2H), 3.12 (d,J= 11.6 Hz,2H), 2.91 (t,J= 10.0 Hz, 2H), 2.69 (t,J= 12.8 Hz, 2H), 1.94 (d,J= 9.2 Hz,2H), 1.72 - 1.48 (m, 8H), 1.47 (s, 9H), 1.38 - 1.32 (m, 4H), 1.28 - 1.25 (m,2H), 1.15 - 1.03 (m, 2H).

[0184] Intermediate 44: 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-4-(difluoromethyl)-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid Int-44 Similar to intermediate 31, 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-4-(difluoromethyl)-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-44, 330 mg, 0.62 mmol) was prepared by replacing 2,6-difluoronicotinic acid and 4-[3-(4-piperidinyl)propyl]piperidinyl]-4,4-difluoropiperidin-1-carboxylic acid tert-butyl ester (Int-19). + )[(M+H) + ]: 536.4.

[0185] Intermediate 45: N-(2-chloro-4-pyridyl)-4-[4-[3-(4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridin-3-carboxamide Int-45 Similar to intermediate 32, N-(2-chloro-4-pyridinyl)-4-[4-[3-(4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridinyl-3-carboxylic acid (Int-31) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-4-(difluoromethyl)-1-piperidinyl]-6-fluoro-pyridinyl-3-carboxylic acid (Int-44). + ) [(M+H) + ]: 535.4.

[0186] Intermediate 46: 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Step (a): 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-4-nitrobenzoic acid Int-46a To a solution of 2-fluoro-4-nitrobenzoic acid (587.72 mg, 3.17 mmol) in DMSO (12 mL), DIEA (1.89 mL, 11.55 mmol) and tert-butyl 4,4-difluoro-3-[3-(4-piperidinyl)propyl]piperidin-1-carboxylate (1000.0 mg, 2.89 mmol, Int-16) were added. After stirring the reaction mixture at 110 °C for 36 hours, the mixture was concentrated. The residue was purified by reverse-phase rapid chromatography (220 g, Welch Ultimate XB_C18 rapid column 20–40 μm; 120 A, water (0.1% FA)-ACN, 80%, 80 mL / min) and then extracted three times with EA (120 mL). The combined organic phases were washed with brine (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-4-nitrobenzoic acid (620.0 mg, 1.21 mmol, Int-46a). MS measured (ESI) + ): 514.4 [(M+H) +].

[0187] Step (b): 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-46 Similar to intermediate 32, tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (Int-31) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4,4-difluoro-piperidin-1-carboxylic acid (Int-46a, 620.0 mg, 1.21 mmol) with 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (Int-46a, 620.0 mg, 1.21 mmol). MS measured (ESI) + ) [(M+H) + ]: 513.4.

[0188] Intermediate 47: 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-methyl-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-47 To a solution of tert-butyl piperidine-1-carboxylate (720.0 mg, 1.99 mmol, Int-23) in NMP (10 mL), DIEA (1026.9 mg, 7.95 mmol) and 2-fluoro-4-nitro-benzamide (438.91 mg, 2.38 mmol) were added. The reaction mixture was stirred at 110 °C for 12 h. The mixture was purified by reverse-phase rapid chromatography (120 g Welch Ultimate XB_C18 20–40 μm; 120 A, water (0.1% FA)-ACN, 80%, 80 mL / min). The fraction was adjusted to pH 9 with saturated NaHCO3 aqueous solution and concentrated under vacuum, and extracted twice with EA (60 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-methyl-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (520.0 mg, 0.99 mmol, Int-47). MS measured (ESI) + ) [(M+H) + ]: 527.3.

[0189] Intermediate 48: 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-ethyl-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-48 Similar to intermediate 47, tert-butyl 4,4-difluoro-3-[2-(4-methyl-4-piperidinyl)ethoxy]piperidin-1-carboxylate (Int-23) was prepared by replacing tert-butyl 4,4-difluoro-piperidinyl)ethoxy]-4,4-difluoro-piperidin-1-carboxylate (836.0 mg, 1.95 mmol, Int-24) with tert-butyl 4-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-ethyl-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylate (638.0 mg, 1.18 mmol, Int-48). MS measured values ​​(ESI) + [M+H] + : 541.4.

[0190] Intermediate 49: 3-[2-[1-(2-carbamoyl-3-methyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-49 Step (a): 2-Chloro-6-methyl-4-nitrobenzylnitrile Int-49a Solution 1: 2-chloro-6-methyl-4-nitroaniline (1 eq, 15 g) and CuCN, 2 eq, 14.4 g, in DMSO (300 mL). Solution 2: t-BuONO (3 eq, 24.869 g), in DMSO (150 mL). Solution 1 was pumped to flow reactor 1 (glass (GL), continuously stirred tank reactor (CSTR), 150 mL, 80 °C) and flow reactor 2 (glass (GL), continuously stirred tank reactor (CSTR), 150 mL, 80 °C) via pump 1 (solution 1, pump 1, 20 mL / min).

[0191] Solution 2 is pumped to flow reactor 1 (flow reactor 1, glass (GL), continuously stirred tank reactor (CSTR), 150 mL, 80 °C) and flow reactor 2 (flow reactor 2, glass (GL), continuously stirred tank reactor (CSTR), 150 mL, 80 °C) via pump 2 (solution 2, pump 2, 10 mL / min) (flow reactor 1, glass (GL), continuously stirred tank reactor (CSTR), 150 mL, 80 °C) ... (flow reactor 2, glass (GL), continuously stirred tank reactor (CSTR

[0192] The residence time in flow reactor 1 was 5 minutes. The residence time in flow reactor 2 was 5,000 minutes. The mixture was collected in a bottle. Pumps 1 and 2 were started simultaneously. The reaction mixture was collected after 10 minutes of operation. Samples were collected for analysis after 10 minutes. Collection of the reaction mixture was stopped after 40 minutes. TLC (PE / EA = 10 / 1, UV = 254 nm) showed that reactant 1 was completely consumed and two new spots were detected. H2O (500 mL) was added to the mixture and it was extracted three times with ethyl acetate (400 mL). The combined organic phases were washed twice with brine (300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) and concentrated under vacuum to give 2-chloro-6-methyl-4-nitrobenzyl nitrile (6.0 g, 30.52 mmol, 37.97% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.41 - 8.37 (m, 1H), 8.36 -8.31 (m, 1H), 2.65 (s, 3H).

[0193] Step (b): 3-[2-[1-(2-cyano-3-methyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-49b To a solution of tert-butyl piperidine-1-carboxylate (4.0 g, 11.48 mmol), 2-chloro-6-methyl-4-nitrobenzyl nitrile (2482.55 mg, 12.63 mmol, Int-49a) and Cs₂CO₃ (11.2 mg, 34.44 mmol) in 1,4-dioxane (60 mL) were added. The mixture was stirred at 100 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) and concentrated under vacuum to give tert-butyl 3-[2-[1-(2-cyano-3-methyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylate (2.06 mg, 4.05 mmol, Int-49b). MS determination (ESI) + ) [(M-Boc+H) + ]: 408.2.

[0194] Step (c): 3-[2-[1-(2-carbamoyl-3-methyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester Int-49 At 0 °C, tert-butyl 3-[2-[1-(2-cyano-3-methyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (2060.0 mg, 4.05 mmol, Int-49b) in DMSO (20 mL) was added with K₂CO₃ (1.68 g, 12.15 mmol) and H₂O₂ (688.6 mg, 6.08 mmol). After stirring at 25 °C for 16 hours, H₂O (50 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) and concentrated under vacuum to give tert-butyl 3-[2-[1-(2-carbamoyl-3-methyl-5-nitro-phenyl)-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (550.0 mg, 1.04 mmol, Int-49). MS determination (ESI) + ) [(M+H) + ]: 527.4.

[0195] Intermediate 50: N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide Int-50 At 0 °C, 2-amino-6-chloropyridine (8.4 g, 65.37 mmol), NMI (17.08 g, 207.98 mmol) (CAS: 616-47-7, Bide), and TCFH (20.01 g, 71.31 mmol) (CAS: 94790-35-9, Bide) were added to a solution of 2-fluoro-4-nitrobenzoic acid (11.0 g, 59.42 mmol) in MeCN (100 mL). The mixture was heated to 45 °C and stirred at 45 °C for 2 hours. The residue was diluted with H2O (50 mL) and a large amount of purple solid precipitated. The suspension was filtered. The filter cake was dried under vacuum to give N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-50, 17.0 g, 57.5 mmol).

[0196] MS measured value (ESI) + )[(M+H) + ]: 296.0. 1H NMR (400 MHz, CDCl3) δ = 8.98 (d,J=10.8 Hz, 1H), 8.36 - 8.28 (m, 2H), 8.20 (dd,J= 8.8 Hz,J= 2.0 Hz, 1H), 8.12(dd,J= 11.2 Hz,J= 2.0 Hz, 1H), 7.76 (t,J= 8.0 Hz, 1H), 7.18 (d,J= 8.0 Hz,1H).

[0197] Intermediate 51: N-(6-bromo-5-methoxy-2-pyridyl)-2-fluoro-4-nitro-benzamide Int-51 Similar to intermediate 50, N-(6-bromo-5-methoxy-2-pyridyl)-2-fluoro-4-nitrobenzamide (Int-51, 700 mg, 1.89 mmol) was prepared by replacing 2-amino-6-chloropyridine with 6-bromo-5-methoxy-pyridin-2-amine. MS measured (ESI) + )[(M+H) + ]: 370.0.

[0198] Intermediate 52: N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro-benzamide Int-52 Step (a): Preparation of 2,6-difluoro-4-nitrobenzoic acid Int-52a LDA (18.86 mL, 37.71 mmol) was added dropwise to a solution of 3,5-difluoronitrobenzene (5.0 g, 31.43 mmol) in THF (50 mL) at -78 °C. The mixture was stirred at -78 °C under N2 for 0.5 h. Carbon dioxide (4.15 g, 94.29 mmol) (dry ice) was added in portions to the mixture under N2. After stirring at -78 °C for 0.5 h, the mixture was quenched with NH4Cl (200 mL) and extracted several times with EA (100 mL). The aqueous layer was acidified to pH 1-2 with HCl (1 M) and extracted three times with EA (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain 2,6-difluoro-4-nitrobenzoic acid (Int-52a, 2270.0 mg, 11.18 mmol).

[0199] Step (b): Preparation of 2,6-difluoro-4-nitro-benzoyl chloride Int-52b At 0 °C, (COCl)₂ (2837.33 mg, 22.35 mmol) and 2,6-difluoro-4-nitro-benzoic acid (2270.0 mg, 11.18 mmol) were added to a solution of 2,6-difluoro-4-nitro-benzoic acid (2270.0 mg, 11.18 mmol) in DCM (30 mL). The mixture was warmed to 25 °C and stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum to give 2,6-difluoro-4-nitro-benzoyl chloride (Int-52b, 2470.0 mg, 11.15 mmol), which was used directly in the next step without further purification.

[0200] Step (c): Preparation of 2,6-difluoro-4-nitro-benzamide Int-52c 2,6-Difluoro-4-nitrobenzoyl chloride (2470.0 mg, 11.15 mmol) was added in portions to NH3H2O ​​(30.0 mL, 11.15 mmol) at 0 °C. The mixture was heated to 25 °C and stirred at 25 °C for 1 hour. The mixture was diluted with H2O (50 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The crude product was purified by column chromatography (SiO2, 35% EA in PE), followed by reverse rapid chromatography (Welch Ultimate XB_C18 20–40 μm; 120 A, water (0.1% FA)-ACN, 27%, 100 mL / min). 2,6-Difluoro-4-nitrobenzamide (Int-52c, 1300.0 mg, 6.43 mmol) was obtained. MS determination (ESI) + ) [(M+H) + ]: 203.0.

[0201] Step (d): Preparation of N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro-benzamide Int-52 Cs₂CO₃ (2411.93 mg, 7.42 mmol), Pd₂(dba)₃ (169.9 mg, 0.19 mmol) (CAS: 51364-51-3, Bide), and xantphos (214.71 mg, 0.37 mmol) (CAS: 1621274-19-8, Sinocompound) were added to a solution of 2,6-dichloropyridine (823.71 mg, 5.57 mmol) and 2,6-difluoro-4-nitro-benzamide (Int-52c, 750.0 mg, 3.71 mmol) in 1,4-dioxane (20 mL) at 25 °C under N₂. The suspension was heated to 100 °C and stirred at 100 °C under N₂ for 12 hours. The suspension was filtered, and the filtrate was concentrated under vacuum. The residue is passed through a reverse fast (Welch Ultimate XB_C) 18Purification was performed at 20–40 μm; 120 A, water (0.1% FA)-ACN, 55%, 100 mL / min. N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro-benzamide (Int-52, 557.0 mg, 1.78 mmol) was obtained. MS determination (ESI) + ) [(M+H) + ]: 314.2.

[0202] Intermediate 53: N-(2-chloropyrimidin-4-yl)-2-fluoro-4-nitro-benzamide Int-53 Step (a): Preparation of 2-fluoro-4-nitro-benzamide Int-53a At 0 °C, (COCl)₂ (13.71 g, 108.04 mmol) and DMF (394.9 mg, 5.4 mmol) were added to a solution of 2-fluoro-4-nitrobenzoic acid (10.0 g, 54.02 mmol) in DCM (100 mL). The reaction mixture was stirred at 20 °C for 2 h. The mixture was then concentrated under vacuum. NH₃·H₂O (50.0 mL, 54.02 mmol) was added dropwise to the residue at 0 °C. After stirring at 20 °C for 1 h, the mixture was filtered and washed with EA (10 mL). The residue was dried under vacuum to give 2-fluoro-4-nitrobenzoamide (Int-53a, 4.20 g, 22.81 mmol). MS values ​​(ESI) were obtained. + )[(M+H) + ]: 185.1.

[0203] Step (b): Preparation of N-(2-chloropyrimidin-4-yl)-2-fluoro-4-nitro-benzamide Int-53 Similar to intermediate 52, N-(2-chloropyrimidin-4-yl)-2-fluoro-4-nitro-benzamide (Int-53, 1.20 g, 4.05 mmol) was prepared by replacing 2,6-dichloropyridine and 2,6-difluoro-4-nitro-benzamide (Int-52c) with 2,4-dichloropyrimidine and 2-fluoro-4-nitro-benzamide (Int-53a). MS results (ESI) + )[(M+H)+ ]:297.0.

[0204] Preparation of Intermediate 54: N-(6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide Int-54 Similar to intermediate 50, N-(6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-54, 4.4 g, 14.83 mmol) was prepared by replacing 2-amino-6-chloropyridine with 2-amino-6-chloropyrazine. MS results (ESI) + ) [(M+H) + ]: 297.2.

[0205] Preparation of Intermediate 55: N-(2-chloro-4-pyridyl)-2-fluoro-4-nitro-benzamide Int-55 Similar to intermediate 50, N-(2-chloro-4-pyridyl)-2-fluoro-4-nitro-benzamide (Int-55, 7.84 g, 26.52 mmol) was prepared by replacing 2-amino-6-chloropyridine with 4-amino-2-chloropyridine. MS results (ESI) + ) [(M+H) + ]: 295.9.

[0206] Preparation of Intermediate 56: N-(3-chlorophenyl)-2-fluoro-4-nitro-benzamide Int-56 Similar to intermediate 50, N-(3-bromophenyl)-2-fluoro-4-nitro-benzamide (Int-56, 3.37 g, 9.95 mmol) was prepared by replacing 2-amino-6-chloropyridine with 3-bromoaniline. MS results (ESI) + ) [(M+H) + ]:340.1.

[0207] Intermediate 57: 2-chloro-6-[1-(2-fluoro-4-nitro-phenyl)triazol-4-yl]pyridine Int-57 Step (a): Preparation of 1-azido-2-fluoro-4-nitro-benzene Int-57a At 0 °C, azidotrimethylsilane (3.5 mL, 26.4 mmol) was added to a solution of 3,4-difluoronitrobenzene (4200.0 mg, 26.4 mmol) and potassium carbonate (7297.32 mg, 52.8 mmol) in DMF (50 mL). After stirring at 0 °C for 1 hour, the mixture was filtered and concentrated under vacuum to obtain 1-azido-2-fluoro-4-nitrobenzene (Int-57a, 4.80 g, 26.36 mmol) in DMF, which was used directly in the next step without further purification.

[0208] Step (b): Preparation of 2-chloro-6-[1-(2-fluoro-4-nitro-phenyl)triazol-4-yl]pyridine Int-57 2-Chloro-6-ethynylpyridine (3407.73 mg, 24.77 mmol) was added to a solution of L-ascorbic acid sodium (12401.36 mg, 62.6 mmol), 1-azido-2-fluoro-4-nitro-benzene (4511.02 mg, 24.77 mmol), and copper sulfate pentahydrate (1563.02 mg, 6.26 mmol) in DMF (60 mL). After stirring at 20 °C for 3 hours, the mixture was poured into water (400 mL), resulting in a large precipitate, which was collected by filtration. The filter cake was dried under vacuum to give 2-chloro-6-[1-(2-fluoro-4-nitro-phenyl)triazol-4-yl]pyridine (6200.0 mg, 19.39 mmol). MS values ​​(ESI) were obtained. + ) [(M+Na) + ]: 341.9. 1 H NMR (400 MHz, CDCl3) δ = 8.85 (d,J=3.2 Hz, 1H), 8.39 (t,J= 9.2 Hz, 1H), 8.29-8.27 (m, 2H), 8.19 (d,J= 7.6 Hz, 1H), 7.81 (t,J= 8.0 Hz, 1 H), 7.34 (d,J= 7.6 Hz, 1H).

[0209] Intermediate 58: N(6-bromo-5-fluoro-2-pyridyl)-2-fluoro-4-nitro-benzamide Int-58 Similar to intermediate 50, N-(6-bromo-5-fluoro-2-pyridyl)-2-fluoro-4-nitrobenzamide (Int-58, 2.0 g, 5.59 mmol) was prepared by replacing 2-amino-6-chloropyridine with 6-bromo-5-fluoro-pyridin-2-amine. MS results (ESI) + ) [(M+H) + ]: 359.9.

[0210] Preparation of Intermediate 59: 4-Bromo-2-fluoro-N-(3-aminosulfonylphenyl)benzamide Int-59 4-Bromo-2-fluorobenzoic acid (3.05 g, 13.94 mmol) and EDCI·HCl (3.34 g, 17.42 mmol) were added to a solution of 3-aminobenzenesulfonamide (2000 mg, 11.61 mmol) in pyridine (25 mL) at room temperature. After stirring at 35 °C for 12 hours, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography to give 4-bromo-2-fluoro-N-(3-aminosulfonylphenyl)benzamide (Int-59, 4.3 g). MS values ​​(ESI) + ) [(M+H) + ]: 188.0.

[0211] Intermediate 70: 4-Allyl-4-fluoro-piperidine Int-70 Step (a): Preparation of tert-butyl 4-allyl-4-fluoro-piperidine-1-carboxylate Int-70a DAST (9.85 mL, 74.59 mmol) was added dropwise to a solution of tert-butyl 4-allyl-4-hydroxy-piperidin-1-carboxylate (15.0 g, 62.16 mmol) in DCM (200 mL) at -60 °C under N2. The mixture was stirred at -60 °C for 2 h, then transferred to dry ice and warmed to 20 °C, and stirred at 20 °C under N2 for 10 h. The mixture was poured into a saturated aqueous solution of NaHCO3 (300 mL) and extracted twice with DCM (200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to give tert-butyl 4-allyl-4-fluoro-piperidin-1-carboxylate (Int-70a, 4.5 g, 18.49 mmol). MS results (ESI) + )[(M-F+H) + ]: 168.0.

[0212] Step (b): Preparation of 4-allyl-4-fluoropiperidine Int-70 A solution of tert-butyl 4-allyl-4-fluoropiperidine-1-carboxylate (1.0 g, 4.11 mmol) in DCM (3 mL) and TFA (1.0 mL, 4.11 mmol) was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum to give 4-allyl-4-fluoropiperidine (Int-70, 1.00 g, 3.89 mmol). 1 H NMR (400 MHz, CDCl3) δ =5.88 - 5.72 (m, 1H), 5.30 - 5.12 (m, 2H), 3.52 - 3.43 (m, 2H), 3.37 - 3.24(m, 2H), 2.53 - 2.40 (m, 2H), 2.16 - 1.80 (m, 4H).

[0213] Intermediate 71: 4-Fluoro-4-vinyl-piperidine Int-71 Step (a): Preparation of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate Int-71a DMSO (11.05 g, 141.46 mmol) was added dropwise to a solution of (COCl)₂ (8.98 g, 70.73 mmol) in DCM (200 mL) at -78 °C. The mixture was stirred at -78 °C for 0.5 h. Then, tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (15.0 g, 64.3 mmol) in DCM (50 mL) was added dropwise to the mixture at -78 °C. The mixture was stirred at -78 °C for 1 h. Then, TEA (32.55 g, 321.5 mmol) was added to the mixture at -78 °C. After stirring at 20 °C for 1 h, the mixture was quenched with H₂O (100 mL) and extracted twice with DCM (200 mL). The organic layer was washed twice with brine (100 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum to obtain tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (Int-70a, 15.0 g, 64.3 mmol). 1 H NMR (400 MHz, CDCl3) δ = 9.72 (d,J= 4.8 Hz, 1H), 4.14 - 3.88 (m,2H), 3.21 - 2.90 (m, 2H), 1.91 - 1.70 (m, 4H), 1.45 (s, 9H).

[0214] Step (b): Preparation of tert-butyl 4-fluoro-4-vinyl-piperidine-1-carboxylate Int-71b DBU (19.09 g, 125.39 mmol) and methyltriphenylphosphine bromide (44.79 g, 125.39 mmol) were added to a solution of tert-butyl 4-fluoro-4-vinyl-piperidin-1-carboxylate (Int-70a, 14.5 g, 62.7 mmol) in MeCN (200 mL) at 20 °C. The reaction mixture was stirred at 80 °C for 12 h under N2. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 10% EA in PE) and concentrated under vacuum to give tert-butyl 4-fluoro-4-vinyl-piperidin-1-carboxylate (Int-70b, 5.0 g, 21.81 mmol). 1H NMR (400MHz, CDCl3) δ = 5.96 - 5.85 (m, 1H), 5.37 - 5.26 (m, 1H), 5.17 (dd,J= 12.8Hz,J= 0.8 Hz, 1H), 4.06 - 3.87 (m, 2H), 3.20 - 3.03 (m, 2H), 1.85 - 1.75 (m, 2H), 1.70 - 1.55 (m, 2H), 1.47 (s, 9H). 19 F NMR (376 MHz, CDCl3) δ = -161.29.

[0215] Step (c): Preparation of 4-fluoro-4-vinyl-piperidine Int-71 A solution of tert-butyl 4-fluoro-4-vinylpiperidine-1-carboxylate (Int-71b, 1.0 g, 4.36 mmol) in DCM (5 mL) and TFA (2.0 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum to give 4-fluoro-4-vinylpiperidine (Int-71, 800.0 mg, 3.29 mmol). 1 H NMR (400 MHz, CDCl3) δ =6.02 - 5.87 (m, 1H), 5.45 - 5.35 (m, 1H), 5.34 - 5.26 (m, 1H), 3.54 - 3.42(m, 2H), 3.37 - 3.27 (m, 2H), 2.17 - 2.01 (m, 4H).

[0216] Intermediate 72: 4-Vinylpiperidine Int-72 A solution of 1-BOC-4-vinylpiperidine (2.00 g, 9.47 mmol) in TFA (3.0 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum to give 4-vinylpiperidine (Int-72, 2.10 g, 9.32 mmol). MS determination (ESI) + ) [(M+H) + ]: 112.1.

[0217] Intermediate 73: tert-butyl 4-allyl-3,3-difluoropyrrolidine-1-carboxylate Int-73 Step (a): Preparation of tert-butyl 4-allyl-3,3-difluoro-pyrrolidine-1-carboxylate Int-73a DAST (7.36 g, 33.29 mmol) was added dropwise to a solution of tert-butyl 3-allyl-4-oxo-pyrrolidine-1-carboxylate (2.50 g, 11.1 mmol) in DCM (50 mL) at 20 °C. After stirring at 20 °C for 12 hours, the mixture was poured into a saturated aqueous solution of NaHCO3 (100 mL) and extracted with DCM (100 mL). The organic layer was washed twice with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (5% to 20% EA in PE) to give tert-butyl 4-allyl-3,3-difluoro-pyrrolidine-1-carboxylate (Int-73a, 1600.0 mg, 6.47 mmol). MS results (ESI) + ) [(M-Bu+H) + ]: 192.1. 1 H NMR (400MHz, DMSO-d6) δ = 5.86 - 5.74 (m, 1H), 5.17 - 5.09 (m, 1H), 5.07 - 5.01 (m,1H), 4.12 - 3.86 (m, 1H), 3.69 - 3.58 (m, 2H), 3.09 - 2.98 (m, 1H), 2.78 -2.62 (m, 1H), 2.38 - 2.29 (m, 1H), 2.18 - 2.08 (m, 1H), 1.39 (s, 9H).

[0218] Step (b): Preparation of 4-allyl-3,3-difluoropyrrolidine Int-73 A solution of tert-butyl 4-allyl-3,3-difluoropyrrolidine-1-carboxylate (Int-73a, 1.60 g, 6.47 mmol) in TFA (4.0 mL) and DCM (10 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum to give 4-allyl-3,3-difluoropyrrolidine (1.30 g, 4.98 mmol). MS values ​​(ESI) + ) [(M+H) + ]: 148.0.

[0219] Example 1 2-Hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 1.1) EDCI (767.55 mg, 4.0 mmol) was added to a solution of 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-31, 1.20 g, 2.67 mmol) and 2-amino-6-chloropyridine (411.79 mg, 3.2 mmol) in pyridine (12 mL). After stirring at 35 °C for 16 hours, the reaction mixture was concentrated. The residue was purified by rapid column chromatography (20% EA in isohexane) to give tert-butyl piperidine-1-carboxylic acid (compound 1.1, 800.0 mg, 1.43 mmol). MS measured value (ESI) + ) [(M+H) + ]: 560.3.

[0220] Step (b): Preparation of N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 1.2) TFA (0.74 mL, 9.65 mmol) was added to a solution of 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 1.1, 800.0 mg, 1.43 mmol) in DCM (6 mL). After stirring at 20 °C for 1 hour, the reaction mixture was concentrated under vacuum to give N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2, 800 mg, 1.39 mmol). MS values ​​(ESI) + ) [(M+H) + ]: 460.4.

[0221] Step (c): 12-Fluoro-1,7,13,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 1.3) PEPPSI-Pd (40.0 mg) (CAS: 1612891-29-8, WuXi) was added to a mixture of N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2, 200.0 mg, 0.35 mmol) and t-BuONa (100.35 mg, 1.05 mmol) in 1,4-dioxane (40 mL) under N2. The mixture was evacuated and backfilled three times with N2. After stirring at 80 °C under N2 for 12 hours, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (30% EA in PE) to give 12-fluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 1.3, 35.0 mg, 0.08 mmol). MS determination (ESI)] + ) [(M+H) + ]: 424.3.

[0222] Step (d): Preparation of 2-hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexene-12-yl) ethanesulfonamide (Example 1) To 12-fluoro-1,7,13,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 2-hydroxyethanesulfonamide (12.41 mg, 0.1 mmol) was added to a mixture of 2-hexene-8-one (compound 1.2, 35.0 mg, 0.05 mmol) and cesium carbonate (0.04 mL, 0.1 mmol) in DMSO (0.5 mL). After stirring at 100 °C for 0.5 hours, the reaction mixture was placed in EA (50 mL) and the organic phase was washed twice with water (50 mL) and then with saturated brine (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was then purified by preparative TLC (8% MeOH in DCM) to give 2-hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexaden-12-yl) ethanesulfonamide (Example 1, 14.43 mg, 0.03 mmol). MS determination (ESI) + ) [(M+H) + ]:529.3. 1 H NMR (400 MHz, chloroform-d) δ = 9.46 (br. s, 1H), 8.14 (d,J= 8.0 Hz, 1H), 7.59 (d,J= 8.0 Hz, 1H), 7.49 (t,J= 8.0 Hz, 1H), 6.67 (d,J= 8.0 Hz, 1H), 6.45(d,J= 8.0 Hz, 1H), 4.21 - 4.07 (m, 4H), 3.77 - 3.60 (m, 4H), 3.22 - 3.04 (m,2H), 2.91 - 2.78 (m, 2H), 1.92 - 1.62 (m, 11H), 1.36 - 1.25 (m, 5H).

[0223] Example 2 2-Hydroxy-N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 2.1) To a solution of 2,4-dichloropyrimidine (348.73 mg, 2.34 mmol) and 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-32, 700.0 mg, 1.56 mmol) in 1,4-dioxane (10 mL), Cs₂CO₃ (0.46 mL, 3.12 mmol), Pd₂(dba)₃ (142.9 mg, 0.16 mmol), and Xantphos (180.59 mg, 0.31 mmol) were added. The mixture was evacuated and backfilled three times with N₂. After stirring at 80 °C under N₂ for 12 hours, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was passed through rapid silica gel chromatography (ISCO; 40 g SepaFlash silica rapid column, gradient: 40% to 70% EA in PE eluent, 80 mL / min) to give 4-[3-[1-[3-[(2-chloropyrimidin-4-yl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 2.1, 460.0 mg, 0.82 mmol). MS determination (ESI) + )[(M+Na) + ]: 583.2.

[0224] Step (b): Preparation of N-(2-chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 2.2) Similar to Example 1, N-(2-chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 2.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridinyl)carbamoyl]-6-fluoro-2-pyridinyl]-4-piperidinyl]propyl]piperidinyl-1-carboxamide (Compound 2.1) with 4-[3-[1-[3-[(2-chloropyrimidin-4-yl)carbamoyl]-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 2.2) in step (b). N-(2-chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 2.2, 430.0 mg, 0.93 mmol).

[0225] MS measured value (ESI) + ) [(M+H) + ]: 461.2.

[0226] Step (c): 12-Fluoro-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 2,4,6(29),9,11,13-hexane-8-one (compound 2.3) Similar to Example 1, 12-fluoro-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 1.2) with N-(2-chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 2.2, 430.0 mg, 0.93 mmol) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2,4,6(29),9,11,13-hexane-8-one (compound 2.3). 12-Fluoro-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 [29-C-2,4,6(29),9,11,13-hexen-8-one (compound 2.3, 101.0 mg, 0.24 mmol). MS determination (ESI)] +) [(M+H) + ]: 425.2. 1 H NMR (400 MHz, CDCl3) δ = 9.77 (br. s, 1H),8.35 - 8.15 (m, 2H), 7.41 (d,J= 5.6 Hz, 1H), 6.61 (dd,J= 3.6, 8.4 Hz, 1H),4.63 - 4.47 (m, 2H), 3.70 - 3.51 (m, 2H), 3.22 - 3.09 (m, 2H), 2.85 (t,J=12.4 Hz, 2H), 1.89 - 1.74 (m, 5H), 1.68 - 1.58 (m, 7H), 1.40 - 1.32 (m, 2H),1.27 - 1.21 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ = -63.214.

[0227] Step (d): 2-Hydroxy-N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 2,4,6(29),9,11,13-hexene-12-yl)ethanesulfonamide (Example 2) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (c) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 1.3) is replaced with 12-fluoro-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [Compound 2.3] 2-hydroxy-N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-C-2,4,6(29),9,11,13-hexaden-12-yl)ethanesulfonamide (Example 2). 2-Hydroxy-N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]15,18 .1 2,6 .0 9,14 [29-(29),9,11,13-hexene-12-yl)ethanesulfonamide (Example 2, 11.18 mg, 0.02 mmol). MS measured (ESI)] + ) [(M+H) + ]: 530.2. 1 H NMR (400 MHz, CDCl3) δ = 9.82 (br. s, 1H), 8.28 (d,J= 5.6 Hz, 1H), 8.15 (d,J= 8.4 Hz, 1H), 7.42 (d,J= 5.6 Hz, 1H), 6.73 (d,J= 8.0Hz, 1H), 4.62 - 4.46 (m, 2H), 4.25 - 4.10 (m, 2H), 3.76 - 3.67 (m, 2H), 3.65- 3.48 (m, 2H), 3.21 - 3.07 (m, 2H), 2.81 (t,J= 12.8 Hz, 2H), 1.92 - 1.63 (m,12H), 1.40 - 1.31 (m, 2H), 1.29 - 1.17 (m, 2H).

[0228] Example 3 N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] Similar to Example 2, N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) was prepared by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 3). N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14[29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 3, 14.43 mg, 0.03 mmol). MS measured (ESI)] + ) [(M+H) + ]: 514.4. 1 H NMR (400 MHz, CDCl3) δ= 9.85 (br. s, 1H), 8.27 (d,J= 5.6 Hz, 1H), 8.15 (d,J= 8.4 Hz, 1H), 7.42 (s,1H), 6.99 (br. s, 1H), 6.77 (d,J= 8.0 Hz, 1H), 4.66 - 4.50 (m, 2H), 3.71 -3.50 (m, 2H), 3.47 (q,J= 7.6 Hz, 2H), 3.23 - 3.09 (m, 2H), 2.87 - 2.74 (m,2H), 1.99 - 1.69 (m, 6H), 1.69 - 1.60 (m, 6H), 1.45 (t, J = 7.2 Hz, 3H), 1.40- 1.32 (m, 2H), 1.27 - 1.19 (m, 2H).

[0229] Example 4 N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 4.1) Similar to Example 1, in step (a) 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridine-3-carboxylic acid (Int-31) is replaced with (2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-iodobenzoic acid (Int-43)). To prepare tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-iodo-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylate (compound 4.1). 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-iodo-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylate (compound 4.1, 2200.0 mg, 3.3 mmol). MS determination (ESI) + ) [(M+H) + ]: 667.2.

[0230] Step (b): Preparation of tert-butyl piperidine-1-carboxylate (compound 4.2) A solution of 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-iodo-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 4.1, 700.0 mg, 1.05 mmol), ethanesulfonamide (343.64 mg, 3.15 mmol), K3PO4 (435.12 mg, 3.15 mmol), and CuI (199.87 mg, 1.05 mmol) in N1,N2-dimethylcyclohexane-1,2-diamine (29.86 mg, 0.21 mmol) / DMF (7 mL). The mixture was evacuated and backfilled with nitrogen three times. The reaction vessel was sealed and heated in a microwave at 130 °C for 5 hours. The mixture was poured into water (50 mL) and then extracted three times with EA (50 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was passed through rapid silica gel chromatography (ISCO; 40 g SepaFlash silica rapid column, gradient: 30% to 70% EA eluent in PE, 100 mL / min) to give 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-(2-hydroxyethylsulfonylamino)phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 4.2, 513.0 mg, 0.77 mmol). MS determination (ESI) + ) [(M+H) + ]: 648.4.

[0231] Step (c): Preparation of N-(6-chloro-2-pyridinyl)-4-(ethylsulfonylamino)-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 4.3) Similar to Example 1, N-(6-chloro-2-pyridyl)-4-(ethylsulfonylamino)-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (Compound 4.3) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidinyl]benzamide (Compound 4.2) with 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-5-(ethylsulfonylamino)phenyl]-4-piperidinyl]propyl]piperidinyl]benzamide (Compound 4.2). N-(6-chloro-2-pyridinyl)-4-(ethylsulfonylamino)-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 4.3, 490.0 mg, 0.89 mmol). MS determination (ESI) + ) [(M+H) + ]: 548.2.

[0232] Step (d): N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 4) Similar to Example 1, N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridinyl)-4-(ethylsulfonylamino)-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 4.3) in step (c). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 4). N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 4, 62.34 mg, 0.12 mmol). MS measured (ESI)] + ) [(M+H) + ]: 512.3. 1H NMR (400 MHz, DMSO-d6) δ = 10.87 (br. s, 1H), 10.19 (br. s, 1H), 7.82 (d,J= 8.0 Hz, 1H), 7.54 (s, 2H), 7.11 (s, 1H), 7.02(dd,J= 1.6, 8.8 Hz, 1H), 6.61 (s, 1H), 4.20 - 4.05 (m, 2H), 3.24 - 3.08 (m,6H), 2.70 - 2.60 (m, 2H), 1.95 - 1.46 (m, 12H), 1.37 - 1.16 (m, 7H).

[0233] Example 5 2-Hydroxy-N-(8-oxo-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 5.1) Similar to Example 2, 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 5.1) was prepared by replacing 2,4-dichloropyrimidine with 2,6-dichloropyrazine in step (a). 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 5.1, 240.0 mg, 0.43 mmol) was obtained. MS results (ESI) + ) [(M+Na) + ]: 583.2.

[0234] Step (b): Preparation of N-(6-chloropyrazin-2-yl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 5.2) Similar to Example 1, N-(6-chloropyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 5.2) was prepared by replacing 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6-fluoro-2-pyridinyl]-4-piperidinyl]propyl]piperidinyl-1-carboxamide (Compound 5.1) with 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 5.2) in step (b). N-(6-chloropyrazin-2-yl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide was obtained (compound 5.2, 420.0 mg, 0.91 mmol). MS determination (ESI) + ) [(M+H) + ]:461.2.

[0235] Step (c): 12-Fluoro-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 5.3) Similar to Example 1, 12-fluoro-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 1.2) with N-(6-chloropyrazin-2-yl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 5.2, 430.0 mg, 0.93 mmol) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2,4,6(29),9,11,13-hexaden-8-one (compound 5.3). 12-Fluoro-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 5.3, 75.0 mg, 0.18 mmol). MS determination (ESI)] + ) [(M+H) + ]: 425.2.

[0236] Step (d): 2-Hydroxy-N-(8-oxo-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexen-12-yl)ethanesulfonamide (Example 5) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (c) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 1.3) is replaced with 12-fluoro-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 To prepare 2-hydroxy-N-(8-oxo-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2] from 29-carbon-2,4,6(29),9,11,13-hexaen-8-one (compound 5.3). 15,18 .1 2,6 .0 9,14 2-hydroxy-N-(8-oxo-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.215,18.12,6.09,14]hexadecano-2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide was obtained (Example 5, 17.34 mg, 0.03 mmol). MS determination (ESI) + ) [(M+H) + ]: 530.3. 1H NMR (400 MHz, DMSO-d6) δ = 10.69 (br. s, 1H), 10.36 (br. s, 1H), 8.69 (s, 1H), 8.11 (s, 1H), 7.75 (d,J= 8.4 Hz, 1H), 6.36(d,J= 8.4 Hz, 1H), 4.92 (br. s, 1H), 4.23 - 4.11 (m, 2H), 3.82 - 3.75 (m,2H), 3.75 - 3.64 (m, 4H), 3.15 - 3.01 (m, 2H), 2.90 - 2.74 (m, 2H), 1.94 -1.82 (m, 1H), 1.69 - 1.43 (m, 11H), 1.26 - 1.16 (m, 4H).

[0237] Example 6 N-(8-oxo-1,4,7,13,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] Similar to Example 5, N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) was prepared by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 6). N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 6, 11.59 mg, 0.02 mmol). MS measured (ESI)] + ) [(M+H) + ]: 514.2. 1H NMR (400 MHz, CDCl3) δ= 9.73 (br. s, 1H), 8.85 (s, 1H), 8.18 (d,J= 8.4 Hz, 1H), 7.96 (s, 1H), 6.99(br. s, 1H), 6.76 (d,J= 8.0 Hz, 1H), 4.24 - 4.09 (m, 2H), 3.65 - 3.54 (m,2H), 3.47 (q,J= 7.6 Hz, 2H), 3.24 - 3.12 (m, 2H), 2.88 - 2.73 (m, 2H), 1.95 -1.59 (m, 12H), 1.45 (t,J= 7.6 Hz, 3H), 1.36 - 1.31 (m, 2H), 1.28 - 1.26 (m, 2H).

[0238] Example 7 2-Hydroxy-N-(8-oxo-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 7.1) Similar to Example 2, 4-[3-[1-[5-[(2-chloropyrimidin-4-yl)carbamoyl]-2-fluoro-4-pyridinyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Compound 7.1) was prepared by replacing 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridinyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-36) with 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridinyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-36). 4-[3-[1-[5-[(2-chloropyrimidin-4-yl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 7.1, 1.0 g, 1.78 mmol). MS determination (ESI) +) [(M+H) + ]:561.5. 1 H NMR (400 MHz, CDCl3) δ = 11.27 (br. s, 1H), 8.80 (s, 1H), 8.55 (d,J=5.6 Hz, 1H), 8.24 (d,J= 5.6 Hz, 1H), 6.67 (s, 1H), 4.12 - 4.01 (m, 2H), 3.34(d,J= 12.0 Hz, 2H), 2.95 - 2.82 (m, 2H), 2.67 (t,J= 12.0 Hz, 2H), 1.86 (d,J=12.4 Hz, 2H), 1.74 - 1.59 (m, 5H), 1.45 (s, 10H), 1.42 - 1.28 (m, 6H), 1.16 -1.00 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ = -60.734.

[0239] Step (b): Preparation of N-(2-chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 7.2) Similar to Example 1, N-(2-chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 7.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridinyl)carbamoyl]-6-fluoro-2-pyridinyl]-4-piperidinyl]propyl]piperidinyl-1-carboxamide (Compound 7.1) with 4-[3-[1-[5-[(2-chloropyrimidin-4-yl)carbamoyl]-2-fluoro-4-pyridinyl]-4-piperidinyl]propyl]piperidinyl-3-carboxamide (Compound 7.2). N-(2-chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 7.2, 800.0 mg, 1.74 mmol). MS determination (ESI) + ) [(M+H) + ]:461.3.

[0240] Step (c): 12-Fluoro-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 7.3) Similar to Example 1, 12-fluoro-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 1.2) with N-(2-chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 7.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 7.3). 12-Fluoro-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 7.3, 190.0 mg, 0.45 mmol). MS determination (ESI)] + ) [(M+H) + ]: 425.3. 1 H NMR (400 MHz, CDCl3)δ =9.48 (br. s, 1H), 8.58 (s, 1H), 8.29 (d,J= 6.0 Hz, 1H), 7.47 (d,J= 5.6 Hz, 1H), 6.52 (s, 1H), 4.63 - 4.46 (m, 2H),3.41 (d,J= 11.2 Hz, 2H), 3.25 - 3.09 (m, 2H), 2.85 - 2.72 (m, 2H), 1.95 -1.74 (m, 6H), 1.71 - 1.66 (m, 2H), 1.59 - 1.46 (m, 4H), 1.39 - 1.30 (m, 2H),1.25 - 1.18 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ = -62.278.

[0241] Step (d): 2-Hydroxy-N-(8-oxo-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .09,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 7) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 1.3) is replaced with 12-fluoro-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 To prepare 2-hydroxy-N-(8-oxo-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2] from 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 7.3). 15,18 .1 2,6 .0 9,14 2-Hydroxy-N-(8-oxo-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.215,18.12,6.09,14]hexadecano-2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide was obtained (Example 7, 25.31 mg, 0.05 mmol). MS determination (ESI) + ) [(M+H) + ]: 530.2.

[0242] 1 H NMR (400 MHz, CDCl3) δ = 9.10 (br. s, 1H), 8.29 (d,J= 5.6 Hz, 1H), 8.26 (s, 1H), 7.36 (d,J= 5.6 Hz, 1H), 6.73 (s, 1H), 4.62 - 4.45 (m, 2H), 4.18- 4.05 (m, 2H), 3.45 (d,J= 10.4 Hz, 2H), 3.37 - 3.31 (m, 2H), 3.23 - 3.09 (m,2H), 2.89 - 2.67 (m, 2H), 1.96 - 1.60 (m, 12H), 1.40 - 1.30 (m, 2H), 1.24 -1.14 (m, 2H).

[0243] Example 8 N-(8-oxo-1,3,7,11,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] Similar to Example 7, N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) was prepared by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 8). N-(8-oxo-1,3,7,13,15,29-hexaazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 8, 22.53 mg, 0.04 mmol). MS determination (ESI)] + ) [(M+H) + ]: 514.3. 1 H NMR (400 MHz, CDCl3): δ9.53 (br. s, 1H), 8.46 - 8.26 (m, 2H), 7.50 (d,J= 6.0 Hz, 1H), 6.80 (s, 1H), 4.57 - 4.45 (m, 2H), 3.48 - 3.36 (m, 2H), 3.28 - 3.16 (m, 4H), 3.83 - 3.74(m, 2H), 1.91 - 1.85 (m, 2H), 1.81 - 1.55 (m, 10H), 1.41 (t,J= 7.2 Hz, 3H),1.35 - 1.16 (m, 4H).

[0244] Example 9 2-Hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29,3,5,9,14,10,12-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 9.1) Similar to Example 1, 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid (compound 9.1) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridin-3-carboxylic acid (Int-35) with 4-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-6-fluoro-pyridin-3-carboxylic acid (Int-35). 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 9.1, 750.0 mg, 1.34 mmol). MS determination (ESI) + ) [(M+H) + ]: 560.3.

[0245] Step (b): Preparation of N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 9.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 9.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidinyl-1-carboxamide (Compound 9.1) with 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]piperidinyl-3-carboxamide (Compound 9.2).

[0246] N-(6-chloro-2-pyridinyl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide was obtained (compound 9.2, 615.0 mg, 1.34 mmol). MS determination (ESI) + ) [(M+H) + ]: 460.2.

[0247] Step (c): 12-Fluoro-1,7,11,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 9.3) Similar to Example 1, 12-fluoro-1,7,11,15,29-pentaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 9.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-hexadeco-2(29),3,5,9,11,13-hexen-8-one (compound 9.3). 12-Fluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 9.3, 120.0 mg, 0.28 mmol). MS determination (ESI)] + ) [(M+H) + ]: 424.2.

[0248] Step (d): 2-Hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9 ,14 Preparation of 29-(29),3,5,9(14),10,12-hexen-12-yl)ethanesulfonamide (Example 9) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (c) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 1.3) is replaced with 12-fluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .09,14 [20.2.2.2] To prepare 2-hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 9.3). 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9(14),10,12-hexene-12-yl)ethanesulfonamide (Example 9). 2-Hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29,3,5,9,14,10,12-hexene-12-yl]ethanesulfonamide (Example 9, 14.86 mg, 0.03 mmol). MS measured (ESI) + ) [(M+H) + ]: 529.2.

[0249] 1 H NMR (400 MHz, CDCl3): δ 11.28 (br. s, 1H), 8.11 (s, 1H), 7.91 (d,J=8.0 Hz, 1H), 7.79 (t,J= 8.4 Hz, 1H), 7.15 (s, 1H), 6.78 (t,J= 8.8 Hz, 1H),4.10 - 4.02 (m, 4H), 3.68 - 3.65 (m, 2H), 3.51 - 3.48 (m, 2H), 3.43 - 3.38(m, 2H), 3.02 - 2.93 (m, 2H), 2.13 - 2.01 (m, 1H), 1.95 - 1.82 (m, 2H), 1.79-1.66 (m, 4H), 1.62-1.50 (m, 4H), 1.42-1.19 (m, 5H).

[0250] Example 10 2-Hydroxy-N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 10.1) Similar to Example 2, tert-butyl piperidine-1-carboxylate (Compound 10.1) was prepared by replacing 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]propyl]piperidin-1-carboxylate (Int-32) and 2,4-dichloropyrimidine with 6-methyl-4-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Int-36) and 2,6-dichloropyrazine in step (a). 4-[3-[1-[5-[(6-chloropyrazin-2-yl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 10.2, 700.0 mg, 1.25 mmol). MS determination (ESI) + ) [(M+H) + ]: 561.3.

[0251] Step (b): Preparation of N-(6-chloropyrazin-2-yl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 10.2) Similar to Example 1, N-(6-chloropyridinyl)-6-fluoro-2-pyridinyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 1.1) was prepared by replacing 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-2-fluoro-4-pyridinyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 10.1). N-(6-chloropyrazin-2-yl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide was obtained (compound 10.2, 500.0 mg, 1.08 mmol). MS determination (ESI) + ) [(M+H) + ]:461.2.

[0252] Step (c): 12-Fluoro-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 10.3) Similar to Example 1, 12-fluoro-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 1.2) with N-(6-chloropyrazin-2-yl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 10.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 10.3). 12-Fluoro-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 10.3, 190.0 mg, 0.45 mmol). MS determination (ESI)] + )[(M+H) + ]: 425.2. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.27 (br s, 1H), 8.86 (s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 6.50 (s, 1H), 4.22 - 4.13 (m, 2H), 3.55 - 3.38 (m, 2H), 3.25 - 3.09 (m, 2H), 2.82 - 2.67 (m, 2H), 1.95 - 1.63 (m, 9H), 1.35 - 1.24 (m, 7H).

[0253] Step (d): 2-Hydroxy-N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 10) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 1.3) is replaced with 12-fluoro-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare 2-hydroxy-N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 10.3). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexane-12-yl)ethanesulfonamide (Example 10). 2-Hydroxy-N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 10, 25.31 mg, 0.05 mmol). MS measured (ESI)] + ) [(M+H) + ]: 530.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.31 (br. s, 1H), 8.67(s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 6.49 (s, 1H), 4.87 (br. s, 1H), 4.26 -4.09 (m, 2H), 3.86 - 3.69 (m, 2H), 3.47 - 3.36 (m, 2H), 3.32 - 3.30 (m, 2H), 3.13 - 3.03 (m, 2H), 2.68 (d,J= 1.8 Hz, 2H), 1.92 - 1.84 (m, 1H), 1.63 - 1.55(m, 4H), 1.53 - 1.37 (m, 7H), 1.22 - 1.14 (m, 4H).

[0254] Example 11 N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide Similar to Example 10, N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexen-12-yl)ethanesulfonamide (Example 11) was prepared by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). N-(8-oxo-1,4,7,11,15,29-hexaazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexen-12-yl)ethanesulfonamide was obtained (Example 11, 8.12 mg, 0.02 mmol). MS measured (ESI) + ) [(M +H) + ]: 514.3. 1 H NMR (400 MHz, CDCl3): δ 8.92 (br. s, 1H), 8.76 (s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.05(s, 1H), 4.18 - 4.11 (m, 2H), 3.62(d,J= 12.0 Hz, 2H), 3.30 (q,J= 7.2 Hz, 2H), 3.24 - 3.17 (m, 2H), 2.92(t,J= 11.2 Hz, 2H), 1.99 - 1.96 (m, 1H), 1.79 - 1.73(m, 2H), 1.67 - 1.62(m, 7H), 1.57 - 1.53 (m, 2H), 1.45 (t,J= 7.6 Hz, 3H), 1.29 - 1.18 (m, 4H).

[0255] Example 12 N-(8-oxo-1,7,13,15,29-pentaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] Similar to Example 1, N-(8-oxo-1,7,13,15,29-pentaazapentacyclo[20.2.2.2]) was prepared by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 12). N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 12, 28.21 mg, 0.06 mmol). MS measured (ESI)] + ) [(M+H) + ]: 513.2. 1 H NMR (400 MHz, chloroform-d) δ= 9.55 (br. s, 1H), 8.14 (d,J= 8.0 Hz, 1H), 7.59 (d,J= 7.6 Hz, 1H), 7.48 (t,J= 8.0 Hz, 1H), 6.92 (br. s, 1H), 6.72 (d,J= 8.4 Hz, 1H), 6.44 (d,J= 8.4 Hz,1H), 4.23 - 4.04 (m, 2H), 3.72 - 3.56 (m, 2H), 3.55 - 3.40 (m, 4H), 3.15 -3.02 (m, 2H), 2.85 - 2.73 (m, 2H), 1.92 - 1.65 (m, 8H), 1.62 - 1.58 (m, 2H), 1.44 (t,J= 7.2 Hz, 3H), 1.33 - 1.26 (m, 4H).

[0256] Example 13 N-(22-fluoro-8-oxo-1,7,11,15,29-pentaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 ]29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid (compound 13.1) Similar to Example 2, 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Compound 13.1) was prepared by replacing 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-39) with 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester (Int-39). 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 13.1, 650.0 mg, 1.12 mmol). MS determination (ESI) + )[(M+H) + ]: 578.3.

[0257] Step (b): Preparation of N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 13.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 13.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidinyl-1-carboxamide (Compound 13.1) with 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 13.2) in step (b). N-(6-chloro-2-pyridinyl)-6-fluoro-4-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (Compound 13.2, 430.0 mg, 0.9 mmol). MS determination (ESI) + )[(M+H) + ]:478.2.

[0258] Step (c): 12,22-Difluoro-1,7,11,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 13.3) Similar to Example 1, 12,22-difluoro-1,7,11,15,29-pentaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 13.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-2,3,5,9,11,13-hexane-8-one (compound 13.3). 12,22-difluoro-1,7,11,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 13.3, 200.0 mg, 0.45 mmol). MS determination (ESI)] + )[(M+H) + ]: 442.2.

[0259] Step (d): N-(22-fluoro-8-oxo-1,7,11,15,29-pentaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)-2-hydroxy-ethanesulfonamide (Example 13) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 1.3) is replaced with 12,22-difluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .09,14 [20.2.2.2] To prepare N-(22-fluoro-8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 13.3). 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 13). N-(22-fluoro-8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 13, 30.07 mg, 0.06 mmol). MS measured (ESI)] + )[(M+H) + ]: 547.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.36 (br.s, 1H), 7.86 (s, 1H), 7.67 - 7.54 (m, 2H), 6.84 - 6.74 (m, 1H), 6.51 (s, 1H),4.98 - 4.75 (m, 1H), 4.17 - 4.02 (m, 2H), 3.80 (t,J= 6.8 Hz, 2H), 3.64 - 3.55(m, 1H), 3.28 - 3.20 (m, 2H), 2.91 - 2.81 (m, 2H), 2.59 - 2.58 (m, 2H), 2.15- 1.98 (m, 2H), 1.60 - 1.38 (m, 11H), 1.20 - 1.04 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ = -137.45.

[0260] Example 14 2-Hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29,3,5,9,14,10,12-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 14.1) Similar to Example 1, 4-[3-[1-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-fluoro-3-pyridyl]-6-fluoro-pyridin-3-carboxylic acid (Int-31) was prepared by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-5-fluoro-pyridin-2-carboxylic acid (Int-37) with 3-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-5-fluoro-pyridin-2-carboxylic acid (Int-37). 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-fluoro-3-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 14.1, 1.60 g, 2.86 mmol). MS determination (ESI) + ) [(M+H) + ]: 560.2.

[0261] Step (b): Preparation of N-(6-chloro-2-pyridyl)-5-fluoro-3-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-2-carboxamide (compound 14.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-5-fluoro-3-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-2-carboxylate (compound 14.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidinyl-1-carboxylate (compound 14.1) with 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-fluoro-3-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-2-carboxamide in step (b). N-(6-chloro-2-pyridinyl)-5-fluoro-3-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-2-carboxamide (compound 14.2, 1450.0 mg, 2.11 mmol). MS determination (ESI) + ) [(M+H) + ]:460.3 Step (c): 12-Fluoro-1,7,10,15,29-pentaazapentacyclo[20.2.2.2]15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 14.3) Similar to Example 1, 12-fluoro-1,7,10,15,29-pentaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-5-fluoro-3-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridinyl-2-carboxamide (compound 14.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 14.3). 12-Fluoro-1,7,10,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 14.3, 35.0 mg, 0.08 mmol). MS determination (ESI)] + ) [(M+H) + ]: 424.2 Step (d): 2-Hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9 ,14 Preparation of 29-(29),3,5,9(14),10,12-hexen-12-yl)ethanesulfonamide (Example 14) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 1.3) is replaced with 12-fluoro-1,7,10,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14[20.2.2.2] To prepare 2-hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 14.3). 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9(14),10,12-hexene-12-yl)ethanesulfonamide (Example 14). 2-Hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29,3,5,9,14,10,12-hexene-12-yl]ethanesulfonamide (Example 14, 1.46 mg, 0.0 mmol). MS measured (ESI) + ) [(M+H) + ]: 529.2. 1 H NMR (400 MHz, CDCl3) δ = 13.00 (br. s, 1H), 8.30 (br. s, 2H), 8.03 (br. s, 1H), 7.75 (t,J= 8.4 Hz, 1H), 7.33 (s, 1H), 7.24 (s,1H), 4.23 - 4.13 (m, 2H), 4.02 - 3.94 (m, 2H), 3.51 - 3.45 (m, 2H), 3.36 -3.30 (m, 2H), 3.28 - 3.21 (m, 2H), 2.94 - 2.87 (m, 2H), 2.20 - 2.15 (m, 2H),1.85 - 1.79 (m, 12H), 1.50 - 1.46 (m, 2H).

[0262] Example 15 N-(20-fluoro-8-oxo-1,7,13,15,29-pentaazapentane[20.2.2.2]) 15,18 .1 2,6 .0 9,14 ]29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 15.1) Similar to Example 2, 4-[3-[1-[3-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-32) was prepared by replacing 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]-2-fluoro-propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-40) with 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidinyl]-2-fluoro-propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 15.1) in step (a). 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]-2-fluoro-propyl]piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 15.1, 120.0 mg, 0.21 mmol). MS determination (ESI) + ) [(M+H) + ]: 578.4.

[0263] Step (b): Preparation of tert-butyl piperidine-1-carboxylate (compound 15.2) Similar to Example 1, tert-butyl piperidine-1-carboxylate (compound 15.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylate (compound 1.1) with 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]-2-fluoro-propyl]piperidin-1-carboxylate (compound 15.1) in step (b). 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]-2-fluoro-propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 15.2, 90.0 mg, 0.16 mmol) was obtained and used directly in the next step without further purification. MS results (ESI) + ) [(M+H) +]: 478.3.

[0264] Step (c): 12,20-difluoro-1,7,13,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 15.3) Similar to Example 1, 12,20-difluoro-1,7,13,15,29-pentaazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 1.2) with 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]-2-fluoro-propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 15.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-hexadeco-2(29),3,5,9,11,13-hexen-8-one (compound 15.3). 12,20-difluoro-1,7,13,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 15.3, 25.0 mg, 0.06 mmol). MS determination (ESI)] + ) [(M+H) + ]: 442.3.

[0265] Step (d): N-(20-fluoro-8-oxo-1,7,13,15,29-pentaazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)-2-hydroxy-ethanesulfonamide (Example 15) Similar to Example 1, by adding 12-fluoro-1,7,13,15,29-pentaazapentane [20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 1.3)] is replaced with 12,20-difluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2]15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare N-(20-fluoro-8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 15.3). 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 15). N-(20-fluoro-8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 ] 29-(29),3,5,9,11,13-hexene-12-yl)-2-hydroxy-ethanesulfonamide (Example 15, 8.04 mg, 0.01 mmol).

[0266] MS measured value (ESI) + ) [(M+H) + ]: 547.3.

[0267] 1 H NMR (400 MHz, chloroform-d) δ = 9.48 (br s, 1H), 8.16 (d,J= 8.0 Hz, 1H), 7.61 (d,J= 7.6 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.11 - 7.07 (m, 1H), 6.71 (d,J=8.0 Hz, 1H), 6.47 (d,J= 8.0 Hz, 1H), 4.79 - 4.64 (m, 1H), 4.37 - 4.32 (m,1H), 4.19 - 4.13 (m, 2H), 3.87 - 3.83 (m, 1H), 3.76 - 3.68 (m, 3H), 3.62 -3.58 (m, 1H), 3.23 - 3.10 (m, 2H), 2.96 - 2.90 (m, 1H), 2.78 - 2.71 (m, 1H), 2.63 (s, 2H), 2.23 - 2.08 (m, 2H), 1.86 - 1.65 (m, 9H), 1.62 - 1.60 (m, 2H).

[0268] Example 20 2-Hydroxy-N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 20.1) TCFH (6784.7 mg, 24.18 mmol) and NMI (6042.39 mg, 73.59 mmol) were added to a solution of 2-amino-6-chloropyridine (3.24 g, 25.23 mmol) and 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidinyl)propyl]-1-piperidinyl]-4-nitrobenzoic acid (Int-33, 10.0 g, 21.03 mmol) in ACN (100 mL) at 0 °C. After stirring at 45 °C for 8 hours, the reaction mixture was then poured into water (250 mL). The solids formed were collected by filtration and the filter cake was dried under vacuum to give tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylate (compound 20.1, 12.03 g, 20.52 mmol). MS determination (ESI) + ) [(M+H) + ]: 586.4.

[0269] Step (b): Preparation of N-(6-chloro-2-pyridinyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 20.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (Compound 20.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidinyl]benzamide (Compound 20.1) with 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidinyl]benzamide (Compound 20.2). N-(6-chloro-2-pyridinyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 20.2, 9900.0 mg, 20.37 mmol). MS determination (ESI) + ) [(M+H) + ]:486.2.

[0270] Step (c): 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 20.3) Similar to Example 1, 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 20.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexadecen-8-one (compound 20.3). 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 20.3, 5.0 g, 11.12 mmol). MS determination (ESI)] + ) [(M+H) + ]:450.2.

[0271] Step (d): 12-Amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 20.4) To 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 20.3, 1250.0 mg, 2.78 mmol) was added to a solution of DMSO (50 mL) with 4,4'-bipyridine (21.71 mg, 0.14 mmol) and B2(OH)4 (997.15 mg, 11.12 mmol). After stirring at 20 °C for 0.1 hours, the mixture was poured into water (270 mL) and extracted three times with EA (300 mL). The combined organic phases were washed several times with brine (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 20.4, 1000.0 mg, 2.38 mmol). MS determination (ESI)] + )[(M+H) + ]: 420.3.

[0272] Step (e): 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] 15,18 .1 2,6 .0 9,14 Preparation of methyl acetate [29,3,5,9,11,13-hexane-12-yl)aminosulfonyl]acetate (compound 20.5) At 0℃, 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] was synthesized. 15,18 .1 2,6 .0 9,14[29,3,5,9,11,13-hexen-8-one (compound 20.4, 2000.0 mg, 4.77 mmol) was added to a solution of DCM (20 mL) with TEA (1.23 mL, 9.53 mmol) and methyl (chlorosulfonyl)acetate (1645.44 mg, 9.53 mmol). After stirring at 25 °C for 4 hours, the resulting mixture was poured into water (270 mL) and extracted three times with DCM (300 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum.] The residue was purified by rapid silica gel chromatography (ISCO; 40 g SepaFlash silica rapid column, gradient: 40% to 70% EA eluent in PE, 100 mL / min) to give 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]). 15,18 .1 2,6 .0 9,14 Methyl acetate [20.5](1.50 g, 2.7 mmol) (29-(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate. MS measured (ESI) + ) [(M+H) + ]: 556.3.

[0273] Step (f): 2-Hydroxy-N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 20) At 0℃, 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] 15,18 .1 2,6 .0 9,14Methyl acetate [29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 20.5, 1500.0 mg, 2.7 mmol) was added to a solution of LAH (1.62 mL, 4.05 mmol) in THF (40 mL). The mixture was evacuated and backfilled three times with N2. After stirring at 25 °C under N2 for 1 hour, the resulting mixture was quenched dropwise at 0 °C with 15% NaOH (15 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO; 40 g SepaFlash silica rapid column, gradient: 0% to 30% methanol eluent in dichloromethane, 80 mL / min), and the crude product was then purified by preparative HPLC (conditions Phenomenexluna C18 150). 40mm Purified with water (TFA)-ACN (22%–52%) to obtain 2-hydroxy-N-(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]). 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 20, 385.86 mg, 0.73 mmol). MS determination (ESI+) [(M+H)] + ]: 529.2. 1 H NMR(400 MHz, DMSO-d6) δ 10.80 (br. s, 1H), 10.13 (br. s, 1H), 7.82 (s, 1H), 7.39- 7.69 (m, 2H), 7.10 - 6.98 (m, 2H), 6.53 - 6.77 (m, 1H), 4.09 - 4.15 (m,2H), 3.75 (t,J=11.2 Hz, 2H), 3.34 (t,J= 6.4 Hz, 2H), 3.31 - 3.37 (m, 2H),3.09 - 3.23 (m, 4H), 2.60 - 2.69 (m, 2H), 1.73 - 1.85 (m, 5H), 1.50 - 1.66 (m, 7H), 1.21 - 1.38 (m, 4H).

[0274] Example 21 2-Hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of N-(6-chloropyrazin-2-yl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 21.1) DIEA (3.21 mL, 19.45 mmol) was added to a solution of N-(6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-54, 2500.0 mg, 8.43 mmol) and 4-[3-(4-piperidinyl)propyl]piperidine (4432.14 mg, 21.07 mmol) in DMSO (30 mL). After stirring at 25 °C for 16 hours, the resulting mixture was poured into water (150 mL) and extracted three times with DCM (150 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product was subjected to preparative HPLC (conditions: Phenomenex luna C18 150). 40mm Purified with water (TFA)-ACN, 35%–75%, at 15 μm, then extracted three times with DCM (150 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give N-(6-chloropyrazin-2-yl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 21.1, 450.0 mg, 0.92 mmol). MS determination (ESI) + ) [(M+H) + ]: 487.2.

[0275] Step (b): 12-Nitro-1,4,7,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 21.2) Similar to Example 1, 12-nitro-1,4,7,15,29-pentazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloropyrazin-2-yl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 21.1) in step (c). 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 21.2). 12-nitro-1,4,7,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 21.2, 186.0 mg, 0.41 mmol). MS determination (ESI)] + ) [(M+H) + ]: 451.4.

[0276] Step (c): 12-Amino-1,4,7,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 21.3) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.3) is replaced with 12-nitro-1,4,7,15,29-pentazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare 12-amino-1,4,7,15,29-pentazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 21.2). 15,18 .1 2 ,6 .0 9,14[29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 21.3). 12-Amino-1,4,7,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 21.3, 40.0 mg, 0.1 mmol). MS determination (ESI)] + ) [(M+H) + ]: 421.2.

[0277] Step (d): 2-[(8-oxo-1,4,7,15,29-pentazopentacyclic[20.2.2.2]] 15,18 .1 2,6 .0 9,14 Preparation of methyl acetate [29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 21.4) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.4) is replaced with 12-amino-1,4,7,15,29-pentazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 To prepare 2-[(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]] from 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 21.3). 15, 18 .1 2,6 .0 9,14 Methyl acetate of 2-[(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]] was obtained. 15,18 .1 2,6 .0 9,14 Methyl acetate [29(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 21.4, 35.0 mg, 0.06 mmol). MS measured (ESI) + ) [(M+H) +]: 557.3.

[0278] Step (e): 2-Hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 21) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .0 9,14 Methyl 2-hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]) was prepared by reacting 2-carbon-2(29),3,5,9,11,13-hexane-12-yl)aminosulfonyl]acetate (compound 21.4). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexane-12-yl)ethanesulfonamide (Example 21). 2-Hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 21, 3.47 mg, 0.01 mmol). MS measured (ESI)] + ) [(M+H) + ]: 529.3. 1H NMR (400 MHz, CDCl3)δ = 10.93 (br. s, 1H), 8.88 (s, 1H), 8.10 - 7.85 (m, 2H), 7.13 (s, 1H), 6.98(s, 1H), 6.78 (s, 1H), 4.25 - 4.11 (m, 4H), 3.36 - 3.17 (m, 6H), 2.87 - 2.66(m, 2H), 1.92 - 1.75 (m, 6H), 1.72 - 1.63 (m, 6H), 1.38 - 1.34 (m, 2H), 1.28- 1.26 (m, 2H).

[0279] Example 22 2-Hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 22.1) Similar to Example 2, 4-[3-[1-[2-[(2-chloropyrimidinyl-4-yl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Compound 22.1) was prepared by replacing 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridinyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-34) with 4-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-34). 4-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 22.1, 600.0 mg, 1.02 mmol). MS measured (ESI) + ) [(M+H) + ]: 587.3.

[0280] Step (b): Preparation of N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 22.2) Similar to Example 1, N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (Compound 22.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridinyl)carbamoyl]-6-fluoro-2-pyridinyl]-4-piperidinyl]propyl]piperidinyl]benzamide (Compound 22.1) with 4-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidinyl]benzamide (Compound 22.2).

[0281] N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 22.2, 500.0 mg, 1.03 mmol). MS determination (ESI) + ) [(M+H) + ]: 487.2.

[0282] Step (c): 12-nitro-1,3,7,15,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 22.3) Similar to Example 1, 12-nitro-1,3,7,15,29-pentazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 22.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-C2(29),3,5,9,11,13-hexane-8-one (compound 22.3). 12-Nitro-1,3,7,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14[29,3,5,9,11,13-hexane-8-one (compound 22.3, 200.0 mg, 0.44 mmol). MS determination (ESI)] + ) [(M+H) + ]: 451.2.

[0283] Step (d): 12-Amino-1,3,7,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 22.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.3) is replaced with 12-nitro-1,3,7,15,29-pentazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare 12-amino-1,3,7,15,29-pentazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 22.3). 15,18 .1 2 ,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 22.4). 12-Amino-1,3,7,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 22.4, 190.0 mg, 0.45 mmol). MS determination (ESI)] + ) [(M+H) + ]: 421.2.

[0284] Step (e): 2-[(8-oxo-1,3,7,15,29-pentazopentacyclic[20.2.2.2]] 15,18 .1 2,6 .0 9,14Preparation of methyl acetate [29,3,5,9,11,13-hexane-12-yl)aminosulfonyl]acetate (compound 22.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.4) is replaced with 12-amino-1,3,7,15,29-pentazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 To prepare 2-[(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2]] from 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 22.4). 15, 18 .1 2,6 .0 9,14 Methyl acetate of 2-[(8-oxo-1,3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 22.5). This yielded 2-[(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .0 9,14 Methyl acetate [29(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 22.5, 250.0 mg, 0.45 mmol). MS measured (ESI) + ) [(M+H) + ]: 557.2.

[0285] Step (f): 2-Hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexen-12-yl)ethanesulfonamide (Example 22) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .0 9,14 Methyl 2-hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2]) was prepared by reacting 2-carbon-2(29),3,5,9,11,13-hexane-12-yl)aminosulfonyl]acetate (compound 22.5). 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 22). 2-Hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 22, 48.27 mg, 0.09 mmol). MS measured (ESI)] + ) [(M+H) + ]: 529.3. 1 H NMR (400 MHz, DMSO-d6) δ = 11.12 (br. s, 1H), 10.21 (br. s, 1H), 8.26 (d,J= 6.0 Hz, 1H), 7.76(d,J= 8.4 Hz, 1H), 7.41 (d,J= 6.0 Hz, 1H), 7.07 (d,J= 2.0 Hz, 1H), 7.01 (dd,J1= 8.4 Hz,J2= 2.0 Hz, 1H), 4.45 - 4.38 (m, 2H), 3.75 (t,J= 6.4 Hz, 2H), 3.35(t,J= 6.4 Hz, 2H), 3.21 - 3.04 (m, 4H), 2.71 - 2.56 (m, 2H), 1.91 - 1.80 (m,3H), 1.79 - 1.43 (m, 9H), 1.40 - 1.22 (m, 2H), 1.20 - 1.07 (m, 2H).

[0286] Example 23 2-Hydroxy-N-(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2])15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of N-(2-chloro-4-pyridinyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide Similar to Example 21, N-(2-chloro-4-pyridinyl)-2-fluoro-4-nitro-benzamide (Int-54) was prepared by replacing N-(6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-55) with N-(2-chloro-4-pyridinyl)-2-fluoro-4-nitro-benzamide (Int-55) in step (a). N-(2-chloro-4-pyridinyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 23.1, 3500.0 mg, 7.2 mmol) was obtained. MS measured (ESI) + ) [(M+H) + ]: 486.3.

[0287] Step (b): 12-Nitro-1,3,7,15-Tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 23.2) Similar to Example 1, 12-nitro-1,3,7,15-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(2-chloro-4-pyridyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 23.1) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 23.2). 12-nitro-1,3,7,15-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6.0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 23.2) (160.0 mg, 0.36 mmol). MS measured (ESI)] + ) [(M+H) + ]:450.3 Step (c): 12-Amino-1,3,7,15-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 23.3) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.3) is replaced with 12-nitro-1,3,7,15-tetraazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare 12-amino-1,3,7,15-tetraazapentacyclo[20.2.2.2], 29(29),3,5,9,11,13-hexane-8-one (compound 23.2). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 23.3). 12-Amino-1,3,7,15-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 23.3, 150.0 mg, 0.36 mmol). MS determination (ESI)] + ) [(M+H) + ]: 420.3.

[0288] Step (d): 2-[(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of methyl acetate [29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 23.4) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 12-amino-1,3,7,15-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 2-[(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]] from 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 23.3). 15,18 .1 2, 6 .0 9,14 Methyl acetate of 2-[(8-oxo-1,3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 23.4). This yielded 2-[(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .0 9,14 Methyl acetate [23.4, 150.0 mg, 0.27 mmol] of 29-(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate was used directly in the next step without further purification. MS results (ESI) + ) [(M+H) + ]: 556.4.

[0289] Step (e): 2-Hydroxy-N-(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexen-12-yl)ethanesulfonamide (Example 23) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .09,14 Methyl 2-hydroxy-N-(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]) was prepared by reacting 2-carbon-2(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 23.4). 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 23). 2-Hydroxy-N-(8-oxo-1,3,7,15-tetraazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 23, 27.49 mg, 0.05 mmol). MS measured (ESI)] + ) [(M+H) + ]: 528.2. 1 H NMR (400 MHz, chloroform-d) δ= 10.85 (br. s, 1H), 8.13 - 8.06 (m, 1H), 7.90 - 7.82 (m, 1H), 7.76 - 7.70(m, 1H), 7.19 - 7.10 (m, 1H), 6.98 - 6.89 (m, 1H), 6.23 - 6.10 (m, 1H), 4.19- 4.04 (m, 4H), 3.40 - 3.29 (m, 2H), 3.25 - 3.14 (m, 4H), 2.75 - 2.68 (m,2H), 2.08 - 1.97 (m, 1H), 1.75 - 1.45 (m, 11H), 1.34 - 1.24 (m, 4H).

[0290] Example 24 2-Hydroxy-N-(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 24.1) Similar to Example 20, 4-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 24.1) was prepared by replacing 2-amino-6-chloropyridine with 6-bromo-5-methoxy-pyridinyl-2-amine in step (a). 4-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 24.1, 1.5 g, 2.27 mmol) was obtained. MS results (ESI) + ) [(M+H) + ]: 662.1.

[0291] Step (b): Preparation of N-(6-bromo-5-methoxy-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 24.2) Similar to Example 1, N-(6-bromo-5-methoxy-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (Compound 24.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidinyl-1-carbamoyl (Compound 24.1) with 4-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]piperidinyl-1-carbamoyl (Compound 24.1). N-(6-bromo-5-methoxy-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 24.2, 1.27 g, 2.27 mmol) was obtained. MS determination (ESI) + ) [(M+H) + ]: 562.2.

[0292] Step (c): 3-Methoxy-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14Preparation of 29-hexane-8-one (compound 24.3) Similar to Example 1, 3-methoxy-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-bromo-5-methoxy-2-pyridinyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 24.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-C2(29),3,5,9,11,13-hexane-8-one (compound 24.3). 3-Methoxy-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15, 18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 24.3, 400.0 mg, 0.83 mmol). MS determination (ESI)] + ) [(M+H) + ]: 480.3.

[0293] Step (d): 12-Amino-3-methoxy-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 24.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.3) is replaced with 3-methoxy-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare 12-amino-3-methoxy-1,7,15,29-tetraazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 24.3). 15,18.1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 24.4). 12-Amino-3-methoxy-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 24.4, 180.0 mg, 0.4 mmol). MS determination (ESI)] + ) [(M+H) + ]:450.3.

[0294] Step (e): 2-[(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] 15,18 .1 2,6 .0 9 ,14 Preparation of methyl acetate [29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 24.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [20.4] 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.4) is replaced with 12-amino-3-methoxy-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 2-[(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] from 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 24.4). 15,18 .1 2,6 .0 9,14 Methyl acetate of 2-[(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] was obtained. 15,18 .1 2, 6 .0 9,14Methyl acetate [24.5, 50.0 mg, 0.09 mmol] (C29-2(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate. MS values ​​(ESI) + ) [(M+H) + ]: 586.2.

[0295] Step (f): 2-Hydroxy-N-(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15, 18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 24) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]]. 15,18 .1 2, 6 .0 9,14 Methyl 2-hydroxy-N-(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was prepared by reacting 2-carbon-2(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 24.5). 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 24). 2-Hydroxy-N-(3-methoxy-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 24, 8.67 mg, 0.02 mmol).

[0296] MS measured value (ESI) + ) [(M+H) + ]: 558.2, 1H NMR (400 MHz, DMSO-d6) δ = 10.91(br. s, 1H), 7.85 (d,J= 8.4 Hz, 1H), 7.75 (d,J= 8.4 Hz, 1H), 7.27 (d,J= 8.8Hz, 1H), 7.08 (s, 1H), 7.00 (d,J= 8.4 Hz, 1H), 3.91 (d,J= 13.2 Hz, 2H), 3.76(s, 3H), 3.75 - 3.72 (m, 2H), 3.20 (d,J= 11.2 Hz, 4H), 2.99 - 2.89 (m, 2H),2.69 - 2.60 (m, 2H), 1.90 - 1.65 (m, 6H), 1.62 - 1.56 (m, 2H), 1.50 - 1.44 (m, 2H), 1.42 - 1.33 (m, 4H), 1.29 - 1.23 (m, 2H).

[0297] Example 25 N-(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 ]29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-6-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 25.1) Similar to Example 21, N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-52) was prepared by replacing N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro-benzamide (Int-54) in step (a) with N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro-6-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 25.1) to N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-6-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 25.1, 895.0 mg, 1.78 mmol) directly for use in the next step without further purification. MS values ​​(ESI)+ ) [(M+H) + ]: 504.2.

[0298] Step (b): 10-Fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 25.3) Similar to Example 1, 10-fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-6-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 25.1) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbocarbon-2(29),3,5,9,11,13-hexaden-8-one (compound 25.2). 10-Fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 25.2, 85.0 mg, 0.18 mmol). MS determination (ESI)] + ) [(M+H) + ]: 468.2 Step (c): 12-Amino-10-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 25.3) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [20.3] 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.3) is replaced with 10-fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .12,6 .0 9,14 [20.2.2.2] To prepare 12-amino-10-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 25.2). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 25.3). 12-Amino-10-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 25.3, 79.0 mg, 0.18 mmol)] was used directly in the next step without further purification. MS values ​​(ESI) + ) [(M+H) + ]: 438.3 Step (d): 2-[(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] 15,18 .1 2,6 .0 9,14 Preparation of methyl acetate [29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 25.4) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [20.4] 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 12-amino-10-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 2-[(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] from 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 25.3). 15,18 .1 2,6 .0 9,14 Methyl acetate of 2-[(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] was obtained.15,18 .1 2,6 .0 9,14 Methyl acetate [25.4, 103.0 mg, 0.18 mmol] of 29-(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate was used directly in the next step without further purification. MS results (ESI) + ) [(M+H) + ]: 574.4.

[0299] Step (e): N-(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexene-12-yl)-2-hydroxy-ethanesulfonamide (Example 25) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .0 9 ,14 [29,3,5,9,11,13-hexaden-12-yl)aminosulfonyl]methyl acetate (compound 25.4) to prepare N-(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 25). N-(10-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 25, 11.79 mg, 0.02 mmol). MS measured (ESI)] + ) [(M+H) + ]: 546.3. 1H NMR(400 MHz, DMSO-d6) δ = 9.81 (br. s, 1H), 7.50 (t,J= 8.0 Hz, 1H), 7.44 (d,J=7.2 Hz, 1H), 6.64 - 6.57 (m, 3H), 4.12 - 4.09 (m, 2H), 3.75 (t,J= 6.4 Hz,2H), 3.31 - 3.27 (m, 4H), 3.06 - 3.00 (m, 2H), 2.63 - 2.58 (m, 2H), 1.84 -1.81 (m, 1H), 1.64 - 1.59 (m, 2H), 1.54 - 1.49 (m, 5H), 1.39 - 1.31 (m, 4H),1.19 - 1.14 (m, 4H).

[0300] Example 26 N-(24-fluoro-1,8,9,10,17,32-hexaazahexacyclo[22.2.2.2]) 17,20 .1 2,6 .1 7,10 .0 11,16 [32,3,5,7,8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl 4-[3-[1-[2-[4-(6-chloro-2-pyridyl)triazol-1-yl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid (compound 26.1) A mixture of 2-chloro-6-[1-(2-fluoro-4-nitro-phenyl)triazol-4-yl]pyridine (Int-57, 428.23 mg, 1.34 mmol), 4-fluoro-4-[3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (400.0 mg, 1.22 mmol, Int-1), and DIEA (428.43 mg, 3.32 mmol) in DMSO (5 mL) was stirred at 140 °C for 5 hours. The mixture was concentrated under vacuum. The residue was subjected to reverse rapid (Welch Ultimate XB_C) 18Purification was performed at 20–40 μm; 120 A, water (0.1% FA)-ACN, 95%, 100 mL / min to give tert-butyl 4-[3-[1-[2-[4-(6-chloro-2-pyridyl)triazol-1-yl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylate (compound 26.1, 362.0 mg, 0.58 mmol). MS results (ESI) + ) [(M-Boc+H) + ]: 528.3.

[0301] Step (b): Preparation of 2-chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-phenyl]triazol-4-yl]pyridine (compound 26.2) Similar to Example 1, 2-chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-phenyl]triazol-4-yl]pyridine (Compound 26.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridinyl)carbamoyl]-6-fluoro-2-pyridinyl]-4-nitro-phenyl]triazol-4-yl]pyridine in step (b). 2-Chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-phenyl]triazol-4-yl]pyridine (compound 26.2, 304.0 mg, 0.58 mmol). MS determination (ESI) + ) [(M+H) + ]: 528.3.

[0302] Step (c): 24-Fluoro-14-nitro-1,8,9,10,17,32-hexaazahexacyclic [22.2.2.2] 17,20 .1 2,6 .1 7, 10 .0 11,16 Preparation of 2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3) Similar to Example 1, 24-fluoro-14-nitro-1,8,9,10,17,32-hexaazahexacyclo[22.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 1.2) with 2-chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-phenyl]triazol-4-yl]pyridine (compound 26.2, 430.0 mg, 0.93 mmol) in step (c). 17,20 .1 2,6 .1 7,10 .0 11 ,16 [C2-2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3). 24-Fluoro-14-nitro-1,8,9,10,17,32-hexaazahexacyclic [22.2.2.2] 17,20 .1 2,6 .1 7,10 .0 11,16 [C2-2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3, 260.0 mg, 0.53 mmol)] was used directly in the next step without further purification. MS results (ESI) + ) [(M+H) + ]: 492.3.

[0303] Step (d): 24-Fluoro-1,8,9,10,17,32-hexahexacyclic [22.2.2.2] 17,20 .1 2,6 .1 7,10 .0 11,16 Preparation of 2(32),3,5,7(31),8,11,13,15-octaen-14-amine (compound 26.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.3) is replaced with 24-fluoro-14-nitro-1,8,9,10,17,32-hexaazahexacyclic [22.2.2.2]. 17,20 .1 2,6 .1 7,10 .0 11,16[22.2.2] 24-fluoro-1,8,9,10,17,32-hexahexacyclic rings were prepared from 32-carbon-2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3). 17,20 .1 2,6 .1 7,10 .0 11,16 [C2-2(32),3,5,7(31),8,11,13,15-octaen-14-amine (compound 26.4). 24-Fluoro-1,8,9,10,17,32-hexaazahexacyclic [22.2.2.2] were obtained.] 17,20 .1 2,6 .1 7,10 .0 11,16 [C2(32),3,5,7(31),8,11,13,15-octaen-14-amine (compound 26.4, 244.0 mg, 0.53 mmol)] was used directly in the next step without further purification. MS results (ESI) + ) [(M+H) + ]: 462.4.

[0304] Step (e): 2-[(2,4-fluoro-1,8,9,10,17,32-hexaazahexacyclic[22.2.2.2]] 17,20 .1 2,6 .1 7,10 .0 11 ,16 Preparation of methyl acetate [32,3,5,7(31),8,11,13,15-octaen-14-yl)aminosulfonyl]acetate (compound 26.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 24-fluoro-1,8,9,10,17,32-hexaazahexacyclic [22.2.2.2]. 17,20 .1 2,6 .1 7,10 .0 11,16 [22.2.2] 2-[(24-fluoro-1,8,9,10,17,32-hexaazahexacyclic[22.2.2.2] 17,20 .1 2,6 .1 7,10.0 11,16 Methyl acetate of 2-[(2,4-fluoro-1,8,9,10,17,32-hexaazahexacyclo[22.2.2.2]] was obtained. 17,20 .1 2,6 .1 7,10 .0 11,16 Methyl acetate [26.5, 156.0 mg, 0.26 mmol] (C22-(32),3,5,7(31),8,11,13,15-octaen-14-yl)aminosulfonyl]acetate. MS values ​​(ESI) + ) [(M+H) + ]:598.3.

[0305] Step (f): N-(2,4-fluoro-1,8,9,10,17,32-hexaazahexacyclic[22.2.2.2]) 17,20 .1 2,6 .1 7,10 .0 11,16 Preparation of 2(32),3,5,7(31),8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide (Example 26) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(24-fluoro-1,8,9,10,17,32-hexaazahexacyclo[22.2.2.2]]. 17,20 .1 2,6 .1 7, 10 .0 11,16 Methyl acetate of [22.2.2.2](compound 26.5) was prepared by reacting methyl acetate of [22.2.2.2](2,4-fluoro-1,8,9,10,17,32-hexaazahexacyclic[ ... 17,20 .1 2,6 .1 7,10 .0 11,16[32,3,5,7(31),8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide (Example 26). N-(24-fluoro-1,8,9,10,17,32-hexaazahexacyclic [22.2.2.2]) was obtained. 17,20 .1 2,6 .1 7,10 .0 11,16 [C2(32),3,5,7(31),8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide (Example 26, 26.38 mg, 0.05 mmol). MS determination (ESI)] + ) [(M+H) + ]: 570.3. 1 H NMR (400 MHz, DMSO-d6) δ = 8.91 (s, 1H), 7.70(t,J= 7.6 Hz, 1H), 7.56 (d,J= 8.4 Hz, 1H), 7.40 (d,J= 7.2 Hz, 1H), 7.06 -7.00 (m, 3H), 4.00 - 3.96 (m, 2H), 3.77 (t,J= 6.4 Hz, 2H), 3.32 - 3.33 (m,2H), 3.24 (t,J= 13.2 Hz, 2H), 2.71 (d,J= 10.8 Hz,, 2H), 2.46 - 2.44 (m, 2H),2.26 - 2.20 (m, 1H), 2.16 - 2.10 (m, 1H), 1.54 - 1.47 (m, 5H), 1.34 - 1.30 (m, 6H), 0.97 - 0.87 (m, 2H).

[0306] Example 27 N-(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 ]29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid benzyl ester (compound 27.1) A mixture of N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-50, 392.61 mg, 1.33 mmol), 4-fluoro-4-[3-(4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylic acid benzyl ester (Int-7, 500.0 mg, 1.33 mmol), and DIEA (513.92 mg, 3.98 mmol) in DMSO (10 mL) was stirred at 100 °C for 12 hours. The mixture was diluted with H2O (100 mL) and extracted three times with EA (80 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% to 50% EA in PE) and concentrated under vacuum to give benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylate (compound 27.1, 610.0 mg, 0.94 mmol). MS determination (ESI) + )[(M+H) + ]: 652.3.

[0307] Step (b): Preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-4-methyl-1-piperidinyl]-4-nitro-benzamide (compound 27.2) A solution of 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid benzyl ester (compound 27.1, 580.0 mg, 0.89 mmol) in TFA (5.0 mL, 0.89 mmol) was stirred at 80 °C for 1 h. The mixture was concentrated under vacuum. The residue was purified by reverse-phase rapid (0.1% FA) to give N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-4-methyl-1-piperidinyl]-4-nitro-benzamide (compound 27.2, 410.0 mg, 0.79 mmol). MS results (ESI) + )[(M+H) + ]: 518.2.

[0308] Step (c): 22-Fluoro-18-methyl-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29-hexane-8-one (compound 27.3) Similar to Example 1, 22-fluoro-18-methyl-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-4-methyl-1-piperidinyl]-4-nitro-benzamide (compound 27.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 27.3). 22-Fluoro-18-methyl-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 27.3, 210.0 mg, 0.44 mmol). MS determination (ESI)] + )[(M+H) + ]: 482.2.

[0309] Step (d): 12-Amino-22-fluoro-18-methyl-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29-hexane-8-one (compound 27.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.3) is replaced with 22-fluoro-18-methyl-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare 12-amino-22-fluoro-18-methyl-1,7,15,29-tetraazapentacyclo[20.2.2.2] from 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 27.3). 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 27.4). 12-Amino-22-fluoro-18-methyl-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 27.4, 150.0 mg, 0.33 mmol). MS determination (ESI)] + )[(M+H) + ]: 452.3.

[0310] Step (e): 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] 15,18 .1 2 ,6 .0 9,14 Preparation of methyl acetate [27.5](29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [20.4] 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 12-amino-22-fluoro-18-methyl-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] from 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 27.4).15,18 .1 2,6 .0 9,14 Methyl acetate of 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] was obtained. 15,18 .1 2,6 .0 9,14 Methyl acetate [27.5, 50.0 mg, 0.09 mmol] (C29-2(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate. MS values ​​(ESI) + )[(M+H) + ]: 588.4.

[0311] Step (f): N-(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2, 6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexene-12-yl)-2-hydroxy-ethanesulfonamide (Example 27) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]]. 15, 18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexaden-12-yl)aminosulfonyl]methyl acetate (compound 27.5) to prepare N-(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 27). N-(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was obtained. 15,18 .12,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 27, 21.24 mg, 0.04 mmol). MS determination (ESI)] + )[(M+H) + ]: 560.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.26 (br. s, 1H), 10.02 (br.s, 1H), 7.65 (d,J= 8.4 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.04 (s, 1H), 6.94 (dd,J= 8.4 Hz,J= 1.6 Hz, 1H), 6.72 (d,J= 7.2 Hz, 1H), 5.01 - 4.83 (m, 1H), 4.03 -3.90 (m, 2H), 3.80 - 3.72 (m, 2H), 3.25 - 3.15 (m, 2H), 3.09 - 2.99 (m, 2H),2.91 - 2.79 (m, 2H), 2.21 - 2.03 (m, 2H), 1.83 - 1.44 (m, 7H), 1.32 - 1.08 (m, 7H), 0.91 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ = -130.95.

[0312] Example 28 2-Hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15, 18 .1 2,6 .0 9,14 [29-hexane-12-yl]ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl piperidine-1-carboxylate (compound 28.1) Similar to Example 27, 4-[2-[[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(trifluoromethyl)-4-piperidinyl]amino]ethyl]piperidin-1-carboxylic acid tert-butyl ester (Compound 28.1) was prepared by replacing 4-fluoro-4-[3-(4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylic acid benzyl ester (Int-7) with 4-[2-[[4-(trifluoromethyl)-4-piperidinyl]amino]ethyl]piperidin-1-carboxylic acid tert-butyl ester (Int-5) in step (a). 4-[2-[[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(trifluoromethyl)-4-piperidinyl]amino]ethyl]piperidin-1-carboxylic acid tert-butyl ester (compound 28.1, 1050.0 mg, 1.6 mmol). MS determination (ESI) + ) [(M+H) + ]:655.2.

[0313] Step (b): Preparation of N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[2-(4-piperidinyl)ethylamino]-4-(trifluoromethyl)-1-piperidinyl]benzamide (compound 28.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[2-(4-piperidinyl)ethylamino]-4-(trifluoromethyl)-1-piperidinyl]benzamide (Compound 28.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-(trifluoromethyl)-1-piperidinyl]benzamide (Compound 28.1) with 4-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(trifluoromethyl)-1-piperidinyl]benzamide (Compound 28.2) in step (b). N-(6-chloro-2-pyridinyl)-4-nitro-2-[4-[2-(4-piperidinyl)ethylamino]-4-(trifluoromethyl)-1-piperidinyl]benzamide (compound 28.2, 889.0 mg). MS determination (ESI) + ) [(M+H) + ]: 555.2.

[0314] Step (c): 12-nitro-18-(trifluoromethyl)-1,7,15,19,29-pentaazapentacyclo[20.2.2.2] 15,18 .1 2 ,6 .0 9,14Preparation of 29-hexane-8-one (compound 28.3) Similar to Example 1, 12-nitro-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[2-(4-piperidinyl)ethylamino]-4-(trifluoromethyl)-1-piperidinyl]benzamide (compound 28.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-2,3,5,9,11,13-hexane-8-one (compound 28.3). 12-nitro-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] was obtained by concentration.] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 28.3, 332.0 mg, 0.64 mmol). MS determination (ESI)] + ) [(M+H) + ]: 519.3.

[0315] Step (d): 12-Amino-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2 ,6 .0 9,14 Preparation of 29-hexane-8-one (compound 28.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 20.3) is replaced with 12-nitro-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14[20.2.2.2] To prepare 12-amino-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] from 29-carbon-2(29),3,5,9,11,13-hexen-8-one (compound 28.3). 15,18 .1 2,6 .0 9,14 [29-2,3,5,9,11,13-hexane-8-one (compound 28.4). 12-Amino-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 [29-(29),3,5,9,11,13-hexen-8-one (compound 28.4, 310.0 mg, 0.63 mmol)] was used directly in the next step without further purification. MS values ​​(ESI) + ) [(M+H) + ]: 489.2.

[0316] Step (e): 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15, 18 .1 2,6 .0 9,14 Preparation of methyl 28.5 of 29-(29),3,5,9,11,13-hexene-12-yl]aminosulfonyl]acetate Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.4) is replaced with 12-amino-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 [28.4] 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14Methyl acetate of 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2]] was obtained. 15,18 .1 2,6 .0 9,14 Methyl 2,9-(29),3,5,9,11,13-hexane-12-yl]aminosulfonyl]acetate (compound 28.5, 482.0 mg, 0.77 mmol) was used directly in the next step without further purification. MS values ​​(ESI) + ) [(M+H) + ]: 625.3.

[0317] Step (f): 2-Hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexene-12-yl ethanesulfonamide (Example 28) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of compound 20.5 (29(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate is replaced with 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Methyl 2-hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] was prepared from 29-carbon-2(29),3,5,9,11,13-hexane-12-yl]aminosulfonyl]acetate (compound 28.5). 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexene-12-yl]ethanesulfonamide (Example 28). To obtain 2-hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .09,14 [29-(29),3,5,9,11,13-hexene-12-yl]ethanesulfonamide (Example 28, 51.67 mg, 0.09 mmol). MS measured (ESI) + ) [(M+H) + ]: 597.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.00 (br.s, 1H), 9.87 (br. s, 1H), 7.66 (d,J= 8.4 Hz, 1H), 7.53 (t,J= 7.6 Hz, 1H), 7.47 (d,J= 7.6 Hz, 1H), 7.09 (s, 1H), 6.89 (d,J= 8.4 Hz, 1H), 6.69 (d,J= 8.4Hz, 1H), 4.97 - 4.91 (m, 1H), 3.98 (d,J= 12.4 Hz, 2H), 3.74 (t,J= 6.8 Hz, 2H),3.59 (t,J= 10.8 Hz, 2H), 3.09 - 3.02(m, 2H), 2.97 - 2.91 (m, 2H), 2.58 - 2.54(m, 2H), 1.91 - 1.85 (m, 3H), 1.83 - 1.82(m, 1H), 1.77 - 1.71 (m, 2H), 1.63 -1.56 (m, 4H), 1.3 (d,J= 8 Hz, 2H).

[0318] Example 29 N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 ]29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylic acid (compound 29.1) Similar to Example 27, 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]piperidin-1-carboxylate benzyl ester (Int-7)] was prepared by replacing 4-fluoro-4-[3-(4-piperidinyl)propyl]piperidin-1-carboxylate tert-butyl ester (Int-1) in step (a) with 4-fluoro-4-[3-(4-piperidinyl)propyl]piperidin-1-carboxylate tert-butyl ester (compound 29.1). This yielded 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-fluoro-piperidin-1-carboxylate tert-butyl ester (compound 29.1, 900.0 mg, 1.49 mmol). MS measured value (ESI) + )[(M+H) + ]: 604.4.

[0319] Step (b): Preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 29.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-nitro-benzamide (Compound 29.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]-4-fluoro-piperidinyl-1-benzamide (Compound 29.1) with 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-fluoro-piperidinyl-1-benzamide (Compound 29.2). N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 29.2, 650.0 mg, 1.29 mmol). MS determination (ESI) + )[(M+H) + ]: 504.3.

[0320] Step (c): 22-Fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 29.3) Similar to Example 1, 22-fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 29.2) in step (c). 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexaden-8-one (compound 29.3). 22-Fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 29.3, 320.0 mg, 0.68 mmol). MS determination (ESI)] + )[(M+H) + ]: 468.2.

[0321] Step (d): 12-Amino-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 29.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [20.2.2] 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.3) is replaced with 22-fluoro-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [20.2.2.2] To prepare 12-amino-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2], 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 29.3). 15,18 .1 2,6 .0 9,14[29,3,5,9,11,13-hexaden-8-one (compound 29.4). 12-Amino-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 29.4, 240.0 mg, 0.55 mmol). MS determination (ESI)] + )[(M+H) + ]: 438.2.

[0322] Step (e): 2-[(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of methyl acetate [29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 29.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [20.4] 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 12-amino-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 2-[(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] from 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 29.4). 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 29.5). 2-[(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Methyl acetate [29,3,5,9,11,13-hexane-12-yl)aminosulfonyl]acetate (compound 29.5, 50.0 mg, 0.09 mmol). MS measured (ESI) + )[(M+H) + ]: 574.3.

[0323] Step (f): N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexene-12-yl)-2-hydroxy-ethanesulfonamide (Example 29) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .0 9 ,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 29.5) was used to prepare N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]). 15,18 .1 2,6 .0 9,14 [29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 29). N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)-2-hydroxy-ethanesulfonamide (Example 29, 15.21 mg, 0.03 mmol). MS measured (ESI)] + )[(M+H) + ]: 546.3. 1H NMR (400MHz, DMSO-d6) δ = 10.54 (br. s, 1H), 10.08 (br. s, 1H), 7.74 (d,J= 8.4 Hz,1H), 7.59 - 7.48 (m, 2H), 7.04 (d,J= 2.0 Hz, 1H), 6.98 (dd,J= 8.4 Hz,J= 2.0Hz, 1H), 6.66 (dd,J= 8.4 Hz,J= 2.0 Hz, 1H), 4.12 - 4.00 (m, 2H), 3.75 (t,J=6.4 Hz, 2H), 3.26 - 3.12 (m, 6H), 2.70 - 2.61 (m, 2H), 2.15 - 2.01 (m, 2H), 1.88 - 1.75 (m, 2H), 1.69 - 1.58 (m, 3H), 1.56 - 1.43 (m, 6H), 1.33 - 1.23 (m, 2H).

[0324] 19 F NMR (376 MHz, DMSO-d6) δ = -134.70.

[0325] Example 30 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexaden-8-one The title compound was synthesized according to the following scheme: Step (a): N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 Preparation of 29(29),3,5,9,11,13-hexene-12-yl)propane-1-sulfonamide (compound 30.1) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14[20.2.2] 29-(29),3,5,9,11,13-hexane-8-one (compound 20.4) and (chlorosulfonyl)acetic acid methyl ester are replaced with 12-amino-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9 ,14 [20.2.2.2] N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by reacting 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 29.4) and 3-chloropropanesulfonyl chloride. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)propane-1-sulfonamide (compound 30.1). N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)propane-1-sulfonamide (compound 30.1, 70.0 mg, 0.12 mmol). MS measured (ESI)] + )[(M+H) + ]: 578.2.

[0326] Step (b): 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (Example 30) N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14A mixture of 29(29),3,5,9,11,13-hexen-12-yl)propane-1-sulfonamide (compound 30.1, 60.0 mg, 0.1 mmol) and K₂CO₃ (43.03 mg, 0.31 mmol) in DMF (2.0 mL) was stirred at 50 °C for 2 h. The mixture was poured into water (20 mL) and then extracted with DCM (20 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was subjected to preparative HPLC (Phenomenexluna C18 150). 40mm 15 μm, water (0.1% FA)-MeCN, 42% to 72% MeCN in H2O, 10 min) purified and lyophilized to give 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexen-8-one (Example 30, 25.44 mg, 0.05 mmol). MS determination (ESI) + )[(M+H) + ]: 542.4. 1 H NMR (400 MHz, DMSO-d6) δ =10.62 (br. s, 1H), 7.81 (d,J= 8.4 Hz, 1H), 7.60 - 7.51 (m, 2H), 6.99 - 6.94(m, 2H), 6.66 (dd,J= 6.8 Hz,J= 1.6 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.82 (t,J=6.4 Hz, 2H), 3.57 (t,J= 6.4 Hz, 2H), 3.28 - 3.13 (m, 4H), 2.75 - 2.61 (m,2H), 2.48 - 2.37 (m, 2H), 2.17 - 1.97 (m, 2H), 1.89 - 1.72 (m, 2H), 1.68 -1.59 (m, 3H), 1.59 - 1.45 (m, 6H), 1.36 - 1.24 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ = -134.59.

[0327] Example 31 N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [20.2.2] 29-(29),3,5,9,11,13-hexane-8-one (compound 20.4) and (chlorosulfonyl)acetic acid methyl ester are replaced with 12-amino-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9 ,14 [20.2.2.2] N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by reacting 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 29.4) and ethanesulfonyl chloride. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide (Example 31). N-(22-fluoro-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]) was obtained. 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 31, 6.86 mg, 0.01 mmol). MS measured (ESI)] + )[(M+H) + ]: 530.3. 1H NMR (400 MHz, DMSO-d6) δ= 10.53 (br. s, 1H), 10.13 (br. s, 1H), 7.74 (d,J= 8.4 Hz, 1H), 7.59 - 7.49(m, 2H), 7.05 (d,J= 2.0 Hz, 1H), 6.99 (dd,J= 8.4 Hz,J= 2.0 Hz, 1H), 6.66 (dd,J= 8.4 Hz,J= 2.0 Hz, 1H), 4.12 - 4.00 (m, 2H), 3.26 - 3.16 (m, 6H), 2.70 -2.60 (m, 2H), 2.13 - 1.99 (m, 2H), 1.87 - 1.74 (m, 2H), 1.71 - 1.60 (m, 3H), 1.56 - 1.45 (m, 6H), 1.33 - 1.25 (m, 2H), 1.20 (t,J= 7.2 Hz, 3H). 19 F NMR (376MHz, DMSO-d6) δ = -134.70.

[0328] Example 32 N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-hexane-12-yl]-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4-piperidinyl]propyl]piperidine-1-carboxylic acid benzyl ester (32.1) Similar to Example 27, 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid benzyl ester (Int-7) was prepared by replacing 4-[3-[4-(difluoromethyl)-4-piperidinyl]amino]ethyl]piperidin-1-carboxylic acid tert-butyl ester (Int-4) in step (a). 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid benzyl ester (compound 32.1, 650.0 mg, 0.97 mmol). MS determination (ESI) + )[(M+H) + ]: 670.2.

[0329] Step (b): Preparation of N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 32.2) Similar to Example 27, N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]-4-fluoro-piperidin-1-carboxylate (compound 27.1) was prepared by replacing 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4-piperidinyl]propyl]piperidin-1-carboxylate (compound 32.1) in step (b). N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 32.2, 350.0 mg, 0.65 mmol). MS determination (ESI) + )[(M+H) + ]: 536.2.

[0330] Step (c): 18-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 32.3) Similar to Example 1, 18-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 32.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 32.3). 18-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 32.3, 130.0 mg, 0.26 mmol). MS determination (ESI)] + )[(M+H) + ]: 500.3.

[0331] Step (d): 12-Amino-18-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29-hexane-8-one (compound 32.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.3) is replaced with 18-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14[Compound 32.3] 29-(29),3,5,9,11,13-hexaden-8-one was used to prepare 12-amino-18-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 32.4). 12-Amino-18-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 32.4, 100.0 mg, 0.21 mmol). MS determination (ESI)] + )[(M+H) + ]: 470.3.

[0332] Step (e): 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2 ,6 .0 9,14 Preparation of methyl 2,9-(29),3,5,9,11,13-hexene-12-yl]aminosulfonyl]acetate (compound 32.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [20.4] 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 12-amino-18-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] from 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 32.4). 15,18 .1 2,6 .0 9,14Methyl acetate of 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Methyl acetate [29(29),3,5,9,11,13-hexene-12-yl]aminosulfonyl]acetate (compound 32.5, 40.0 mg, 0.07 mmol). MS measured (ESI) + )[(M+H) + ]: 606.3.

[0333] Step (f): N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexene-12-yl]-2-hydroxy-ethanesulfonamide (Example 32) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of compound 20.5 (29(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate is replaced with 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15, 18 .1 2,6 .0 9,14 Methyl [20.2.2.2]acetate (compound 32.5) was prepared by reacting 29-(29),3,5,9,11,13-hexaden-12-yl]aminosulfonyl]acetate (compound 32.5). 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexaden-12-yl]-2-hydroxy-ethanesulfonamide (Example 29). N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14[29-(29),3,5,9,11,13-hexane-12-yl]-2-hydroxy-ethanesulfonamide (Example 32, 3.88 mg, 0.01 mmol). MS measured (ESI) + )[(M+H) + ]: 578.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.11 (br. s, 1H), 10.03 (br. s,1H), 7.66 (d,J= 8.4 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.58 - 7.53 (m, 1H), 7.03(d,J= 1.6 Hz, 1H), 6.92 (dd,J= 8.0 Hz,J= 1.2 Hz, 1H), 6.71 (d,J= 8.0 Hz, 1H), 6.10 (t,J= 20.0 Hz, 1H), 4.06 - 3.96 (m, 2H), 3.75 (t,J= 6.4 Hz, 2H), 3.33 -3.29 (m, 2H), 3.20 - 3.16 (m, 2H), 3.06 - 2.97 (m, 4H), 2.00 - 1.89 (m, 1H),1.77 - 1.56 (m, 6H), 1.49 - 1.34 (m, 6H), 1.25 - 1.21 (m, 2H). 19 F NMR (376MHz, CDCl3) δ = -128.34.

[0334] Example 33 N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15, 19 .0 2,7 [29,11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl 3-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid (compound 33.1) Similar to Example 27, 3-[2-[1-[2-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Compound 33.1) was prepared by replacing 4-fluoro-4-[3-(4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylic acid benzyl ester (Int-7) with 4,4-difluoro-3-[2-(4-piperidinyl)ethoxy]piperidin-1-carboxylic acid tert-butyl ester (Int-16) in step (a). 3-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (compound 33.1, 820.0 mg, 1.31 mmol). MS determination (ESI) + ) [(M+H) + ]: 624.3.

[0335] Step (b): Preparation of N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3-piperidinyl)oxy]ethyl]-1-piperidinyl]-4-nitro-benzamide (compound 33.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3-piperidinyl)oxy]ethyl]-1-piperidinyl]-4-nitro-benzamide (Compound 33.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (Compound 33.1) with 3-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]ethoxy]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Compound 33.2). N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3-piperidinyl)oxy]ethyl]-1-piperidinyl]-4-nitro-benzamide (compound 33.2, 520.0 mg, 0.99 mmol). MS determination (ESI) + ) [(M+H) + ]: 524.1 Step (c): 18,18-difluoro-4-nitro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10, 14 .1 15,19 .0 2,7Preparation of 29-carbon-2,4,6,10(29),11,13-hexen-8-one (compound 33.3) Similar to Example 1, 18,18-difluoro-4-nitro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3-piperidinyl)oxy]ethyl]-1-piperidinyl]-4-nitro-benzamide (compound 33.2) in step (c). 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexane-8-one (compound 33.3). 18,18-difluoro-4-nitro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexen-8-one (compound 33.3, 550.0 mg). MS determination (ESI)] + ) [(M+H) + ]: 488.1. 1 H NMR (400 MHz, CDCl3): δ = 12.08 (br. s, 1H), 8.41 (d,J= 8.6 Hz, 1H), 8.17 (d,J= 1.6 Hz,1H), 8.11 - 8.03 (m, 1H), 7.70 (d,J= 8.0 Hz, 1H), 7.58 (t,J= 8.0 Hz, 1H), 6.49 (d,J= 8.4 Hz, 1H), 4.18 - 4.12 (m, 1H), 4.12 - 3.81 (m, 2H), 3.71 - 3.53(m, 4H), 3.38 - 3.31 (m, 2H), 2.97 - 2.80 (m, 2H), 2.41 - 2.26 (m, 1H), 2.24 - 2.09 (m, 1H), 1.97 - 1.67 (m, 7H).

[0336] Step (d): 4-Amino-18,18-difluoro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10, 14 .115,19 .0 2,7 Preparation of 29-carbon-2,4,6,10(29),11,13-hexen-8-one (compound 33.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [29),3,5,9,11,13-hexaden-8-one (compound 20.3) is replaced with 18,18-difluoro-4-nitro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [21.2.2.1] To prepare 4-amino-18,18-difluoro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1], 29-carbon-2,4,6,10(29),11,13-hexaden-8-one (compound 33.3). 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexane-8-one (compound 33.4). 4-Amino-18,18-difluoro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-C-2,4,6,10(29),11,13-hexen-8-one (compound 33.4, 530.0 mg, 1.16 mmol). MS measured (ESI)] + ) [(M+H) + ]: 458.2.

[0337] Step (e): 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10 ,14 .1 15,19 .0 2,7 Preparation of methyl acetate [2,4,6,10(29),11,13-hexene-4-yl)aminosulfonyl]acetate (compound 33.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14[29,3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 4-amino-18,18-difluoro-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 To prepare 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]] from 2,4,6,10(29),11,13-hexaden-8-one (compound 33.4). 10,14 .1 15,19 .0 2,7 Methyl acetate of 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]] was obtained. 10,14 .1 15,19 .0 2,7 Methyl acetate [2,4,6,10(29),11,13-hexene-4-yl)aminosulfonyl]acetate (compound 33.5, 420.0 mg, 0.71 mmol). MS measured (ESI) + ) [(M+H) + ]:594.2.

[0338] Step (f): N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10 ,14 .1 15,19 .0 2,7 Preparation of 2,4,6,10(29),11,13-hexene-4-yl)-2-hydroxy-ethanesulfonamide (Example 33) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate 20.5 (compound 20.5) is replaced with 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]]. 10,14 .1 15,19 .0 2,7Methyl acetate of 2,4,6,10(29),11,13-hexane-4-yl)aminosulfonyl]acetate (compound 33.5) was used to prepare N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29,11,13-hexaden-4-yl)-2-hydroxy-ethanesulfonamide (Example 33). N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1]) was obtained. 10, 14 .1 15,19 .0 2,7 [29-(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide (Example 33, 64.03 mg, 0.11 mmol). MS measured (ESI)] + ) [(M+H) + ]: 566.3. 1 H NMR (400 MHz, DMSO-d6)δ = 12.32 (br. s, 1H), 8.00 (d,J= 8.4 Hz, 1H), 7.64 - 7.50 (m, 2H), 7.23 (d,J= 1.6 Hz, 1H), 7.14 - 7.04 (m, 1H), 6.67 (d,J= 7.6 Hz, 1H), 4.14 - 4.03 (m,1H), 3.99 - 3.89 (m, 1H), 3.78 - 3.54 (m, 6H), 3.51 - 3.41 (m, 1H), 3.29 -3.24 (m, 2H), 3.18 - 3.11 (m, 2H), 2.78 - 2.67 (m, 2H), 2.18 - 2.01 (m, 2H), 1.90 - 1.79 (m, 1H), 1.74 - 1.58 (m, 6H).

[0339] Example 34 2-Hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide] The title compound was synthesized according to the following scheme: Step (a): Preparation of N-(3-bromophenyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 34.1) Similar to Example 21, N-(3-bromophenyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 34.1) was prepared by replacing N-(6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-54) with N-(3-bromophenyl)-2,4-difluoro-benzamide (Int-56) in step (a). N-(3-bromophenyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 34.1, 2844.0 mg, 5.37 mmol) was obtained. MS measured (ESI) + ) [(M+H) + ]: 531.3. 1 H NMR (400 MHz, CDCl3): δ = 12.06(br. s, 1H), 8.42 (d,J= 8.8 Hz, 1H), 8.15 - 8.11 (m, 2H), 8.01 (t,J= 2.0 Hz,1H), 7.66 (dt,J1= 1.2 Hz,J2= 7.6 Hz, 1H), 7.33 - 7.30 (m, 1.5H), 7.28 - 7.26(m, 0.5H), 3.41 - 3.29 (m, 4H), 2.95 - 2.84 (m, 4H), 1.98 - 1.89 (m, 2H),1.53 - 1.46 (m, 6H), 1.39 - 1.34 (m, 6H).

[0340] Step (b): 12-nitro-1,7,15-triazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 34.2) Similar to Example 1, 12-nitro-1,7,15-triazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridinyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(3-bromophenyl)-4-nitro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]benzamide (compound 34.1) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 34.2). This yields 12-nitro-1,7,15-triazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 34.2, 478.0 mg, 1.07 mmol). MS determination (ESI)] + ) [(M+H) + ]: 449.2.

[0341] Step (c): 12-Amino-1,7,15-triazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of 29-hexane-8-one (compound 34.3) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 20.3) is replaced with 12-nitro-1,7,15-triazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 12-amino-1,7,15-triazapentacyclo[20.2.2.2], 29(29),3,5,9,11,13-hexen-8-one (compound 34.2). 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 34.3). 12-Amino-1,7,15-triazapentacyclo[20.2.2.2] 15,18 .12,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 34.3, 425.0 mg, 1.02 mmol). MS measured (ESI)] + ) [(M+H) + ]: 419.3.

[0342] Step (d): 2-[(8-oxo-1,7,15-triazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 Preparation of methyl acetate [29,3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 34.4) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexane-8-one (compound 20.4) is replaced with 12-amino-1,7,15-triazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 To prepare 2-[(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]], 2(29),3,5,9,11,13-hexane-8-one (compound 34.3). 15,18 .1 2,6 .0 9,14 Methyl acetate of 2-[(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]] was obtained. 15,18 .1 2,6 .0 9,14 Methyl acetate [29(29),3,5,9,11,13-hexene-12-yl)aminosulfonyl]acetate (compound 34.4, 265.0 mg, 0.48 mmol). MS measured (ESI) + ) [(M+H) + ]: 555.3.

[0343] Step (e): 2-Hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14Preparation of 29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 34) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of 29-(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate (compound 20.5) is replaced with 2-[(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]]. 15,18 .1 2,6 .0 9,14 Methyl 2-hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]) was prepared by reacting 2-carbon-2(29),3,5,9,11,13-hexane-12-yl)aminosulfonyl]acetate (compound 34.4). 15,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexane-12-yl)ethanesulfonamide (Example 34). 2-Hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2]) was obtained. 15 ,18 .1 2,6 .0 9,14 [29(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide (Example 34, 30.03 mg, 0.06 mmol). MS determination (ESI)] + ) [(M+H) + ]: 527.2. 1H NMR (400 MHz, CDCl3): δ = 11.30(br. s, 1H), 8.09 (d,J= 9.2 Hz, 1H), 7.96 (d,J= 9.6 Hz, 1H), 7.34 - 7.28 (m,1H), 7.19 (s, 1H), 6.98 (d,J= 9.6 Hz, 1H), 6.82 (d,J= 8.8 Hz, 1H), 6.62 (s,1H), 4.13 (s, 2H), 3.72 (d,J= 11.2 Hz, 2H), 3.32 - 3.21 (m, 6H), 2.76 - 2.74(m, 2H), 2.02 - 1.99 (m, 2H), 1.83 - 1.65 (m, 7H), 1.48 - 1.31 (m, 7H).

[0344] Example 35 N-(18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 ]29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid (compound 35.1) Similar to Example 27, 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester (Compound 35.1) was prepared by replacing 4-fluoro-4-[3-(4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-15) with 4-fluoro-4-[3-(4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-15) in step (a). 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4,4-difluoro-piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 35.1, 650.0 mg, 1.04 mmol). MS determination (ESI) +) [(M+H) + ]: 622.2.

[0345] Step (b): Preparation of N-(6-chloro-2-pyridinyl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (compound 35.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridine-3-carboxamide (Compound 35.2) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidinyl]propyl]-4,4-difluoro-piperidinyl-1-carboxamide (Compound 35.1) with 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4,4-difluoro-piperidinyl-1-carboxamide (Compound 35.2). N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 35.2, 610.0 mg, 1.17 mmol). MS determination (ESI) + ) [(M+H) + ]: 522.2.

[0346] Step (c): 18,18-difluoro-4-nitro-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 Preparation of 29-hexane-8-one (compound 35.3) Similar to Example 1, 18,18-difluoro-4-nitro-1,9,15,29-tetraazapentacyclo[21.2.2.1] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidinyl)propyl]-1-piperidinyl]-4-nitro-benzamide (compound 35.2) in step (c). 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexane-8-one (compound 35.3). 18,18-difluoro-4-nitro-1,9,15,29-tetraazapentacyclo[21.2.2.1]10,14 .1 15,19 .0 2,7 [29-C-2,4,6,10,12,14(29)-hexen-8-one (compound 35.3) (520.0 mg, 1.07 mmol). MS measured (ESI)] + ) [(M+H) + ]: 486.2.

[0347] Step (d): 4-Amino-18,18-difluoro-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 Preparation of 29-hexane-8-one (compound 35.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexaden-8-one (compound 20.3) is replaced with 18,18-difluoro-4-nitro-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29)-hexane-8-one (compound 35.3) was used to prepare 4-amino-18,18-difluoro-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexane-8-one (compound 35.4). 4-Amino-18,18-difluoro-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-8-one (compound 35.4, 200.0 mg, 0.44 mmol). MS measured (ESI)] + ) [(M+H) + ]: 456.2.

[0348] Step (e): 2-[(18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .115, 19 .0 2,7 Preparation of methyl acetate of 29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)aminosulfonyl]acetate (compound 35.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 4-amino-18,18-difluoro-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 To prepare 2-[(18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]] from 29-carbon-2,4,6,10,12,14(29)-hexane-8-one (compound 35.4). 10,14 .1 15,19 .0 2,7 Methyl acetate of 2,4,6,10,12,14(29)-hexaden-4-yl)aminosulfonyl]acetate (compound 35.5). This yielded 2-[(18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]]. 10,14 .1 15,19 .0 2,7 Methyl acetate [29-hexene-4-yl]aminosulfonyl]acetate (compound 35.5, 250.0 mg, 0.42 mmol). MS measured (ESI) + ) [(M+H) + ]: 592.1.

[0349] Step (f): N-(18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1]) 10,14 .1 15, 19 .0 2,7 Preparation of 29-hexane-4-yl)-2-hydroxy-ethanesulfonamide (Example 35) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14Methyl acetate [20.5] was prepared by replacing methyl acetate (compound 20.5) with methyl acetate (compound 35.5) of 2-[[(E)-3-[4-[3-[1-[(E)-aminomethyliminomethyl]-4,4-difluoro-3-piperidinyl]propyl]-1-piperidinyl]but-2-enyl]sulfonamide][21.2.2.1] 10,14 .1 15,19 .0 2,7 [29)-hexaden-4-yl)-2-hydroxy-ethanesulfonamide (Example 35). N-(18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl)-2-hydroxy-ethanesulfonamide (Example 35, 48.39 mg, 0.09 mmol). MS measured (ESI)] + ) [(M+H) + ]: 564.3. 1 H NMR(400 MHz, DMSO-d6) δ = 11.49 (br. s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.68 (d,J = 7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.15 - 7.00 (m, 2H), 6.59 (d, J =8.0 Hz, 1H), 3.92 - 3.66 (m, 4H), 3.56 - 3.39 (m, 2H), 3.30 - 3.26 (m, 2H), 3.20 - 3.09 (m, 2H), 2.84 - 2.60 (m, 2H), 2.19 - 1.93 (m, 5H), 1.80 - 1.41 (m, 9H).

[0350] Examples 35A and 35b 2-Hydroxy-N-[(19S)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10, 14 .1 15,19 .0 2,7[29-carbon-2,4,6,10,12,14(29)-hexane-4-yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexene-4-yl] ethanesulfonamide (Examples 35A and 35B) Examples 35A and 35B Using SFC with column DAICEL CHIRALPAK IG (250mm) The compound of Example 35 was separated by CO2-EtOH (0.1%NH3H2O), 40%, 150 ml / min to give Example 35A (faster elution, 19.59 mg) and Example 35B (slower elution, 16.23 mg).

[0351] Example 35A (faster elution): 19.59 mg, 0.03 mmol. MS measured value (ESI) + ) [(M+H) + ]: 564.3.

[0352] 1 H NMR (400 MHz, DMSO-d6) δ = 11.46 (br. s, 1H), 10.16 (br. s, 1H), 8.01 (d,J= 8.8 Hz, 1H), 7.67 (d,J= 8.0 Hz, 1H), 7.58 (t,J= 8.0 Hz, 1H), 7.22- 7.00 (m, 2H), 6.57 (d,J= 8.0 Hz, 1H), 4.96 (br. s, 1H), 3.93 - 3.63 (m,4H), 3.53 - 3.35 (m, 3H), 3.29 - 3.08 (m, 3H), 2.82 - 2.61 (m, 2H), 2.16 -1.93 (m, 5H), 1.75 - 1.39 (m, 9H).

[0353] Example 35B (slower elution): 16.23 mg, 0.03 mmol. MS measured values ​​(ESI) + ) [(M+H) + ]: 564.3.1 H NMR (400 MHz, DMSO-d6) δ = 11.47 (br. s, 1H), 10.12 (br. s, 1H), 8.00 (d,J=8.8 Hz, 1H), 7.68 (d,J= 8.0 Hz, 1H), 7.58 (t,J= 8.0 Hz, 1H), 7.11 (d,J= 2.0Hz, 1H), 7.08 - 7.01 (m, 1H), 6.57 (d,J= 8.0 Hz, 1H), 5.00 (br. s, 1H), 3.93- 3.63 (m, 4H), 3.53 - 3.35 (m, 3H), 3.29 - 3.08 (m, 3H), 2.82 - 2.61 (m,2H), 2.16 - 1.93 (m, 5H), 1.75 - 1.39 (m, 9H).

[0354] Example 36 N-[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-hexane-12-yl]-2-hydroxy-ethanesulfonamide The title compound was synthesized according to the following scheme: Step (a): Preparation of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-(difluoromethyl)piperidin-1-carboxylic acid (compound 36.1) Similar to Example 27, 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-(difluoromethyl)piperidin-1-carboxylic acid tert-butyl ester (Int-2) was prepared by replacing 4-fluoro-4-[3-(4-methyl-4-piperidinyl)propyl]piperidin-1-carboxylic acid tert-butyl ester (Int-2) in step (a). 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-(difluoromethyl)piperidin-1-carboxylic acid tert-butyl ester was obtained (compound 36.1, 600.0 mg, 0.94 mmol). MS determination (ESI) + )[(M+H) + ]: 636.4.

[0355] Step (b): Preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]-1-piperidinyl]-4-nitro-benzamide (compound 36.2) Similar to Example 1, N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]piperidin-1-carboxylic acid tert-butyl ester (compound 1.1) was prepared by replacing 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-(difluoromethyl)piperidin-1-carboxylic acid tert-butyl ester (compound 36.1) with 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidinyl]propyl]-4-(difluoromethyl)piperidin-1-carboxylic acid tert-butyl ester (compound 36.2). N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]-1-piperidinyl]-4-nitro-benzamide (compound 36.2, 430.0 mg, 0.8 mmol). MS determination (ESI) + )[(M+H) + ]: 536.2.

[0356] Step (c): 22-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 36.3) Similar to Example 1, 22-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidinyl)propyl]-1-piperidinyl]pyridin-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4-piperidinyl]propyl]-1-piperidinyl]-4-nitro-benzamide (compound 36.2) in step (c). 15,18 .1 2,6 .0 9,14 [29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 36.3). 22-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29,3,5,9,11,13-hexen-8-one (compound 36.3, 120.0 mg, 0.24 mmol). MS measured (ESI)] + )[(M+H) + ]: 500.2.

[0357] Step (d): 12-Amino-22-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexen-8-one (compound 36.4) Similar to Example 20, by adding 12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (d) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexane-8-one (compound 20.3) is replaced with 22-(difluoromethyl)-12-nitro-1,7,15,29-tetraazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14[20.2.2.2] To prepare 12-amino-22-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2] from 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 36.3). 15,18 .1 2,6 .0 9,14 [29-2,3,5,9,11,13-hexaden-8-one (compound 36.4). 12-Amino-22-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-8-one (compound 36.4, 60.0 mg, 0.13 mmol). MS determination (ESI)] + )[(M+H) + ]: 470.2.

[0358] Step (e): 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2 ,6 .0 9,14 Preparation of methyl 2,9-(29),3,5,9,11,13-hexane-12-yl]aminosulfonyl]acetate (compound 36.5) Similar to Example 20, by adding 12-amino-1,7,15,29-tetraazapentacyclo[20.2.2.2] in step (e) 15,18 .1 2,6 .0 9,14 The 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 20.4) is replaced with 12-amino-22-(difluoromethyl)-1,7,15,29-tetraazapentacyclo[20.2.2.2]. 15,18 .1 2,6 .0 9,14 To prepare 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] from 29-carbon-2(29),3,5,9,11,13-hexaden-8-one (compound 36.4). 15,18 .1 2,6 .0 9,14Methyl acetate of 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] was obtained. 15,18 .1 2,6 .0 9,14 Methyl hexadecimal [29,3,5,9,11,13-hexen-12-yl]aminosulfonyl]acetate (compound 36.5, 40.0 mg, 0.07 mmol). MS measured (ESI) + )[(M+H) + ]: 606.3.

[0359] Step (f): N-[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2, 6 .0 9,14 Preparation of 29-(29),3,5,9,11,13-hexene-12-yl]-2-hydroxy-ethanesulfonamide (Example 36) Similar to Example 20, by adding 2-[(8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2]] in step (f) 15,18 .1 2,6 .0 9,14 Methyl acetate of compound 20.5 (29(29),3,5,9,11,13-hexaden-12-yl)aminosulfonyl]acetate is replaced with 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15, 18 .1 2,6 .0 9,14 Methyl [2,2-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] was prepared by reacting 2,9-carbon-2(29),3,5,9,11,13-hexaden-12-yl]aminosulfonyl]acetate (compound 36.5). 15,18 .1 2,6 .0 9,14 [29-hexadecimal-2(29),3,5,9,11,13-hexen-12-yl]-2-hydroxy-ethanesulfonamide (Example 36). N-[22-(difluoromethyl)-8-oxo-1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14[29-(29),3,5,9,11,13-hexane-12-yl]-2-hydroxy-ethanesulfonamide (Example 36, 18.74 mg, 0.03 mmol). MS measured (ESI) + )[(M+H) + ]: 578.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.73 (br s, 1H), 10.11 (br.s, 1H), 7.80 (d,J= 8.4 Hz, 1H), 7.62 - 7.45 (m, 2H), 7.08 (s, 1H), 7.01 (d,J=8.4 Hz, 1H), 6.69 - 6.55 (m, 1H), 5.96 (t,J= 56.8 Hz, 1H), 4.21 - 4.09 (m,2H), 3.75 (t,J= 6.8 Hz, 2H), 3.33 - 3.30 (m, 2H), 3.22 - 3.15 (m, 4H), 2.71 -2.60 (m, 2H), 1.89 - 1.71 (m, 4H), 1.69 - 1.54 (m, 3H), 1.52 - 1.44 (m, 4H), 1.43 - 1.30 (m, 4H). 19 F NMR (376 MHz, DMSO-d6) δ = -128.87.

[0360] Example 37 N-(17,17-difluoro-8-oxo-19...

Claims

1. A compound of formula (I), (I) in Each of A1, A2, and A3 is independently selected from N and CR. a , where R a H, halogen or C 1-6 alkyl; R 1 Selected from H, halogen, cyano, OH, NO2, CON(R) b1 (R) b2 ), NR b1 SO2R b2 , 、N(R b1 (R) b2 SO2R b1 SO2(R) b1 (R) b2 OR b1 -N=SO(R) b1 (R) b2 ), -PO(R b1 (R) b2 ) and C, optionally substituted with one, two or three independent substituents selected from halogens and OH. 1-6 alkyl, R b1 and R b2 Each of them is independently selected from H and C. 3-10 Cycloalkyl groups and C groups optionally substituted with one, two, or three independent substituents selected from halogens and OH. 1-6 alkyl; L1 is selected from CONH, NHCO, and , Each of B1, B2, and B3 is independently selected from N and CR. 2 ; R 2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; L2 is selected from , SO2NR d And O, Y is N, Z1 is O or CH2. Z2 is CH. Each of m1 and m2 is independently 0, 1, or 2. R c It appears once or twice and is independently selected from H, halogens, and halogenated C. 1-6 alkyl, R d For H, C 1-6 Alkyl or halogenated C 1-6 alkyl; L3 is an optional location along R e Substituted (CH2) q1 (CH2) q2 NH or -(CH2) r -O-(CH2) s -, q is 2, 3, 4, 5, or 6. r is 0, 1, or 2. s is 0, 1, or 2. R e Halogen, C 3-10 cycloalkyl or C 1-6 alkyl; Each of n1 and n2 is independently 0 or 1; R 3 For those that are absent or selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein... A1 is N or CH; A2 is N or CH; A3 is N or CR a , where R a It can be H, fluorine, or methyl.

3. The compound according to claim 1 or claim 2, wherein... Each of A1 and A2 is CH. A3 is CR a , where R a It can be H or methyl.

4. The compound according to any one of claims 1 to 3, wherein... R 1 For NR b1 SO2R b2 or , R b1 For H, R b2 C that is optionally substituted with OH 1-6 alkyl.

5. The compound according to any one of claims 1 to 4, wherein... R 1 For NR b1 SO2R b2 , R b1 For H, R b2 Selected from methyl, ethyl and hydroxyethyl.

6. The compound according to any one of claims 1 to 5, wherein... L1 is selected from CONH, NHCO and .

7. The compound according to any one of claims 1 to 6, wherein... R 2 Selected from H, fluorine, methyl and methoxy.

8. The compound according to any one of claims 1 to 5, wherein... B1 is N or CH. B2 is N, B3 is N or CR 2 , R 2 For H or C 1-6 alkyl.

9. The compound according to any one of claims 1 to 8, wherein... R 2 It can be H or methyl.

10. The compound according to any one of claims 1 to 9, wherein... m1 is 1 or 2. m2 is 0 or 1. R c It appears once or twice, and for each R c Independently selected from H, fluorine, and difluoromethyl. R d It can be H, methyl, or difluoroethyl.

11. The compound according to any one of claims 1 to 9, wherein... L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1. Each R c It is independently selected from H and halogens.

12. The compound according to any one of claims 1 to 9, wherein... L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1; R c It is H or fluorine.

13. The compound according to any one of claims 1 to 12, wherein... L3 is an optional location along R e Substituted (CH2) q1 (CH2) q2 NH or -(CH2) r -O-(CH2) s -, q1 is 3, 4, 5, or 6. q2 is 2. r is 0, s is 2, R e It is either fluorine or methyl.

14. The compound according to any one of claims 1 to 12, wherein... L3 is (CH2) q1 Or -(CH2) r -O-(CH2) s -, q1 is 3. r is 0, s is 2.

15. The compound according to any one of claims 1 to 14, wherein... Each of n1 and n2 is 1.

16. The compound according to any one of claims 1 to 15, wherein... R 3 It is either absent or selected from fluorine, methyl, ethyl, difluoromethyl and trifluoromethyl.

17. The compound according to claim 1, wherein, Each of A1 and A2 is CH. A3 is CR a , where R a For H or C 1-6 alkyl; R 1 For NR b1 SO2R b2 , R b1 For H, R b2 Hydroxyl C 1-6 alkyl; L1 is NHCO, B1 is N or CH; B2 is N; B3 is N or CR 2 ; R 2 For H or C 1-6 alkyl; L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1. Each R c Independently selected from H and halogens; L3 is (CH2) q1 Or -(CH2) r -O-(CH2) s -, q1 is 3. r is 0, s is 2; Each of n1 and n2 is 1; R 3 For those that are absent or selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl.

18. The compound according to claim 17, wherein... Each of A1 and A2 is CH. A3 is CR a , where R a It is H or methyl. R 1 For NR b1 SO2R b2 , R b1 For H, R b2 It is hydroxyethyl; L1 is NHCO, B1 is N or CH; B2 is N; B3 is N or CR 2 ; R 2 It is H or methyl; L2 is , Y is N, Z1 is C(R) c )2, Z2 is CH. m1 is 1 or 2. m2 is 0 or 1. R c It is H or fluorine; L3 is (CH2) q1 Or -(CH2) r -O-(CH2) s -, q1 is 3. r is 0, s is 2; Each of n1 and n2 is 1; R 3 It is either absent or selected from fluorine, methyl, ethyl and difluoromethyl.

19. A compound selected from: 2-Hydroxy- N -(8- Oxygenation -1,7,13,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,3,7,13,15,29-hexaazapentacyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(8- Oxygenation -1,3,7,13,15,29-hexaazapentacyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,4,7,13,15,29-hexaazapentacyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(8- Oxygenation -1,4,7,13,15,29-hexaazapentacyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,3,7,11,15,29-hexaazapentacyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(8- Oxygenation -1,3,7,11,15,29-hexaazapentacyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,7,11,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9(14),10,12-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,4,7,11,15,29-hexaazapentacyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(8- Oxygenation -1,4,7,11,15,29-hexaazapentacyclo[20.2.2.215,18.12,6.09,14]neco-2(29),3,5,9,11,13-hexaden-12-yl)ethanesulfonamide, N -(8- Oxygenation -1,7,13,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(22-Fluoro-8- Oxygenation -1,7,11,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,7,10,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9(14),10,12-hexene-12-yl)ethanesulfonamide,] N -(20-Fluoro-8- Oxygenation -1,7,13,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,4,7,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,3,7,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(8- Oxygenation -1,3,7,15-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] 2-Hydroxy- N -(3-methoxy-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(10-Fluoro-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] N -(24-Fluoro-1,8,9,10,17,32-hexaazahexacyclic[22.2.2.2]) 17,20 .1 2,6 .1 7,10 .0 11,16 [32-C2(32),3,5,7(31),8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide,] N -(22-Fluoro-18-methyl-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy- N -[8- Oxygenation -18-(trifluoromethyl)-1,7,15,19,29-pentazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9 ,14 [29-hexane-12-yl]ethanesulfonamide, N -(22-Fluoro-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29-tetraazapentacyclo[20.2.2.215,18.12,6.09,14]nonadecano-2(29),3,5,9,11,13-hexaden-8-one, N -(22-Fluoro-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -[18-(difluoromethyl)-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-hexane-12-yl]-2-hydroxy-ethanesulfonamide, N -(18,18-difluoro-8- Oxygenation -20-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -(8- Oxygenation -1,7,15-triazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(18,18-difluoro-8- Oxygenation -1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15, 19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15, 19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N -[22-(difluoromethyl)-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-hexane-12-yl]-2-hydroxy-ethanesulfonamide, N -(17,17-difluoro-8- Oxygenation -19-oxa-1,9,15,28-tetraazapentacyclo[20.2.2.1] 10,14 .1 15,18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(18 S )-17,17-difluoro-8-oxo-19-oxa-1,9,15,28-tetraazapentacyclo[20.2.2.1] 10 ,14 .1 15,18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexene-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(18 R )-17,17-difluoro-8-oxo-19-oxa-1,9,15,28-tetraazapentacyclo[20.2.2.1] 10 ,14 .1 15,18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexene-4-yl]ethanesulfonamide, N -(18,18-difluoro-8- Oxygenation -1,9,13,15,29-pentazonocyclic[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N -(18,18-difluoro-12-methyl-8- Oxygenation -1,9,13,15,29-pentazonocyclic[21.2.2.1] 10,14 .1 15,19 .0 2 ,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -(18,18,23-trifluoro-8- Oxygenation -1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexene-4-yl)ethanesulfonamide,] 2-Hydroxy- N -[(19 S )-18,18,23-trifluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15 ,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-18,18,23-trifluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15 ,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N -[23-(difluoromethyl)-18,18-difluoro-8- Oxygenation -1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15, 19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexene-4-yl]-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N -(18,18-difluoro-8- Oxygenation -1,5,9,15,29-pentazonocyclic[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N -[23-(difluoromethyl)-18,18-difluoro-8- Oxygenation -1,5,9,15,29-pentazonocyclic[21.2.2.1] 10,14 .1 15 ,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl]-2-hydroxy-ethanesulfonamide, N -(18,18-difluoro-23-methyl-8- Oxygenation -1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-18,18-difluoro-23-methyl-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10 ,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-18,18-difluoro-23-methyl-8-oxo-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10 ,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N -(18,18-difluoro-8- Oxygenation -1,9,13,15-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N -(18,18-difluoro-8- Oxygenation -1,3,9,15,29-pentazonocyclic[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -(13,18,18-trifluoro-8- Oxygenation -1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexene-4-yl)ethanesulfonamide,] N -(18,18-difluoro-8- Oxygenation -1,9,15,29-tetraazahexacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 .0 17,19 [29-carbon-2,4,6,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -(8- Oxygenation -18-oxa-1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10(29),11,13-hexene-4-yl)ethanesulfonamide,] N -(18,18-difluoro-13-methoxy-8- Oxygenation -1,9,15,29-tetraazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-carbon-2(7),3,5,10(29),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N -(22-Fluoro-3-methoxy-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] N -(22-Fluoro-3-methoxy-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)methanesulfonamide,] N -(17,17-difluoro-8- Oxygenation -1,9,15,28-tetraazapentacyclo[20.2.2.1] 10,14 .1 15,18 .0 2,7 [28-C-2,4,6,10,12,14(28)-hexane-4-yl)-2-hydroxy-ethanesulfonamide, N -(18,22-difluoro-8- Oxygenation -1,3,7,15,29-pentazonocyclic[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] N -(18,22-difluoro-3-methoxy-8- Oxygenation -1,7,15,29-tetraazapentacyclo[20.2.2.2] 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexane-12-yl)-2-hydroxy-ethanesulfonamide,] 2-Hydroxy- N -(7-oxo-1,8,15,29-tetraazapentacyclo[20.2.2.2]) 15,18 .1 2,6 .0 9,14 [29-(29),3,5,9,11,13-hexene-12-yl)ethanesulfonamide,] N -(8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N -(8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)methanesulfonamide, N -(8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptadec-2(7),3,5,10(27),11,13-hexaden-4-yl)ethanesulfonamide, N -(17-methyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N -(21-methyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N -[16-(2,2-difluoroethyl)-8,15,15-trioxo-15λ] 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl]ethanesulfonamide, N -(16-methyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)ethanesulfonamide, N -(16,21-dimethyl-8,15,15-trioxo-15λ) 6 -Thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacarbon-2(7),3,5,10(26),11,13-hexane-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -(8-oxo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1]) 10,14 .0 2,7 [27-hexadecimal-2(7),3,5,10,12,14(27)-hexene-4-yl)ethanesulfonamide, N -(18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10, 14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N -(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N -(23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, N -(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1]) 10,14 .1 15,19 .0 2,7 [29-carbon-2,4,6,10,12,14(29)-hexene-4-yl)-2-hydroxy-ethanesulfonamide, 2-Hydroxy- N -[(19 S )-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, 2-Hydroxy- N -[(19 R )-18,18-difluoro-6,12-dimethyl-8- Oxygenation -20- Oxygen -1,9,13,15,29-pentazonocyclic[21.2.2.1] 10,14 .1 15,19 .0 2,7 [29-hexane-4-yl]ethanesulfonamide, Or its pharmaceutically acceptable salt.

20. A method for preparing compounds having the structure of formula (Ia), (Ib), (Ic) or (Id). (Ia) (Ib) (Ic) (Id) The method includes one of the following steps: (a) Make compound of formula III (III) With NH2SO2R b2 A substitution reaction is carried out in a solvent in the presence of a base to provide a compound of formula (Ia). Wherein Q is fluorine, the base is preferably TEA, DIPEA, K2CO3 or Cs2CO3, and the solvent is preferably DMF, DMSO, dioxane or CH3CN; (b) To make compound IIb (IIb) A reduction reaction is carried out in a solvent in the presence of a reducing agent to provide a compound of formula (Ib). The reducing agent is preferably LiAlH4 or LiBH4, and the solvent is preferably DCM or THF; (c) To make compound IIc (IIc) With NH2SO2R b2 A compound of formula (Ic) is provided by reacting an inorganic base in an organic solvent in the presence of CuI and MNPMO. The organic solvent is preferably DMF or DMSO, and the inorganic base is preferably potassium tripolyphosphate; (d) Make the IId compound (IId) With NH2SO2R b2 The reaction is carried out in an organic solvent using an inorganic base in the presence of CuI and MNPMO. The organic solvent is preferably DMF or DMSO, and the inorganic base is preferably potassium tripolyphosphate; Among them, L3, R 2 R 3 R b2 R c R d A1, A2, A3, B1, B2, B3, Y, Z1, Z2, n1, n2, m1, m2 as defined in any one of claims 1 to 18.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, prepared according to the method of claim 20.

22. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, used as a therapeutically active substance.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, for the treatment of cancer.

25. Use of the compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the treatment of cancer.

26. Use of the compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the inhibition of KIF18A.

27. Use of any compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

28. Use of any compound of claim 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting KIF18A.

29. A method for treating cancer, the method comprising administering an effective amount of a compound as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

30. The use according to any one of claims 25 to 28 or the method according to claim 29, wherein the cancer is ovarian cancer ( For example High-grade serous ovarian cancer), breast cancer ( For example Triple-negative breast cancer), lung cancer ( For example (Non-small cell lung cancer), stomach cancer, esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer, or endometrial cancer.

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