WO2025190888A1

WO2025190888A1 - Macrocyclic kif18a inhibitors and their use thereof

Info

Publication number: WO2025190888A1
Application number: PCT/EP2025/056508
Authority: WO
Inventors: Dong DING; Chungen Liang; Kun MIAO; Jianping Wang; Kuan Wang; Yao Wu; Zhengyuan XIN; Hongying Yun; Ge Zou
Original assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Current assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Priority date: 2024-03-12
Filing date: 2025-03-11
Publication date: 2025-09-18
Anticipated expiration: 2026-09-12

Abstract

The present invention provides novel compounds having general formula (I), wherein L₁, L₂, L₃, R¹, R², R³, 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.

Description

Macrocyclic KIF18A inhibitors and their use thereof FIELD OF THE INVENTION The present invention relates to organic compounds, in particular to KIF18A (Kinesin Family Member 18A) inhibitors, useful for treatment of cancers in a mammal. In particular, the present invention relates to macrocyclic compounds that have KIF18A inhibition activity, as well as their manufacture, pharmaceutical compositions containing them and their potential use as medicaments. BACKGROUND OF THE INVENTION KIF18A is a mitotic kinesin possessing an ATPase activity. It is thought to regulate dynamics at the plus end of kinetochore microtubules for proper chromosome positioning during cell mitosis (Rath and Kozielsky. Nat. Rev. Cancer.2012, 12(8)). The motor domain of KIF18A mediates the plus-end-directed sliding in an ATP-dependent manner and adopts conformational changes upon ATP hydrolysis. In addition, the accumulation of KIF18A at the plus end of microtubules requires the C-terminal tail domain. Genetic evidence has demonstrated that KIF18A plays dual roles in chromosome alignment and microtubule depolymerization/ stabilization. Depletion of KIF18A leads to aberrant spindles, misaligned chromosomes and activation of spindle assembly checkpoint (SAC). KIF18A depolymerizes longer microtubules more quickly than shorter ones. Genetic ablation of KIF18A results in long microtubules (Mayr et al. Curr. Biol.2007, 17(6)). There is increasing evidence suggesting involvement of KIF18A in cancer progression as the overexpression of KIF18A is often linked with poor prognosis in various tumor types, e.g., liver cancer, colorectal cancer, kidney cancer and pancreatic cancer. Several independent studies have demonstrated that KIF18A is a synthetic lethal partner with different 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)). Depletion of KIF18A selectively induces mitotic arrest, lagging chromosome, micronuclei formation, cell cycle arrest and apoptosis in CIN-high tumor cells, but marginal effects on diploid cells. Consistently, pharmacological inhibition of KIF18A phenocopies KIF18A loss leading to persistent SAC activation, prolonged mitosis, misaligned chromosomes and apoptosis in WGD+ cancer cells. SUMMARY OF THE INVENTION Objects of the present invention are novel compounds of formula (I), their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as KIF18A inhibitors for the treatment of cancers. The compounds of formula (I) show superior KIF18A inhibition activity, in particular, time dependent inhibition. In addition, the compounds of formula (I) also show good safety and good PK profiles, e.g., good microsome stability, solubility, hepatic clearance and safety margin. One aspect of the invention pertains to a compound of formula (I), wherein each of A₁, A₂, and A₃ is independently selected from N and CR^a, wherein R^a is H, halogen, or C_1-6aalkyl; R¹ is selected from H, halogen, cyano, OH, NO2, CON(R^b1)(R^b2), NR^b1SO2R^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_1-6aalkyl optionally substituted with one, two, or three substituents independently selected from halogen and OH, each of R^b1 and R^b2 is independently selected from H, C_3-10cycloalkyl, and C_1-6alkyl optionally substituted with one, two, or three substituents independently selected from halogen and OH; L_{1 is selected from CONH, NHCO, a , anda ,} each of B1, B2, and B3 is independently selected from N and CR²; R² is selected from H, halogen, C_1-6alkyl, and C_1-6aalkoxy; 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 occurs once or twice and is independently selected from H, halogen, haloC_1-6alkyl, R^d is H, C_1-6aalkyl, or haloC_1-6aalkyl; L3 is (CH2)q1, (CH2)q2NH, or -(CH2)r-O-(CH2)s-, optionally substituted by R^e, q is 2, 3, 4, 5, or 6, r is 0, 1, or 2, s is 0, 1, or 2, R^e is halogen, C_3-10cycloalkyl or C_1-6alkyl; each of n₁ and n₂ is independently 0 or 1; R³ is absent or selected from halogen, C_1-6aalkyl, and haloC_1-6aalkyl; or a pharmaceutically acceptable salt thereof. Another aspect of the invention pertains to a process for the preparation of a compound of formula (I), as well as a compound of formula (I) or a pharmaceutically acceptable salt thereof when manufactured according to the process. Another aspect of the invention pertains to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Another aspect of the invention pertains to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as therapeutically active substance. Another aspect of the invention pertains to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer. Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the inhibition of KIF18A. Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer. Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the inhibition of KIF18A. Another aspect of the invention pertains to a method for the treatment of cancer, which method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention. The nomenclature used in this application is based on IUPAC systematic nomenclature, unless indicated otherwise. The term “compound(s) of this invention” and “compound(s) of the present invention” refers to compounds of formula (I), and stereoisomers, solvates or salts thereof (e.g., pharmaceutically acceptable salts). The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. As used herein, the term “C_1-6aalkyl” alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 2 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Particular “C_1- ₆alkyl” groups are methyl, ethyl, propyl, isopropyl, and isopentyl. The term “C_1-6aalkoxy” denotes C_1-6aalkyl-O-. The term “C_3-10cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl. The term “halogen” or “halo” denotes fluoro, chloro, bromo, or iodo. The term “haloC_1-6aalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloC_1-6alkyl include monochloro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, for example difluoromethyl. The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those 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, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435. Particular are the sodium salts of the compounds of formula (I). The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof. INHIBITOR OF KIF18A The present invention relates to (i) a compound of formula (I), wherein each of _A1, _A2, and _A3 is independently selected from N and CR^a, wherein R^a is H, halogen, or C_1-6alkyl; R¹ is selected from H, halogen, cyano, OH, NO2, CON(R^b1)(R^b2), NR^b1SO2R^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_1-6alkyl optionally substituted with one, two, or three substituents independently selected from halogen and OH, each of _R ^b1 and _R ^b2 is independently selected from H, C_3-10cycloalkyl, and C_1-6alkyl optionally substituted with one, two, or three substituents independently selected from halogen and OH; L_{1 is selected from CONH, NHCO, a , anda ,} each of B₁, B₂, and B₃ is independently selected from N and CR²; R² is selected from H, halogen, C_1-6aalkyl, and C_1-6aalkoxy; 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 occurs once or twice and is independently selected from H, halogen, haloC_1-6aalkyl, R^d is H, C_1-6alkyl, or haloC_1-6alkyl; L₃ is (CH2)q1, (CH2)q2NH, or -(CH2)r-O-(CH2)s-, optionally substituted by R^e, q is 2, 3, 4, 5, or 6, r is 0, 1, or 2, s is 0, 1, or 2, R^e is halogen, C3-10cycloalkyl or C_1-6aalkyl; each of _n1 and _n2 is independently 0 or 1; R³ is absent or selected from halogen, C_1-6alkyl, and haloC_1-6alkyl; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (ii) a compound according to embodiment (i), wherein A₁ is N or CH; A2 is N or CH; A₃ is N or CR^a, wherein R^a is H, fluoro, or methyl. A further embodiment of present invention is (iii) a compound according to embodiment (i) or embodiment (ii), wherein each of _A1 and _A2 is CH, _A3 is CR^a, wherein R^a is H or methyl. A further embodiment of present invention is (iv) a compound according to any one of embodiments (i) - (iii), wherein R¹ is NR^b1SO2R^b2 or , R^b1 is H, R^b2 is C_1-6aalkyl optionally substituted with OH. A further embodiment of present invention is (v) a compound according to any one of embodiments (i) - (iv), wherein R¹ is NR^b1SO₂R^b2, R^b1 is H, R^b2 is selected from methyl, ethyl, and hydroxyethyl. A further embodiment of present invention is (vi) a compound according to any one of embodiments (i) - (v), wherein L_{1 is selected from CONH, NHCO, and a .} A further embodiment of present invention is (vii) a compound according to any one of embodiments (i) - (vi), wherein R² is selected from H, fluoro, methyl, and methoxy. A further embodiment of present invention is (viii) a compound according to any one of embodiments (i) - (v), wherein B1 is N or CH, B2 is N^， B₃ is N or CR²， R² is H or C_1-6alkyl. A further embodiment of present invention is (ix) a compound according to any one of embodiments (i) - (viii), wherein R² is H or methyl. A further embodiment of present invention is (x) a compound according to any one of embodiments (i) - (ix), wherein m₁ is 1 or 2, m₂ is 0 or 1, R^c occurs once or twice and each R^c is independently selected from H, fluoro, and difluoromethyl, R^d is H, methyl, or difluoroethyl. A further embodiment of present invention is (xi) a compound according to any one of embodiments (i) - (ix), wherein L₂ is ^c , ( )_m2 R^c ( )_m1 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 is independently selected from H and halogen. A further embodiment of present invention is (xii) a compound according to any one of embodiments (i) - (ix), wherein L₂ is ^c , ( )_m2 R^c ( )_m1 _Y is N, Z₁ is C(R^c)₂, Z2 is CH, m₁ is 1 or 2, m₂ is 0 or 1; R^c is H or fluoro. A further embodiment of present invention is (xiii) a compound according to any one of embodiments (i) - (xii), wherein L3 is (CH2)q1, (CH2)q2NH, or -(CH2)r-O-(CH2)s-, optionally substituted by R^e, q1 is 3, 4, 5, or 6, q₂ is 2, r is 0, s is 2, R^e is fluoro or methyl. A further embodiment of present invention is (xiv) a compound according to any one of embodiments (i) - (xii), wherein L3 is (CH2)q1 or -(CH2)r-O-(CH2)s-, q₁ is 3, r is 0, s is 2. A further embodiment of present invention is (xv) a compound according to any one of embodiments (i) - (xiv), wherein each of n1 and n2 is 1. A further embodiment of present invention is (xvi) a compound according to any one of embodiments (i) - (xv), wherein R³ is absent or selected from fluoro, methyl, ethyl, difluoromethyl, and trifluoromethyl. A further embodiment of present invention is (xvii) a compound according to embodiment (i), wherein, each of A1 and A2 is CH, A3 is CR^a, wherein R^a is H or C_1-6aalkyl; R¹ is NR^b1SO₂R^b2, R^b1 is H, R^b2 is hydroxyC_1-6aalkyl; L1 is NHCO^, B₁ is N or CH; B₂ is N; B3 is N or CR²; R² is H or C_1-6aalkyl; L2 is ^c , ( )_m2 R^c ( )_m1 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 is independently selected from H and halogen; 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; R³ is absent or selected from halogen, C_1-6aalkyl, and haloC_1-6aalkyl. A further embodiment of present invention is (xviii) a compound according to embodiment (xvii), wherein each of A1 and A2 is CH, A₃ is CR^a, wherein R^a is H or methyl; R¹ is NR^b1SO2R^b2, R^b1 is H, R^b2 is hydroxyethyl; L1 is NHCO^, B₁ is N or CH; B₂ is N; B3 is N or CR²; R² is H or methyl; L₂ is c , ( )_m2 R^c ( )_m1 Y is N, Z₁ is C(R^c)₂, Z₂ is CH, m1 is 1 or 2, m₂ is 0 or 1, R^c is H or fluoro; 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; R³ is absent or selected from fluoro, methyl, ethyl, and difluoromethyl. A further embodiment of present invention is (xix) a compound selected from: 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(20-fluoro-8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 2-hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide, 15,18 2,6 9,14 N-(10-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 17,20 2,6 7,10 11,16 N-(24-fluoro-1,8,9,10,17,32-hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta- 2(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-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 2-hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29- tetrazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13-hexaen-8-one, 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 15,18 2,6 9,14 N-[22-(difluoromethyl)-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy-ethanesulfonamide, N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(18S)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(18R)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl]-2- hydroxy-ethanesulfonamide, 2-hydroxy-N-[(19S)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl]-2-hydroxy- ethanesulfonamide, N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,3,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 2-hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29- tetrazapentacyclo[21.2.2.1^10,14.1^15,19.0^2,7]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide, 10,14 15,19 2,7 17,19 N-(18,18-difluoro-8-oxo-1,9,15,29-tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 10,14 15,19 2,7 2-hydroxy-N-(8-oxo-18-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)ethanesulfonamide, N-(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)methanesulfonamide, N-(17,17-difluoro-8-oxo-1,9,15,28-tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa- 2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, N-(18,22-difluoro-8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, N-(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-(7-oxo-1,8,15,29-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)methanesulfonamide, N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptacosa- 2(7),3,5,10(27),11,13-hexaen-4-yl)ethanesulfonamide, N-(17-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-(21-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-[16-(2,2-difluoroethyl)-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl]ethanesulfonamide, N-(16-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-(16,21-dimethyl-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 10,14 2,7 2-hydroxy-N-(8-oxo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- 2(7),3,5,10,12,14(27)-hexaen-4-yl)ethanesulfonamide, N-(18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-(23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-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- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xx) a process for the preparation of a compound having the structure of formula (Ia), (Ib), (Ic), or (Id)

comprising one of the following steps: (a) substituent reaction of compound formula III with NH₂SO₂R_b2 in the presence of a base in a solvent provides compound of formula (Ia), wherein Q is fluoro, the base is preferably TEA, DIPEA, K2CO3, or Cs2CO3, the solvent is preferably DMF, DMSO, dioxane or CH3CN; (b) reduction reaction of compound of formula IIb ( ) in the presence of a reducing agent in a solvent provides compound of formula (Ib), wherein the reducing agent is preferably LiAlH₄ or LiBH₄, the solvent is preferably DCM or THF; (c) the reaction of compound of formula _IIc with NH2SO2R^b2 in the presence of CuI and MNPMO in organic solvent using inorganic base provides compound of formula (Ic), wherein the organic solvent is preferably DMF or DMSO, the inorganic base is preferably potassium triphosphate; (d) the reaction of compound of formula IId with NH2SO2R^b2 in the presence of CuI and MNPMO in organic solvent using inorganic base, wherein the organic solvent is preferably DMF or DMSO, the inorganic base is preferably potassium triphosphate; wherein L3, R², R³, R^b2, R^c, R^d, A1, A2, A3, B1, B2, B3, Y, Z1, Z2, n1, n2, m1, m2 are as defined in any one of embodiments (i) to (xix). A further embodiment of present invention is (xxi) a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments (i) to (xix), when manufactured according to the process of embodiment (xx). PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit KIF18A. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 1 to about 100 (e.g., 25 to 100) mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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 formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 1 to 1000 mg (e.g., 25mg, 50mg, 100mg, 250mg, or 500mg) of the compound of the invention compounded with about 1 to 1000 (e.g., 90-30) mg anhydrous lactose, about 1 to 1000 (e.g., 5-40) mg sodium croscarmellose, about 1 to 1000 (e.g., 5-30) mg polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 (e.g., 1-10) mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound of the invention, for example 1 to 1000 (e.g., 5-400 mg), in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer. The following embodiments illustrate typical compositions of the present invention, but serve merely as representative thereof. Composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compounds of the invention trap KIF18A in a microtubule-bound state thus inhibiting KIF18A ATPase activity. Accordingly, the compounds of the invention are useful for inducing mitotic arrest, micronucleus formation and apoptosis in particular cancer cells. Compounds of the invention are useful for triggering synthetic lethal vulnerability in cancer cells that possess high levels of chromosomal instability, e.g., 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. Another embodiment includes a method of treating cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof. Cancer includes but is 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. A further embodiment of present invention is (xxiii) a compound of the invention for use as therapeutically active substance. A further embodiment of present invention is (xxiv) a compound of the invention for use in the treatment or cancer. A further embodiment of present invention is (xxv) the use of a compound of the invention for the treatment of cancer. A further embodiment of present invention is (xxvi) the use of a compound of the invention for the inhibition of KIF18A. A further embodiment of present invention is (xxvii) the use of a compound of the invention for the preparation of a medicament for the treatment of cancer. A further embodiment of present invention is (xxviii) the use of a compound of the invention for the preparation of a medicament for the inhibition of KIF18A. A further embodiment of present invention is (xxix) a method for the treatment of cancer, which method comprises administering an effective amount of a compound of the invention. A further embodiment of present invention is (xxx) the use of 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. SYNTHESIS The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, L₁, L₂, L₃, R¹, R², R³, 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 unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic routes for preparing the compound of formula (I) are shown below.

Scheme 1 wherein Q is F or NO₂, PG is protecting group (such as Boc or Cbz), X is Cl or Br. A compound of formula (Ia) can be prepared according to the synthetic route outlined in Scheme 1: a) Compound of formula VI

can be prepared by a substitution reaction of compound of formula X with compound of formula IX, in the presence of base (such as, TEA, DIPEA or K₂CO₃) in a solvent such as (DMF, DMSO, dioxane or CH3CN); b) compound of formula V V can be prepared by amidation reaction of compound of formula VI with compound of formula _VIIIa in the presence of NMI/TCFH, EDCI/Pyridine, or HATU/DIPEA in a solvent (such as DMF, CH3CN, THF, DCM, or pyridine), Alternatively, compound of formula _V can also be obtained by the crossing coupling reaction of compound of formula VII with compound of formulation VIIIb in the presence of Pd catalyst (such as Pd2dba3/xantphos) with base (such as TEA, DIPEA or Cs2CO3) in a solvent (such as DMF, CH3CN, THF, DCM, pyridine, or 1,4-dioxane), Compound of formula VII can be obtained by amidation of compound of formula VI with ammonium chloride in the presence of NMI/TCFH, EDCI/Pyridine, or HATU/DIPEA in a solvent (such as DMF, CH3CN, THF, DCM, or pyridine); c) Compound of formula _IV can be prepared by deprotection of compound of formula V in the presence of an strong acid (such as HCl or TFA) in a solvent such as (DCM or dioxane) or via a neat reaction using TFA without any solvent; d) Compound of formula III can be prepared by a intramolecular coupling reaction using 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 of formula Ia can be prepared by substituent reaction of compound formula IIIa (Q = F) with NH2SO2Rb2 in the presence of a base (such as TEA, DIPEA, K2CO3, or Cs2CO3) in a solvent (such as DMF, DMSO, dioxane or CH3CN). A compound of formula (Ib, Ic)

can be prepared according to the synthetic route outlined in Scheme 1: f) Compound of formula IIa can be obtained by a reduction reaction of compound of formula _III (Q = NO₂) in the presence of Pd/C-H₂ or B₂(OH)₄/4,4’-bipyridine in a solvent (such as DMF, MeOH, DCM or THF); g) Compound of formula IIb can be prepared by a coupling reaction of using compound of formula IIa with ClSO2CH2COOEt, in the presence of an organic base (such TEA, DIEPA or DMAP), in a solvent such as (THF, EtOAc, DMF or DCM); h) Compound of formula Ib can be prepared by reduction reaction of compound of formula IIb in the presence of a reducing agent (such as LiAlH4 or LiBH4) in a solvent (such as DCM or THF). Scheme 2 XIa a wherein PG is H, or a protected group such as Boc or Cbz, X is Cl or Br. Compound of formula _Va can be prepared by a substitution reaction of compound of formula X with compound of formula XIa, in the presence of a base (such as TEA, DIPEA or K2CO3), in a solvent (such as DMF, DMSO, Dioxane or CH3CN). Scheme 3 Compound of formula IIIc can be prepared according to the synthetic route outlined in scheme 3: a1) compound of formula XIVb

can be prepared by a substitution reaction of compound of formula XIb with compound of formula XVa, in the presence of a base (such as TEA or DIPEA), in a solvent such as (DMF, DMSO, dioxane or CH₃CN); b1) compound of formula XIII can be prepared by cross coupling reaction of compound of formula _XIVb with compound of formula XVb in the presence of Pd catalyst (such as Pd2dba3/xantphos or Pd-PEPPSi-Ipent), with an inorganic base (such as Cs2CO3 or K2CO3) in a solvent (such as 1, 4-dioxane or t-BuOH); a2) Alternatively, compound of formula _XIVa can be prepared by cross coupling reaction of compound of formula XIb with compound of formula XVb in the presence of Pd catalyst (such as Pd2dba3/xantphos or Pd-PEPPSi-Ipent), with an inorganic base (such as Cs₂CO₃ or K₂CO₃) in a solvent (such as 1,4-dioxane or t-BuOH); b2) compound of formula XIII can be prepared by a substitute reaction of compound of formula XIVa with compound of formula XVa in the presence of a base (such as TEA or DIPEA), in a solvent (such as DMF, DMSO, dioxane, or CH₃CN); c) Compound of formula XII can be prepared by ring-closing metathesis reaction in the presence of Grubbs second generation catalyst or Hoveyda-grubbs catalyst, in a solvent (such as DCM, DCE, or Toluene); d) Compound of formula _IIIc

can be prepared by hydrogenation of compound of formula _XII, in the presence of Pd/C in a solvent such as (THF, MeOH, or DCM). Scheme 4 Compound of formula Ic

can be prepared according to the synthetic route outlined in scheme 4: a) Compound of formula _Vc can be prepared by a substitution reaction of compound of formula _XIc with compound of formula XVc, in the presence of a base (such as TEA or DIPEA), in a solvent (such as DMF, DMSO, dioxane, or CH3CN) under microwave irradiation, b) Compound of formula IIc can be prepared by the intramolecule Mitsunobu reaction of compound of formula Vc in the presence of CMBP in a solvent (such as THF, Toluene, or mixture of solvent THF and Toluene); c) Compound of formula Ic can be prepared by the reaction of compound of formula IIc with amine NH2SO2R^b2 in the presence of CuI and MNPMO in organic solvent (such as DMF, DMSO) using inorganic base (such as potassium triphosphate). Compound of formula Id can be prepared according to the synthetic route outlined in scheme 4: d) Compound of formula IId IId can be prepared by Mitsunobu reaction of compound of formula IIc with SO2R^b2OH in the presence of CMBP in a solvent (such as THF, Toluene, or mixture of solvent THF and Toluene); e) Compound of formula Id can be prepared by the reaction of compound of formula IId with NH2SO2R^b2 in the presence of CuI and MNPMO in organic solvent (such as DMF or DMSO) using inorganic base (such as potassium triphosphate). EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows: ACN: acetonitrile BAST: bis(2-methoxyethyl)aminosulfur trifluoride B2(OH)4: (dihydroxyboranyl)boronic acid (CAS: 13675-18-8, PharmaBlock) CMBP: (Tributylphosphoranylidene)acetonitrile DAST: (Diethylamino)sulfur trifluoride DIPEA(DIEA): N-ethyl-N-propan-2-ylpropan-2-amine DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DCM: Dichloromethane DMAP: 4-Dimethylaminopyridine DMF: N,N-Dimethylmethanamide DMP: 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess–Martin periodinane) DMSO: methylsulfinylmethane EDCI: 3-(ethyliminomethylideneamino)propyl-dimethylazanium;chloride ESI⁺: positive electrospray ionization mode EtOAc (EA): ethyl acetate FA: Formic acid Grabs' 2^nd : (1,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylid,ene)dichloro(phenylmethylene)(tricyclohexylphosphi,ne)ruthenium 1H NMR: Proton nuclear magnetic resonance IPA: Propan-2-ol LAH: Lithium aluminium hydride LCMS: Liquid chromatography mass spectrometry LDA: Lithium diisopropylamide LiHMDS: lithium bis(trimethylsilyl)azanide NaH: sodium hydride (60% purity in mineral) NMI: 1-methylimidazole NMP: Methylpyrrolidone obsd.: observed Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium(II) dichloride PE: Petroleum ether PEPPSI-Pd: [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]- dichloro-(2-methylpyridin-1-ium-1-yl)palladium PMA: phosphomolybdic acid hydrate Prep: preparative Py: pyridine Rf: Retention factor value rt: room temperature sat. aq.: saturated aqueous solution Selectfluor: 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate t-BuOK: potassium-t-butoxide t-BuONa: sodium-t-butoxide TCFH: N,N,N‘,N‘-Tetramethylchloroformamidinium-hexafluorophosphate TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatography TsOH: 4-methylbenzenesulfonic acid UV: UV light at 254 nm wavelength Xantphos: (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (CAS: 161265-03-8, Bide) GENERAL EXPERIMENTAL CONDITIONS Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module; ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400. Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge^TM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFire^TM Prep-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 in water; or acetonitrile and water). For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm) or AD (10 µm, 30 × 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3∙H2O in MeOH), back pressure 100bar, detection UV@ 254 or 220 nm. LC/MS spectra of compounds were obtained using a LC/MS (Waters^TM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H₂O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H₂O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic condition II: A: 0.025% NH₃·H₂O in H₂O; B: acetonitrile; Neutral condition: A: H₂O; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH)⁺. NMR Spectra were obtained using Bruker Avance 400 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted. PREPARATIVE EXAMPLES Intermediate-1: tert-butyl 4-fluoro-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate Int-1 Step (a): preparation of benzyl 4-(3-hydroxypropyl)piperidine-1-carboxylate Int-1a To a solution of 3-(4-piperidyl)propan-1-ol in methanol (150 mL) was added N- (benzyloxycarbonyloxy)succinimide (26.1 g, 104.73 mmol) at 20 °C. After being stirred for 12 hrs at 20 °C, the resultant mixture was concentrated in vacuo. The residue was purified by silica gel column (5% to 30% EA in PE) to afford benzyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (Int-1a, 26.0 g, 93.74 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 278.1. Step (b): preparation of benzyl 4-(3-iodopropyl)piperidine-1-carboxylate Int-1b To a mixture of imidazole (8.06 g, 118.33 mmol) and triphenylphosphine (27.78 g, 105.91 mmol) in DCM (200 mL) was added iodine (27.78 g, 109.44 mmol) at 0 ^oC. The mixture was stirred for 1 hr at 0 ^oC. Then a solution of benzyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (Int-1a, 25.0 g, 90.14 mmol) in DCM (60 mL) was added at 0 ^oC. After being stirred for 12 hrs at 20 °C, the reaction mixture was dilute with DCM (200 mL), washed with Na2SO3 (500 mL), brine (200 mL). The organic layer was dried over aqueous Na₂SO₄, and concentrated in vacuo. The crude was then purified by silica gel column (10% to 20% EA in PE) to afford benzyl 4-(3- iodopropyl)piperidine-1-carboxylate (Int-1b, 30.0 g, 77.47 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 388.0. Step (c): preparation of O1-tert-butyl O4-methyl 4-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]piperidine-1,4-dicarboxylate Int-1c To a solution of N-BOC-piperidine-4-carboxylic acid methyl ester (3.77 g, 15.49 mmol) in THF (50 mL) was added LDA (8.39 mL, 16.78 mmol) at -60 ^oC dropwise. The mixture was stirred at -60 ^oC for 1 hr. Then to the mixture was added benzyl 4-(3-iodopropyl)piperidine-1- carboxylate (Int-1b, 5.0 g, 12.91 mmol) in THF (5 mL) dropwise at -60 ^oC. After being stirred at 20 ^oC for 12 hrs, the mixture was poured into H₂O (100 mL), extracted with EA (100 mL) three times. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (0% to 15% EA in PE) to afford O1-tert-butyl O4-methyl 4-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]piperidine-1,4-dicarboxylate (Int-1c, 5.6 g, 11.14 mmol). MS obsd. (ESI⁺)[(M+Na)⁺]: 525.3. Step (d): Preparation of 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-1-tert- butoxycarbonyl-piperidine-4-carboxylic acid Int-1d A mixture of O1-tert-butyl O4-methyl 4-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]piperidine-1,4-dicarboxylate (Int-1c, 5.60 g, 11.14 mmol), NaOH (4.45 g, 111.41 mmol) in methanol (50 mL) and water (50 mL) was stirred at 70 °C for 6 hrs. The mixture was concentrated in vacuo. The residue was acidified with 1.0 N HCl to pH = 6, extracted with DCM (50 mL) three times. The organic layer was concentrated in vacuo. The residue was purified by reversed phase flash (0.1% FA) to afford 4-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (Int-1d, 3.0 g, 6.14 mmol). MS obsd. (ESI⁺)[(M+Na)⁺]: 511.3. Step (e): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- fluoro-piperidine-1-carboxylate Int-1e A mixture of 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-1-tert-butoxycarbonyl- piperidine-4-carboxylic acid (_Int-1d, 3.00 g, 6.14 mmol), AgNO₃ (1.59 g, 9.36 mmol), Selectfluor (4.35 g, 12.28 mmol) (CAS: 140681-55-6, PharmaBlock) in Acetone (40 mL) and water (40 mL) was degassed under N2 three times. After being stirred at 20 °C for 12 hrs under N₂. The mixture was diluted with H₂O (100 mL), extracted with EA (100 mL) three times. The organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (10% to 30% EA in PE) to afford tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1- carboxylate (Int-1e, 2.40 g, 5.19 mmol) as yellow oil. MS obsd. (ESI⁺)[(M+Na)⁺]: 485.3. Step (f): preparation of tert-butyl 4-fluoro-4-[3-(4-piperidyl)propyl]piperidine-1- carboxylate Int-1 To a solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro- piperidine-1-carboxylate (Int-1e, 2.40 g, 5.19 mmol) in EtOAc (100 mL) was degassed under N₂ three times, then to the mixture was added Pd/C (600.0 mg, 10% loaded on active carbon) under N2. The mixture was degassed and purged with H2 for three times and stirred at 20 °C for 12 hrs under H₂ balloon (15 psi). The mixture was filtered through celite, washed with MeOH (30 mL). The filtrate was concentrated in vacuo to afford tert-butyl 4-fluoro-4-[3-(4- piperidyl)propyl]piperidine-1-carboxylate (Int-1, 1.40 g, 4.26 mmol). MS obsd. (ESI⁺[(M+H)⁺].): 329.2 Intermediate 2: tert-butyl 4-(difluoromethyl)-4-[3-(4-piperidyl)propyl]piperidine-1- carboxylate Int-2 Step (a): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- formyl-piperidine-1-carboxylate Int-2a To a solution of 1-BOC-4-piperidinecarboxaldehyde (4.00 g, 18.75 mmol) in DMF (50 mL) was added t-BuOK (28.13 mL, 28.13 mmol, 1.0 M in THF) and benzyl 4-(3- iodopropyl)piperidine-1-carboxylate (_Int-1b, 7.26 g, 18.75 mmol) in DMF (10 mL) dropwise at 0 °C. After being stirred for 12 hrs at 25 °C. The mixture was quenched with H2O (100 mL), extracted with EA (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (5% to 30% EA in PE) to afford tert-butyl 4-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]-4-formyl-piperidine-1-carboxylate (Int-2a, 2.40 g, 5.08 mmol). MS obsd. (ESI⁺)[(M+Na)⁺]: 495.3. Step (b): Preparation of ^tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- (difluoromethyl)piperidine-1-carboxylate Int-2b To a solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-formyl- piperidine-1-carboxylate (Int-2a, 2.40 g, 5.08 mmol) in DCM (50 mL) was added BAST (3.37 g, 15.23 mmol) (CAS: 202289-38-1, Shanghai Haohong Pharmaceutical Co., Ltd) at 20 ^oC. After being stirred at 45 °C for 4 hrs, the mixture was poured into sat. NaHCO3 (100 mL), extracted with EA (100 mL) three times. The organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (5% to 20% EA in PE) and concentrated in vacuo to afford tert-butyl 4-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]-4-(difluoromethyl)piperidine-1-carboxylate (Int-2b, 1.50 g, 3.03 mmol). MS obsd. (ESI⁺)[(M-Boc+H)⁺]: 395.3. Step (c): Preparation of tert-butyl 4-(difluoromethyl)-4-[3-(4- piperidyl)propyl]piperidine-1-carboxylate Int-2 Tert-butyl 4-(difluoromethyl)-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-2) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert- butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-(difluoromethyl)piperidine-1-carboxylate (Int-2b). Tert-butyl 4-(difluoromethyl)-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-2, 570.0 mg, 1.58 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 361.2. Intermediate 3: tert-butyl 4-methyl-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate Int-3 Step (a): Preparation of ^tert-butyl 4-formyl-4-methyl-piperidine-1-carboxylate Int-3a To a solution of 1-BOC-4-piperidinecarboxaldehyde (50.0 g, 234.44 mmol) in DMF (500 mL) were added t-BuOK (52.61 g, 468.89 mmol) and iodomethane (29.32 mL, 468.89 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with H₂O (400 mL), extracted with EA (400 m) three times. The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column (5% to 10% EA in PE) to afford tert-butyl 4-formyl-4-methyl-piperidine-1-carboxylate (Int-3a, 30.0 g, 131.98 mmol). MS obsd. (ESI⁺) [(M-C₄H₈+H)⁺]: 128.2. Step (b): Preparation of tert-butyl 4-[(Z)-2-methoxyvinyl]-4-methyl-piperidine-1- carboxylate Int-3b To a solution of (methoxymethyl)triphenylphosphonium chloride (20.51 g, 59.83 mmol) in THF (60 mL) were added the solution of t-BuOK (70.39 mL, 70.39 mmol) dropwise under N2 balloon, and the reaction mixture was stirred at 25 °C for 30 min, followed by addition of the solution of tert-butyl 4-formyl-4-methyl-piperidine-1-carboxylate (_Int-3a, 8.0 g, 35.2 mmol) in THF (20 mL). The reaction mixture was stirred at 25°C for 12 hrs. It was diluted with H₂O (100 mL), extracted with EA (100 mL) three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (10% to 30% EA in PE) to afford tert-butyl 4-[(Z)-2-methoxyvinyl]-4- methyl-piperidine-1-carboxylate (Int-3b, 6.2 g, 24.28 mmol). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 156.2. Step (c): Preparation of ^tert-butyl 4-methyl-4-(2-^oxoethyl)piperidine-1-carboxylate Int-3c To a solution of tert-butyl 4-[(Z)-2-methoxyvinyl]-4-methyl-piperidine-1-carboxylate (Int- 3b, 6.8 g, 26.63 mmol) in acetone (50 mL) was added the solution of TsOH (13.76 g, 79.89 mmol) in water (25 mL). The reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with H2O (50 mL), extracted with EA (100 mL) three times. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to afford tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1- carboxylate (Int-3c, 6.0 g, 24.86 mmol), which was used in next step directly without further purification.¹H NMR (400 MHz, 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). 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)piperidine-1-carboxylate (Int-3c, 6.0g, 24.86 mmol) in methanol (50 mL) was stirred at 25 °C for 12 hrs under N2. The mixture was concentrated in vacuo. The residue was purified by silica gel column (5% to 10% EA in PE) to afford tert-butyl 4-methyl-4-prop-2-ynyl-piperidine-1-carboxylate (_Int-3d, 4.0 g, 16.85 mmol). MS obsd. (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 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 LPBchem Technology Co., Ltd), TEA (15.65 mL, 112.2 mmol) in DMF (10 mL) was added tert-butyl 4-methyl-4-prop-2- ynyl-piperidine-1-carboxylate (Int-3d, 2.93 g, 12.34 mmol) at 20 °C under N2. The mixture was degassed under N2 three times. The suspension was stirred at 80 °C for 2 hrs under N2. The reaction mixture was filtered through by a pad of celite. It was diluted with H₂O (40 mL), extracted with EA (40 mL) three times. The combined organic layers were concentrated in vacuo to get the residue. The residue was purified by silica gel column (5% to 10% EA in PE) to afford tert-butyl 4-methyl-4-[3-(4-pyridyl)prop-2-ynyl]piperidine-1-carboxylate (_Int-3e, 3.1 g, 9.86 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 315.2. Step (f): Preparation of tert-butyl 4-methyl-4-[3-(4-piperidyl)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 becoming clear solution. Adjust the H₂ back pressure regulator to 2.5 MPa, the flow rate of H2 to 30 mL/min, heated the fixed bed (5% Ru/Al2O3, 5mL, 2.5 g) to 100 °C. Then the solution was pumped into the reactor at a flow rate of 0.3 mL/min. After the reaction was finished, wash the tubing with MeOH 100 mL, collected all the reaction solution and concentrated in vacuo to afford tert-butyl 4-methyl-4-[3-(4-piperidyl)propyl]piperidine-1- carboxylate (Int-3, 3.1 g, 9.55 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 325.2. I_{ntermediate 4:} benzyl 4-[3-[4-(difluoromethyl)-4-piperidyl]propyl]piperidine-1- carboxylate Int-4 Step (a): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- formyl-piperidine-1-carboxylate Int-4a To a solution of 1-BOC-4-piperidinecarboxaldehyde (4.00 g, 18.75 mmol) in DMF (50 mL) was added t-BuOK (28.13 mL, 28.13 mmol, 1.0 M in THF) and benzyl 4-(3- iodopropyl)piperidine-1-carboxylate (_Int-1b, 7.26 g, 18.75 mmol) in DMF (10 mL) dropwise at 0 °C. After being stirred for 12 hrs at 25 °C, the mixture was quenched with H₂O (100 mL), extracted with EA (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford tert-butyl 4-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]-4-formyl-piperidine-1-carboxylate (Int-4a, 2.40 g). MS obsd. (ESI⁺) [M+Na⁺]: 495.3. Step (b): Preparation of ^tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- (difluoromethyl)piperidine-1-carboxylate Int-4b To a solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-formyl- piperidine-1-carboxylate (Int-4a, 2.40 g, 5.08 mmol) in DCM (50 mL) was added BAST (3.37 g, 15.23 mmol) at 20 ^oC. After being stirred at 45 °C for 4 hrs, the mixture was poured into sat. NaHCO₃ (100 mL), extracted with EA (100 mL) three times. The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-(difluoromethyl)piperidine-1-carboxylate (Int-4b, 1.50 g). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 395.3. Step (c): preparation of benzyl 4-[3-[4-(difluoromethyl)-4-piperidyl]propyl]piperidine- 1-carboxylate Int-4 A solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- (difluoromethyl)piperidine-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 hrs. The mixture was poured into sat. NaHCO₃ (100 mL), extracted with EA (100 mL) three times. The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo to afford benzyl 4- [3-[4-(difluoromethyl)-4-piperidyl]propyl]piperidine-1-carboxylate (Int-4, 700.0 mg). MS obsd. (ESI⁺)[(M+H)⁺]: 395.2. Intermediate 5: ^tert-butyl 4-[2-[[4-(trifluoromethyl)-4- piperidyl]amino]ethyl]piperidine-1-carboxylate Int-5 Step (a): 4-(trifluoromethyl)piperidin-4-amine Int-5a To a solution of tert-butyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate (3.19 g, 11.89 mmol) in DCM (40 mL) was added TFA (8.0 mL, 11.89 mmol). After being stirred for 2 hrs at 20 °C. The resultant mixture was concentrated in vacuo to afford 4- (trifluoromethyl)piperidin-4-amine (Int-5a, 3.36.0 g, 11.89 mmol), which was used in next step directly without further purification. Step (b): benzyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate Int-5b To a solution of 4-(trifluoromethyl)piperidin-4-amine (Int-5a, 3.355 g, 11.89 mmol) in THF (20 mL) was added a solution of K₂CO₃ (6572.32 mg, 47.56 mmol) in water (20 mL), then N- (benzyloxycarbonyloxy)succinimide (2963.01 mg, 11.89 mmol) was added to the mixture. After being stirred for 12 hrs at 25 °C, the mixture was diluted with EA (200 mL), washed with sat. K₂CO₃ (200 mL), brine (200 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude. The crude was purified by silica gel column (20% EA in PE). Benzyl 4- amino-4-(trifluoromethyl)piperidine-1-carboxylate (Int-5b, 3.32 g, 10.98 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 303.3 Step (c): benzyl 4-[[2-(1-tert-butoxycarbonyl-4-piperidyl)acetyl]amino]-4- (trifluoromethyl)piperidine-1-carboxylate Int-5c To a solution of benzyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate (Int-5b, 3.32 g, 10.98 mmol) and 1-BOC-4-piperidylacetic acid (2.94g, 12.08 mmol) in Pyridine (30 mL) was added phosphorus oxychloride (2.05 mL, 21.96 mmol) dropwise at 0°C. The mixture was warmed to 20 °C and stirred at 20 °C for 2 hrs. The mixture was quenched by H₂O (30 mL). The mixture was extracted with EA (100 mL) three times. The combined organic layers were washed with 1N HCl (250 mL) and brine (150 mL) three times, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a crude. The crude was purified by reversed flash (Welch Ultimate XB_C1820-40μm; 120 A, water (0.1% FA)-ACN, 56%, 100ml/min) to afford benzyl 4-[[2-(1-tert-butoxycarbonyl-4-piperidyl)acetyl]amino]-4- (trifluoromethyl)piperidine-1-carboxylate (_Int-5c, 3610.0 mg, 6.84 mmol). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 428.2 Step (d): benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidyl)ethylamino]-4- (trifluoromethyl)piperidine-1-carboxylate Int-5d A solution of BH₃/THF (16.11 mL, 16.11 mmol) was cooled to 0°C. A solution of benzyl 4- [[2-(1-tert-butoxycarbonyl-4-piperidyl)acetyl]amino]-4-(trifluoromethyl)piperidine-1- carboxylate (Int-5c, 1.70 g, 3.22 mmol) in THF (5 mL) was added to the mixture dropwise at 0°C. The mixture was warmed to 25 °C and stirred at 25 °C for 72 hrs. The mixture was quenched by MeOH (20 mL) at 0°C. After being stirred at 70°C for 3h, the mixture was concentrated in vacuo. The crude was purified by reversed flash (Welch Ultimate XB_C1820- 40μm; 120 A, water (0.1% FA)-ACN, 100%, 100ml/min) to afford benzyl 4-[2-(1-tert- butoxycarbonyl-4-piperidyl)ethylamino]-4-(trifluoromethyl)piperidine-1-carboxylate (Int-5d, 1.228 g, 2.39 mmol) by concentration. MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 414.3. Step (e): ^tert-butyl 4-[2-[[4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine-1- carboxylate Int-5 Tert-butyl 4-[2-[[4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine-1-carboxylate was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (_Int-1e) with benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidyl)ethylamino]-4-(trifluoromethyl)piperidine-1-carboxylate (Int-5d). tert-butyl 4-[2-[[4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine-1-carboxylate (Int-5, 848.0 mg, 2.23 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 380.2. Intermediate 7: 4-fluoro-1-methyl-4-[3-(4-methyl-4-piperidyl)propyl]piperidine Int-7 Step (a): Preparation of tert-butyl 4-(3-methoxy-3-oxo-propyl)-4-methyl-piperidine-1- carboxylate Int-7a To a solution of trimethyl phosphonoacetate (13.62 g, 74.79 mmol) in THF (60 mL) was added the solution of t-BuOK (87.99 mL, 87.99 mmol, 1.0 M in THF) dropwise at 0 °C under N2. The reaction mixture was stirred at 25 °C for 30 min, followed by addition of the solution of tert- butyl 4-formyl-4-methyl-piperidine-1-carboxylate (10.0 g, 43.99 mmol) in THF (60 mL) dropwise at 0 °C. After being stirred at 25 °C for 12 hrs, the mixture was diluted with H2O (200 mL), extracted with EA (300 mL) three times. The combined organic layers was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered. The filtrate was concentrated in vacuo. The crude was purified by silica gel column (5% to 10% EA in PE) and concentrated in vacuo to afford tert-butyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1-carboxylate (Int- _7a, 10.0 g, 35.29 mmol).¹H 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). Step (b): Preparation of ^tert-butyl 4-(3-methoxy-3-^oxo-propyl)-4-methyl-piperidine-1- carboxylate Int-7b To a solution of tert-butyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1- carboxylate (_Int-7a, 10.0 g, 35.29 mmol) in methanol (100 mL) was added Pd/C (5.0 g, 10% loaded on active carbon) under N₂. The suspension was degassed in vacuo and purged with H₂ three times. The reaction mixture was stirred at 25 °C for 2 hrs under H2 balloon. The mixture was filtered through celite, washed with DCM (200 mL). The filtrate was concentrated in vacuo to afford tert-butyl 4-(3-methoxy-3-oxo-propyl)-4-methyl-piperidine-1-carboxylate (Int-7b, 9.1 g, 31.89 mmol).¹H 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). Step (c): Preparation of tert-butyl 4-(3-iodopropyl)-4-methyl-piperidine-1-carboxylate Int-7c To a solution of tert-butyl 4-(3-methoxy-3-oxo-propyl)-4-methyl-piperidine-1-carboxylate (Int-7b, 7.0 g, 24.53 mmol) in THF (70 mL) was added LiAlH4 (1.86 g, 49.06 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hrs under N₂ balloon. The suspension was quenched with Na₂SO₄ ^.10H₂O (10 g) in portions at 0 ^oC. After being stirred at 25 °C for 2 hrs, the suspension was filtered. The filtrate was concentrated in vacuo to afford tert-butyl 4-(3- hydroxypropyl)-4-methyl-piperidine-1-carboxylate (Int-7c, 5.8 g, 22.54 mmol), which was used in next step directly without further purification. MS obsd. (ESI⁺)[(M-Bu+H)⁺]: 202.2. Step (d): Preparation of tert-butyl 4-(3-iodopropyl)-4-methyl-piperidine-1-carboxylate Int-7d To a mixture of imidazole (2.01 g, 29.58 mmol) and triphenylphosphine (6.94 g, 26.48 mmol) in DCM (60 mL) was added iodine (6.94 g, 27.36 mmol) at 25 °C. The mixture was stirred for 1 hr at 25 °C under N₂, then a solution of tert-butyl 4-(3-hydroxypropyl)-4-methyl- piperidine-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 being stirred for 12 hrs at 25 °C under N₂, the reaction was diluted with DCM (100 mL), washed with Na₂SO₃ (100 mL), brine (100 mL). The organics was dried (MgSO4), concentrated in vacuo. The crude was purified by silica gel column (5% to 10% EA in PE) to afford tert-butyl 4-(3-iodopropyl)-4-methyl-piperidine-1-carboxylate (Int-7d, 5.0 g, 13.61 mmol). MS obsd. (ESI⁺)[(M-Bu+H)⁺]: 312.0. Step (e): Preparation of O1-benzyl O4-methyl 4-[3-(1-tert-butoxycarbonyl-4-methyl-4- piperidyl)propyl]piperidine-1,4-dicarboxylate Int-7e To a solution of N-Cbz-4-piperidinecarboxylic acid methyl ester (3.17 g, 11.44 mmol) in THF (50 mL) was added LiHMDS (12.87 mL, 12.87 mmol, 1.0 M in THF) at -60 ^oC dropwise. The mixture was stirred at -60 ^oC for 1 hr. Then to the mixture was added tert-butyl 4-(3- iodopropyl)-4-methyl-piperidine-1-carboxylate (_Int-7d, 3.5 g, 9.53 mmol) in THF (10 mL) dropwise at -60 ^oC. After being stirred at 20 ^oC for 12 hrs, the mixture was poured into H2O (100 mL), extracted with EA (100 mL) three times. The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (5% to 20% EA in PE) to afford O1-benzyl O4-methyl 4-[3-(1-tert- butoxycarbonyl-4-methyl-4-piperidyl)propyl]piperidine-1,4-dicarboxylate (Int-7e, 2.00 g, 3.87 mmol). MS obsd. (ESI⁺)[(M+Na)⁺]: 539.3. Step (f): preparation of 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4-methyl-4- piperidyl)propyl]piperidine-4-carboxylic acid Int-7f A mixture of O1-benzyl O4-methyl 4-[3-(1-tert-butoxycarbonyl-4-methyl-4- piperidyl)propyl]piperidine-1,4-dicarboxylate (Int-7e, 1.50 g, 2.9 mmol), NaOH (1.16 g, 29.03 mmol) in Ethanol (20 mL) and water (20 mL) was stirred at 70 °C for 6 hrs. The mixture was diluted with H₂O (100 mL), extracted with EA (200 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash (0.1% FA) to afford 1-benzyloxycarbonyl-4-[3-(1-tert- butoxycarbonyl-4-methyl-4-piperidyl)propyl]piperidine-4-carboxylic acid (_Int-7f, 1.20 g, 2.39 mmol). MS obsd. (ESI⁺)[(M-Boc+H)⁺]: 503.3. Step (g): Preparation of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-fluoro-4- piperidyl)propyl]-4-methyl-piperidine-1-carboxylate Int-7g A mixture of 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4-methyl-4- piperidyl)propyl]piperidine-4-carboxylic acid (Int-7f, 1.20 g, 2.39 mmol), AgNO3 (811.08 mg, 4.77 mmol), Selectfluor (2018.05 mg, 5.7 mmol) in Acetone (10 mL) and water (10 mL) was degassed and purged with N2 three times. After being stirred at 20 °C for 12 hrs under N2, the mixture was diluted with H2O (30 mL), extracted with DCM (30 mL) three times. The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (10% to 40% EA in PE) to afford tert-butyl 4-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidyl)propyl]-4-methyl-piperidine-1-carboxylate (Int- _7g, 800.0 mg, 1.68 mmol. MS obsd. (ESI⁺)[(M+Na)⁺]: 499.3. Step (h): Preparation of benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine- 1-carboxylate Int-7 A solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidyl)propyl]-4-methyl- piperidine-1-carboxylate (Int-7g, 600.0 mg, 1.26 mmol) in TFA (3.0 mL) and DCM (10 mL) was stirred at 20 °C for 2 hrs. The mixture was diluted with H2O (30 mL), basified with solid NaHCO₃ to pH = 8, extracted with DCM (30 mL) three times. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo to afford benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (Int- ₇, 450.0 mg, 1.2 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 377.3. Intermediate 15: tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1- carboxylate Int-15 Step (a): preparation of O1-tert-butyl O3-methyl 3-[3-(1-benzyloxycarbonyl-4- piperidyl)propyl]-4-oxo-piperidine-1,3-dicarboxylate Int-15a To a solution of O1-tert-butyl O3-methyl 4-oxopiperidine-1,3-dicarboxylate (5.5 g, 21.38 mmol) in DMF (50 mL) was added K2CO3 (5.91 g, 42.75 mmol) and benzyl 4-(3- iodopropyl)piperidine-1-carboxylate (Int-1b, 9.93 g, 25.65 mmol) at 0 °C. After being stirred at 50 °C for 16 hrs, the mixture was poured into water (200 mL), then extracted with EA (150 mL) three times. The combined organic phase was washed with brine (200 mL) twice, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (60% EA in PE) to afford O1-tert-butyl O3-methyl 3-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-oxo-piperidine-1,3-dicarboxylate (Int-15a, 9100.0 mg, 17.61 mmol). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 417.4. Step (b): preparation of ^tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- oxo-piperidine-1-carboxylate Int-15b To a solution of O1-tert-butyl O3-methyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- oxo-piperidine-1,3-dicarboxylate (_Int-15a, 8.7 g, 16.84 mmol) in NMP (90 mL) was added LiCl (4.28 g, 101.04 mmol). After being stirred at 150 °C for 2 hrs, the mixture was poured into water (150 mL), then extracted with EA (120 mL) twice. The combined organic phase was washed with brine (100 mL) three times, dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo The residue was purified by silica gel column (35% EA in PE) to afford tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-oxo-piperidine-1-carboxylate (Int- 15b, 5.1 g, 11.12 mmol). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 359.1. Step (c): preparation of tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4,4- difluoro-piperidine-1-carboxylate Int-15c To a solution of tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-oxo-piperidine- 1-carboxylate (Int-15b, 5.1 g, 11.12 mmol) in DCM (60 mL) was added DAST (13.64 mL, 111.21 mmol) at 0 °C. After being stirred at 25 °C for 12 hrs, the mixture was poured into sat. NaHCO3 (200 mL) at 0 °C, then extracted with DCM (80 mL) twice. The organic layers were dried with anhydrous Na2SO4, filtered, concentrated in vacuo. The residue was purified by silica gel column (25% EA in PE) to afford tert-butyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]- 4,4-difluoro-piperidine-1-carboxylate (Int-15c, 4.2 g, 8.74 mmol). MS obsd. (ESI⁺) [(M- Boc+H)⁺]: 381.2. Step (d): preparation of tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1- carboxylate Int-15 Tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-15) was prepared in analogy to _{intermediate 1} in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert- butyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4,4-difluoro-piperidine-1-carboxylate (Int- _15c). tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (_Int-15b, 2.8 g, 8.08 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 347.2. Intermediate-16: tert-butyl 4,4-difluoro-3-[2-(4-piperidyl)ethoxy]piperidine-1- carboxylate Int-16 Step (a): preparation of benzyl 4-(2-iodoethyl)piperidine-1-carboxylate (Int-16a) Int-16a To a solution of imidazole (1.02 g, 14.96 mmol) and triphenylphosphine (3.51 g, 13.39 mmol) in DCM (40 mL) was added iodine (3.51 g, 13.83 mmol) at 25 °C. The mixture was stirred for 1 hr at 25 °C, then a solution of benzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (3.0 g, 11.39 mmol) in DCM (2 mL) was added to the mixture. After being stirred for 3 hrs at 25 °C, the mixture was poured into sat. aq Na₂SO₃ (150 mL), then extracted with DCM (150 mL) three times. The combined organic phase was washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 5% to 35% EA in PE gradient @ 120 mL/min) to afford benzyl 4-(2-iodoethyl)piperidine-1-carboxylate (Int- 16a, 3800.0 mg, 10.18 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 374.0. Step (b): preparation of tert-butyl 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethoxy]-4,4- difluoro-piperidine-1-carboxylate (Int-16b) Int-16b 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) was added sodium hydride (674.39 mg, 16.86 mmol) at 0 °C. The mixture was evacuated and backfilled with N₂ three times. After being stirred for 2 hrs at 25 °C under N2, the mixture was poured into sat. NH4Cl (150 mL), extracted with EA (150 mL) three times. The combined organic phase was washed with brine (400 mL) twice, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 30~60% EA in PE gradient @ 80 mL/min) to afford tert-butyl 3-[2-(1-benzyloxycarbonyl-4- piperidyl)ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int-16b, 1400.0 mg, 2.9 mmol). MS obsd. (ESI⁺) [(M+Na)⁺]: 505.2. Step (c): preparation of ^tert-butyl 4,4-difluoro-3-[2-(4-piperidyl)ethoxy]piperidine-1- carboxylate (Int-16) Int-16 tert-butyl 4,4-difluoro-3-[2-(4-piperidyl)ethoxy]piperidine-1-carboxylate (Int-16) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert- butyl 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int- 16b). Tert-butyl 4,4-difluoro-3-[2-(4-piperidyl)ethoxy]piperidine-1-carboxylate (Int-16, 1130.0 mg, 3.24 mmol) was obtained, which was used in next step directly without further purification. Intermediate-17: tert-butyl 3,3-difluoro-4-[2-(4-piperidyl)ethoxy]pyrrolidine-1- carboxylate Int-17 Step (a): tert-butyl 3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate Int-17a 4,4-Difluoropyrrolidin-3-ol; hydrochloride (1000.0 mg, 6.27 mmol) in THF (5 mL) and water (5 mL) was added NaHCO₃ (1316.28 mg, 15.67 mmol) and tert-butyl 3,3-difluoro-4- hydroxy-pyrrolidine-1-carboxylate (1399.0 mg, 6.27 mmol) at 25 °C. After being stirred at 25 °C for 12 hrs, the mixture was poured into water (30 mL) and extracted with EA (20 mL) three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give tert-butyl 3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate (Int- 17a, 1399.0 mg, 6.27 mmol), which was used in next step directly without further purification. 1H 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). Step (b): benzyl 4-[2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3- yl)oxyethyl]piperidine-1-carboxylate Int-17b 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) was added NaH (401.4 mg, 10.03 mmol) at 0°C. The suspension was stirred at 0°C for 0.5 hr. A solution of benzyl 4-[2-(p- tolylsulfonyloxy)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 hrs. The suspension was quenched with sa.NH4Cl (5 mL) at 0°C under N2. The mixture was extracted with EA (70 mL) three times. The combined organic layers was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude was purified by reversed phase flash (80g Flash Column Welch Ultimate XB_C1820-40μm; 120 A, water (0.1% FA)-ACN, 100%, 100ml/min) to afford benzyl 4-[2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3- yl)oxyethyl]piperidine-1-carboxylate (Int-17b, 869.0 mg, 1.85 mmol). MS obsd. (ESI⁺) [(M+Na)⁺]: 491.2. Step (c): tert-butyl 3,3-difluoro-4-[2-(4-piperidyl)ethoxy]pyrrolidine-1-carboxylate Int-17 Tert-butyl 3,3-difluoro-4-[2-(4-piperidyl)ethoxy]pyrrolidine-1-carboxylate (_Int-17, 610.0 mg, 1.82 mmol) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4- [3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with benzyl 4-[2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl)oxyethyl]piperidine-1- carboxylate (Int-17b). MS obsd. (ESI⁺) [(M+H)⁺]: 335.3. Intermediate 18: tert-butyl 4,4-difluoro-3-[3-(4-fluoro-4-piperidyl)propyl]piperidine-1- carboxylate Int-18 Step (a): ^tert-butyl 3-allyl-4-^oxo-piperidine-1-carboxylate Int-18a To a solution of LDA (56.0 mL, 112.0 mmol) in THF (50 mL) was added 1-BOC-4- piperidone (20.0 g, 100.38 mmol) in THF (150 mL) at -78°C under N2. The mixture was stirred for 2 hrs at -78°C, 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 hr and warmed to 20°C and stirred at 20 °C for 12 hrs. After the reaction was completed, the temperature was cooled to 0 °C, and 300 mL of sat. NH4Cl was added dropwise for quenching at 0°C and extracted by EA (150 mL) twice. The organic phases were combined, and the organic layer was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column (8% EA in PE). Tert-butyl 3-allyl-4-oxo- piperidine-1-carboxylate (Int-18a, 5.48 g, 22.9 mmol) was obtained. MS obsd. (ESI⁺) [(M-tBu +H)⁺]: 184.1. Step (b): tert-butyl 3-allyl-4,4-difluoro-piperidine-1-carboxylate Int-18b 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) was added BAST (50.66 g, 228.98 mmol) dropwise at 25°C under N₂. The mixture was heated to 45°C and stirred at 4 °C for 2 hrs. The mixture was cooled to 25°C and quenched by sat. aq. NaHCO3 to pH = 7~8. The mixture was extracted with DCM (150 mL) three times. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude was purified by column (4% EA in PE). Tert-butyl 3-allyl-4,4- difluoro-piperidine-1-carboxylate (Int-18b, 4686.0 mg, 17.93 mmol) was obtained. MS obsd. (ESI⁺) [(M tBu +H)⁺]: 206.1. Step (c): tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)piperidine-1-carboxylate Int-18c The compound was synthesized by 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 (3eq., 3M,9mL), Set bath to 25°C ±2°C, Set pump A =2.4 mL/min, pump B =2.0 mL/min, pump C =1.5 mL/min Time = 0 tart pump A and pump B Time = 5 mins, start pump C Time = 10-15 mins, take sample for TLC Quench: transfer FLR2 to 0-5°C Na₂SO₃ (10%, 2 eq.) as continuous flow The combined collected phase were extracted by EA (150 mL) twice. The organic phases were combined, and the organic layer was dried over anhydrous Na2SO4 and concentrated to afford tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)piperidine-1-carboxylate (Int-18c, 2358.0 mg, 8.44 mmol). Step (d): tert-butyl 4,4-difluoro-3-(3-iodopropyl)piperidine-1-carboxylate Int-18d To a solution of imidazole (0.75 g, 11.08 mmol) and triphenylphosphine (2.6 g, 9.92 mmol) in DCM (200 mL) was added iodine (2.6 g, 10.25 mmol) at 0°C under N₂. The mixture was stirred for 1 hr at 0°C, 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 being stirred for 12 hrs at 20°C under N₂, the mixture was poured into sat. Na₂SO₃ (250 mL), then extracted with DCM (200 mL) three times. The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude was then purified by flash column chromatography eluting 8% EA in isohexane. The desired fractions were concentrated in vacuo to afford tert-butyl 4,4-difluoro-3- (3-iodopropyl)piperidine-1-carboxylate (Int-18d, 1800.0 mg, 4.62 mmol). MS obsd. (ESI⁺) [(M- C4H9+H)⁺]: 344.0. Step (e): tert-butyl 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidyl)propyl]-4,4- difluoro-piperidine-1-carboxylate Int-18e To a solution of 4-formyl-N-CBZ-piperidine (600.0 mg, 2.43 mmol) in DMF (15 mL) was added 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) dropwise at 0°C. After being stirred for 5 hrs at 25°C, the mixture was poured into water (70 mL), then extracted with EA (60 mL) three times. The combined organic phase was washed with brine (80 mL) twice, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by prep-HPLC (condition Phenomenex luna C18150*40mm* 15um, water (FA)-ACN, 40%-80%), then extracted with EA (50 mL) three times. The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to afford tert-butyl 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidyl)propyl]-4,4-difluoro- piperidine-1-carboxylate (Int-18e, 440.0 mg, 0.87 mmol). MS obsd. (ESI⁺) [(M+Na)⁺]: 531.2 Step (f): 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3- piperidyl)propyl]piperidine-4-carboxylic acid Int-18f To a solution of sodium chlorite (234.72 mg, 2.6 mmol) in water (1.6 mL) was added tert- butyl 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidyl)propyl]-4,4-difluoro-piperidine-1- carboxylate (Int-18e, 440.0 mg, 0.87 mmol), sodium dihydrogenphosphate 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) at 25°C. After being stirred at 25°C for 0.5 hr, the mixture was quenched by H2O (20 mL) and extracted with EA (15 mL) three times. The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The crude was purified by reversed flash (120g Flash Column Welch Ultimate XB_C1820-40μm; 120 A, water (0.1% FA)-ACN, 76%, 80ml/min).1-benzyloxycarbonyl-4-[3-(1-tert- butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]piperidine-4-carboxylic acid (Int-18f, 355.0 mg, 0.68 mmol) was obtained. MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 425.3. Step (g): tert-butyl 3-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidyl)propyl]-4,4- difluoro-piperidine-1-carboxylate Int-18g To a mixture of 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3- piperidyl)propyl]piperidine-4-carboxylic acid (Int-18f, 350.0 mg, 0.67 mmol) and Selectfluor (472.7 mg, 1.33 mmol) in acetone (6 mL) water (6 mL) was added AgNO₃ (181.46 mg, 1.07 mmol) under N₂. The mixture was degassed under N₂ three times. After being stirred at 20°C for 3 hrs under N2, the mixture was diluted with H2O (40 mL), extracted with EA (20 mL) three times. The organic layer was dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column (18% EA in PE). Tert-butyl 3-[3-(1- benzyloxycarbonyl-4-fluoro-4-piperidyl)propyl]-4,4-difluoro-piperidine-1-carboxylate (Int-18g, 189.0 mg, 0.38 mmol) was obtained. MS obsd. (ESI⁺) [(M+Na)⁺]: 521.2 Step (h): tert-butyl 4,4-difluoro-3-[3-(4-fluoro-4-piperidyl)propyl]piperidine-1- carboxylate Int-18 Tert-butyl 4,4-difluoro-3-[3-(4-fluoro-4-piperidyl)propyl]piperidine-1-carboxylate (Int-18) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (_Int-1e) with tert- butyl 3-[3-(1-benzyloxycarbonyl-4-fluoro-4-piperidyl)propyl]-4,4-difluoro-piperidine-1- carboxylate (Int-18g). Tert-butyl 4,4-difluoro-3-[3-(4-fluoro-4-piperidyl)propyl]piperidine-1- carboxylate (_Int-18, 138.0 mg, 0.38 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 365.3. Intermediate 19: tert-butyl 4,4-difluoro-3-[3-(4-methyl-4-piperidyl)propyl]piperidine- 1-carboxylate Int-19 Step (a): ^tert-butyl 3-[3-[1-benzyloxycarbonyl-4-(difluoromethyl)-4-piperidyl]propyl]- 4,4-difluoro-piperidine-1-carboxylate Int-19a To a solution of tert-butyl 3-[3-(1-benzyloxycarbonyl-4-formyl-4-piperidyl)propyl]-4,4- difluoro-piperidine-1-carboxylate (Int-18e, 150.0 mg, 0.29 mmol) in DCM (6 mL) was added (0.54 mL, 2.95 mmol) at 0 °C. After being stirred at 45 °C for 16 hrs, the mixture was poured into NaHCO3 (30 mL) at 0 °C, extracted with EA (30 mL) twice. The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was then purified by flash column chromatography (20% EA in Isohexane). The desired fractions were concentrated to dryness in vacuo to afford tert-butyl 3- [3-[1-benzyloxycarbonyl-4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (_Int-19a, 150.0 mg, 0.28 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 531.2. Step (b): tert-butyl 3-[3-[4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate Int-19 Tert-butyl 3-[3-[4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (Int-19, 127.0 mg, 0.32 mmol) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1- carboxylate (Int-1e) with tert-butyl 3-[3-[1-benzyloxycarbonyl-4-(difluoromethyl)-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Int-19a). Intermediate 20: ^tert-butyl 6,6-difluoro-1-[3-(4-piperidyl)propyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate Int-20 Step (a): benzyl 4-[3-(1-tert-butoxycarbonyl-2,5-dihydropyrrol-3-yl)propyl]piperidine- 1-carboxylate Int-20a To a solution of benzyl 4-(3-iodopropyl)piperidine-1-carboxylate (_Int-1b, 3.0 g, 7.75 mmol) in DMF (50 mL) and Water (10 mL) was added 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-dioxaborolan-2- yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2744.11 mg, 9.3 mmol). The reaction mixture was stirred at 90 °C for 12 hrs under N₂. The crude mixture was filtered through a pad celit, and the filtrate was concentrated in vacuo. The mixture was diluted with EA (160 mL), washed with water (90 mL) and brine (60 mL) three times, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (Column: Phenomenex luna C18150*40mm* 15um; Condition: water (TFA)-ACN; B%: 60-90%; FlowRate (mL/min): 60). The fraction was adjusted with sat. aq. NaHCO3 to pH = 9 and concentrated in vacuo to remove MeCN, extracted with EA (80mL) twice. The combined organic phase was dried with anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo to afford benzyl 4-[3-(1-tert-butoxycarbonyl-2,5-dihydropyrrol-3-yl)propyl]piperidine-1- carboxylate (_Int-20a, 700.0 mg, 1.63 mmol). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 329.2 Step (b): tert-butyl 1-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate Int-20b To a solution of benzyl 4-[3-(1-tert-butoxycarbonyl-2,5-dihydropyrrol-3- yl)propyl]piperidine-1-carboxylate (_Int-20a, 350.0 mg, 0.82 mmol) in THF (3 mL) was added NaI (73.45 mg, 0.49 mmol) and trifluoromethyltrimethylsilane (1509.7 mg, 10.62 mmol). The reaction mixture was stirred at 66 °C for 5 hrs under N2. The mixture was concentrated in vacuo. The residue was purified by column (30% EA in PE) to afford tert-butyl 1-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int-20b, 1509.7 mg, 10.62 mmol). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 379.2. Step (c): tert-butyl 6,6-difluoro-1-[3-(4-piperidyl)propyl]-3-azabicyclo[3.1.0]hexane-3- carboxylate Int-20 Tert-butyl 6,6-difluoro-1-[3-(4-piperidyl)propyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int-20, 287.0 mg, 0.83 mmol) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1- carboxylate (Int-1e) with tert-butyl 1-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-6,6-difluoro- 3-azabicyclo[3.1.0]hexane-3-carboxylate (Int-20b). Intermediate 21: tert-butyl 2-[3-(4-piperidyl)propyl]morpholine-4-carboxylate Int-21 Step (a): tert-butyl 2-formylmorpholine-4-carboxylate Int-21a Into a 500 mL 3-necked round-bottom flask and maintained with an inert atmosphere of nitrogen, were placed (COCl)₂ (2.36 mL, 27.62 mmol), DCM (30 mL). After that, DMSO (4.9 mL, 69.04 mmol) was added at - 78°C. Then the mixture was stirred for 1 hr at -78°C. A solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (3000.0 mg, 13.81 mmol) in DCM (10 mL) was added dropwise at -78°C, then the mixture was stirred for 30 minutes. This was followed by the addition of TEA (9.6 mL, 69.04 mmol) at -78°C. After being stirred at -78°C for 2 hrs, the mixture was poured into water (150 mL), then extracted with EA (150 mL) three times. The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to afford tert-butyl 2-formylmorpholine-4- carboxylate (Int-21a, 3.2 g, 14.87 mmol). 1H 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): ^tert-butyl 2-[1-hydroxy-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate Int-21b To a solution of 4-ethynylpyridine (1317.44 mg, 12.78 mmol) in THF (25 mL) was added n-BuLi (5.57 mL, 13.94 mmol) at -60 °C under N2. The reaction mixture was further stirred for 6 min, then a solution of tert-butyl 2-formylmorpholine-4-carboxylate (_Int-21a, 2.5 g, 11.61 mmol) in THF (5 mL) was added to the mixture under N₂. After being stirred for 2 hrs at -60 °C under N2, the mixture was poured into sat. NH4Cl (150 mL), then extracted with EA (100 mL) three times. The combined organic phase was washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 80~100% EA in PE gradient @ 120 mL/min). The desired fractions were concentrated in vacuo to afford tert- butyl 2-[1-hydroxy-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate (_Int-21b, 1300.0 mg, 4.08 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 319.3. Step (c): tert-butyl 2-[1-(imidazole-1-carbothioyloxy)-3-(4-pyridyl)prop-2- ynyl]morpholine-4-carboxylate Int-21c To a solution of tert-butyl 2-[1-hydroxy-3-(4-pyridyl)prop-2-ynyl]morpholine-4- carboxylate (Int-21b, 1.3 g, 4.08 mmol) in DCM (13 mL) was added 1,1'- thiocarbonyldiimidazole (873.22 mg, 4.9 mmol). After being stirred for 16 hrs at 25 °C, the mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (condition Phenomenex luna C18150*40mm* 15um, water (FA)-ACN, 30%-60%) to afford [tert-butyl 2- [1-(imidazole-1-carbothioyloxy)-3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate (Int-21c, 400.0 mg, 0.93 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 429.2. Step (d): tert-butyl 2-[3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate Int-21d To a solution of tert-butyl 2-[1-(imidazole-1-carbothioyloxy)-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) was added Bu3SnH (0.5 mL, 1.87 mmol). The mixture was evacuated and backfilled with N₂ three times. After being stirred for 1.5 hrs at 80 °C under N₂, the mixture was poured into sat. CsF (100 mL), then extracted with EA (60 mL) three times. The combined organic phase was washed with brine (120 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 20% to 50% EA in PE gradient @ 45 mL/min) to afford tert-butyl 2-[3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate (Int-21d, 200.0 mg, 0.66 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 303.2. Step (e): ^tert-butyl 2-[3-(4-piperidyl)propyl]morpholine-4-carboxylate Int-21 A solution of tert-butyl 2-[3-(4-pyridyl)prop-2-ynyl]morpholine-4-carboxylate (_Int-21d, 200.0 mg, 0.66 mmol) in THF (20 mL) was stirred at 25 ℃ until becoming clear solution. Adjust the H2 back pressure regulator to 2.5 MPa, the flow rate of H2 to 30 mL/min, heated the fixed bed (10% Ru/SiO₂, 3 g) to 90 ℃. Then the solution was pumped into the reactor at a flow rate of 0.3 mL/min. After the reaction was finished, wash the tubing with MeOH 50 mL, collected all the reaction solution for analysis. After the reaction was finished, the reaction solution was concentrated in vacuo to get tert-butyl 2-[3-(4-piperidyl)propyl]morpholine-4-carboxylate (_Int- 21, 180.0 mg, 0.58 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 313.2. Intermediate 22: tert-butyl 4,4-difluoro-3-[3-(4-methyl-4-piperidyl)propyl]piperidine- 1-carboxylate Int-22 Step (a): benzyl 4-formyl-4-methyl-piperidine-1-carboxylate Int-22a To a solution of 4-formyl-N-CBZ-piperidine (25.0 g, 101.1 mmol) in DMF (500 mL) was added t-BuOK (24.51 g, 202.19 mmol) and iodomethane (12.64 mL, 202.19 mmol) at 0 °C and then stirred at 25 °C for 12 hrs. The reaction mixture was diluted with water (500 mL), extracted with EA (100 mL) four times. The combined organic layers were washed with brine (200 mL) twice, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0% to 30% EA in PE) and the desired fractions were concentrated in vacuo to afford benzyl 4-formyl-4-methyl-piperidine-1-carboxylate (Int-22a, 14.5 g, 55.49 mmol). MS obsd. (ESI+) [(M+Na)⁺]: 262.3 Step (b): benzyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1- carboxylate Int-22b To a solution of trimethyl phosphonoacetate (16.59 g, 91.08 mmol) in THF (100 mL) was added t-BuOK (12.02 g, 107.15 mmol) in potions at 0°C, then stirred at 25°C for 0.5 hr. Benzyl 4-formyl-4-methyl-piperidine-1-carboxylate (Int-22a, 14.0 g, 53.57 mmol) in THF (100 mL) was added dropwise to the mixture at 0°C, and then stirred at 25 °C for 12 hrs. The reaction mixture was diluted with water (300mL), extracted with EA (150 mL) four times. The combined organic layers were washed with brine (200 mL) twice, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0% to 30% EA in PE). The residue was purified by reversed-phase HPLC (0.1% FA condition) and lyophilized to afford benzyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1- carboxylate (Int-22b, 5.0 g, 15.75 mmol).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 obsd. (ESI+) [(M+Na)⁺]: 318.2 Step (c): Preparation of methyl 3-(4-methyl-4-piperidyl)propanoate Int-22c A solution of benzyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1- carboxylate (Int-22b, 5.0 g, 15.75 mmol) in methanol (20 mL) was added Pd/C (500.0 mg) under N₂, then the mixture was degassed and purged with H₂ for three times and stirred at 25 °C for 2 hrs. The reaction mixture was filtered to afford methyl 3-(4-methyl-4-piperidyl)propanoate (Int-22c, 2.9 g, 15.56 mmol), which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 186.2. Step (d): benzyl 4-(3-methoxy-3-^oxo-propyl)-4-methyl-piperidine-1-carboxylate Int-22d A solution of CbzOSu (3120.8 mg, 12.52 mmol), methyl 3-(4-methyl-4- piperidyl)propanoate (Int-22c, 2.32 g, 12.52 mmol) in methanol (50 mL) was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated in vacuo. The oil was diluted with water (50 mL), extracted with EA (50 mL) four times. The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to afford benzyl 4-(3- methoxy-3-oxo-propyl)-4-methyl-piperidine-1-carboxylate (Int-22d, 3.94 g, 12.34 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 320.2. Step (e): benzyl 4-(3-hydroxypropyl)-4-methyl-piperidine-1-carboxylate Int-22e NaBH4 (604.05 mg, 15.97 mmol) was added to the solution of benzyl 4-(3-methoxy-3-oxo- propyl)-4-methyl-piperidine-1-carboxylate (Int-22d, 3.4 g, 7.98 mmol) in ethanol (35 mL) at 0°C, then stirred at 25°C for 1 hr. The reaction mixture was quenched with water (120 mL), extracted with EA (40 mL) four times. The combined organic layers were washed with brine (50 mL) twice, dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0% to 30% EA in PE) and the organic layer was concentrated in vacuo to afford benzyl 4-(3-hydroxypropyl)-4-methyl-piperidine-1-carboxylate (Int-22e, 1.58 g, 5.42 mmol). MS obsd. (ESI⁺) [(M+Na)⁺]: 314.2. 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), PPh₃ (1.66 g, 6.34 mmol) in DCM (12 mL) was stirred at 25 °C for 0.5 hr. Then benzyl 4-(3- hydroxypropyl)-4-methyl-piperidine-1-carboxylate (Int-22e, 1.58 g, 5.42 mmol) in DCM (10 mL) was added to the mixture and then stirred at 25 °C for 12 hrs. The reaction mixture was diluted with Na2SO3 (60 mL), extracted with DCM (30 mL) four times. The combined organic layers was washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0% to 10% EA in PE) and the organic layer was concentrated in vacuo to afford benzyl 4-(3-iodopropyl)-4- methyl-piperidine-1-carboxylate (Int-22f, 2.01 g, 5.01 mmol).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 obsd. (ESI⁺) [(M+H)⁺]: 402.1 Step (g): O1-tert-butyl O3-methyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4- piperidyl)propyl]-4-oxo-piperidine-1,3-dicarboxylate Int-22g To a solution of benzyl 4-(3-iodopropyl)-4-methyl-piperidine-1-carboxylate (2.0 g, 4.98 mmol) and O1-tert-butyl O3-methyl 4-oxopiperidine-1,3-dicarboxylate (Int-22f, 1282.31 mg, 4.98 mmol) in DMF (25 mL) was added K₂CO₃ (1377.56 mg, 9.97 mmol) and then stirred at 50 °C for 12 hrs. The reaction mixture was diluted with water (120 mL), extracted with EA (40 mL) four times. The combined organic layers were washed with brine (50 mL) twice, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0% to 30% EA in PE) to afford O1-tert-butyl O3-methyl 3-[3-(1- benzyloxycarbonyl-4-methyl-4-piperidyl)propyl]-4-oxo-piperidine-1,3-dicarboxylate (Int-22g, 1790.0 mg, 3.37 mmol). MS obsd. (ESI⁺) [(M+Na)⁺]: 553.4. Step (h): ^tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)propyl]-4-^oxo- piperidine-1-carboxylate Int-22h To a solution of O1-tert-butyl O3-methyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl) propyl]-4-oxo-piperidine-1,3-dicarboxylate (Int-22g, 1.69 g, 3.18 mmol) in NMP (17 mL) was added LiCl (810.0 mg, 19.11 mmol). After being stirred at 150 °C for 0.5 hr, the reaction mixture was diluted with water (120 mL), extracted with EA (40 mL) four times. The combined organic layers were washed with brine (50 mL) twice, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0% to 30% EA in PE) to afford tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)propyl]-4-oxo- piperidine-1-carboxylate (Int-22h, 1.32 g, 2.79 mmol). MS obsd. (ESI⁺) [M-C₄H₈+H]⁺: 473.3. Step (i): tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl) propyl]-4-oxo- piperidine-1-carboxylate Int-22i To a solution of tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)propyl]-4-oxo- piperidine-1-carboxylate (Int-22h, 1200.0 mg, 2.54 mmol) in DCM (20 mL) was added 4- (trifluoro-λ⁴-sulfanyl)morpholine (4446.78 mg, 25.39 mmol) at 0°C and stirred at 30 °C for 16 hrs. The reaction mixture was diluted with water (120 mL), extracted with EA (40 mL) four times. The combined organic layers were washed with brine (50 mL) twice, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (to afford tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)propyl]- 4,4-difluoro-piperidine-1-carboxylate (_Int-22h, 780.0 mg, 1.58 mmol). MS obsd. (ESI⁺) [M+Na]⁺: 495.3. Step (j): tert-butyl 4,4-difluoro-3-[3-(4-methyl-4-piperidyl)propyl]piperidine-1- carboxylate Int-22 Tert-butyl 4,4-difluoro-3-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (Int 22, 524.0 mg, 1.45 mmol₎ was prepared in analogy to _{intermediate 1} in step (f) by replacing tert- butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl) propyl]-4,4-difluoro- piperidine-1-carboxylate (_Int-22). MS obsd. (ESI⁺) [M+H]⁺: 361.3. Intermediate 23: ^tert-butyl 4,4-difluoro-3-[2-(4-methyl-4-piperidyl)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-methyl-piperidine-1-carboxylate (2.0 g, 8.22 mmol) in TFA (3.0 mL, 8.22 mmol) was stirred at 25 °C for 10 hrs. The residue was dissolved in THF (20 mL). Then to the mixture was added a solution of Na2CO3 (2.61g, 24.66 mmol) in water (5 mL) dropwise, then N-(benzyloxycarbonyloxy)succinimide (2.05 g, 8.22 mmol) was added. After being stirred for 12 hrs at 25 °C, the reaction mixture was concentrated to dryness and the residue was taken up in EtOAc (50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), concentrated to afford benzyl 4-(2-hydroxyethyl)-4- methyl-piperidine-1-carboxylate (Int-23a, 3.20 g, 11.54 mmol) and used directly next step without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 278.1. Step (b): benzyl 4-methyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate Int-23b To a solution of benzyl 4-(2-hydroxyethyl)-4-methyl-piperidine-1-carboxylate (3.2 g, 11.54 mmol, Int-23a) in DCM (35 mL) was added TEA (1.81 g, 17.88 mmol) and p-toluenesulfonyl chloride (3.3g, 17.31 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 16 hrs. Then the reaction mixture was quenched by H2O (120 mL) and extracted with DCM (100 mL) twice. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude was purified by column (30% EA in PE) to afford benzyl 4- methyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (2.5 g, 5.79 mmol, Int-23b). MS obsd. (ESI⁺) [(M+H)⁺]: 432.1. Step (c): tert-butyl 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)ethoxy]-4,4-difluoro- piperidine-1-carboxylate Int-23c To a solution of tert-butyl 4,4-difluoro-3-hydroxy-piperidine-1-carboxylate (750.0 mg, 3.16 mmol) in NMP (15 mL) was added NaH (505.8 mg, 12.64 mmol) in portions at 0 °C under N2. The suspension was stirred at 0 °C for 0.5 hr. A solution of benzyl 4-methyl-4-[2-(p- tolylsulfonyloxy)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 for 11.5 hrs under N2. The suspension was quenched by aqueous saturated NH4Cl (80 mL) at 0 °C under N2. The reaction mixture was extracted with EA (50 mL) twice. The combined organic layers were washed with brine (30 mL) three times, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column (30% EA in PE) to afford tert- butyl 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine-1- carboxylate (1.0 g, 2.01 mmol, _Int-23c). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 397.3. Step (d): tert-butyl 4,4-difluoro-3-[2-(4-methyl-4-piperidyl)ethoxy]piperidine-1-carboxylate Int-23 To a solution of tert-butyl 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)ethoxy]-4,4- difluoro-piperidine-1-carboxylate (1.0 g, 2.01 mmol, Int-23c) in ethyl acetate (20 mL) was added Pd/C (0.1 g, 10% purity on charcoal) and Pd(OH)2/C (0.1 g, 10% purity on charcoal) under N₂. The suspension was degassed in vacuo and purged with H₂ three times. The suspension was stirred at 25 °C for 2 hrs under H₂ balloon. The crude mixture was filtered through a pad celit, and the filtrate was concentrated in vacuo to afford tert-butyl 4, 4-difluoro-3-[2-(4-methyl- 4-piperidyl)ethoxy]piperidine-1-carboxylate (720.0 mg, 1.99 mmol, _Int-23). Intermediate 24: tert-butyl 3-[2-(4-ethyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine-1- carboxylate Int-24 Step (a): benzyl 4-ethyl-4-formyl-piperidine-1-carboxylate Int-24a To a solution of 4-formyl-N-CBZ-piperidine (40.0 g, 161.75 mmol) in DMF (500 mL) were added t-BuOK (36.3 g, 323.51 mmol) and iodoethane (25.88 mL, 323.51 mmol) at 0°C. The reaction mixture was stirred at 25 °C for 16 hrs. Then the reaction mixture was diluted with H2O (1000 mL), extracted with EA (400 mL) three times. The combined organic layers were concentrated in vacuo. The residue was purified by silica column (PE/EA= 20/1 to 10/1, Rf = 0.45) and concentrated to afford benzyl 4-ethyl-4-formyl-piperidine-1-carboxylate (20.0 g, 72.63 mmol, Int-24a) was obtained.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). Step (b): benzyl 4-ethyl-4-vinyl-piperidine-1-carboxylate Int-24b To a solution methyltriphenylphosphonium bromide (50.6 g, 141.64 mmol) of in tetrahydrofuran (130 mL) was added t-BuOK (21.56 g, 141.64 mmol) at 0°C and the mixture was stirred at 40℃ for 1 hr, then a solution of benzyl 4-ethyl-4-formyl-piperidine-1-carboxylate (13.0 g, 47.21 mmol, Int-24a) in THF (50 mL) was added and the resulting mixture was stirred at 40℃ for 1 hr under N₂. The mixture was quenched with water (400 mL) and extracted with EA (100 mL) twice, the combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA=1/0 to 10/1), TLC (PE: EA= 3:1, PMA) and concentrated in vacuo to afford benzyl 4-ethyl-4-vinyl-piperidine-1-carboxylate (10.3 g, 37.68 mmol, Int-24b). ¹H 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) . Step (c): benzyl 4-ethyl-4-(2-hydroxyethyl)piperidine-1-carboxylate Int-24c The intermediate 24c was obtained by flower 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%, 7.5g) in NaOH, 3 eq, 4.389 g (2M, 55 mL) The solution 1 was pumped by Pump 1 S1, P1, 7.667 mL/min to flow reactor 1 FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, 25 °C The solution 2 was pumped by Pump 2 S2, P2, 5.156 mL/min to flow reactor 1 FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, 25 °C The solution 3 was pumped by Pump 3 S3, P3, 4.345 mL/min to flow reactor 2 FLR2, GL, CSTRs, 100 mL,0 °C The residence time of flow reactor 1 was FLR1, 5 min The residence time of flow reactor 2 was FLR2, 5.825 min. TLC (PE: EA = 3:1) showed the starting material was consumed completely and desired spot was detected. The mixture was collected with a bottle (contained 50 mL 1M aq.Na2SO3). The mixture was extracted with EA (200 mL) twice. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to afford benzyl 4-ethyl-4-(2-hydroxyethyl)piperidine-1-carboxylate (10.6 g, 36.38 mmol, 86.9% yield, Int-24c). 1H 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). Step (d): benzyl 4-ethyl-4-(2-iodoethyl) piperidine-1-carboxylate Int-24d To a solution of imidazole (2.93 g, 42.98 mmol) and triphenylphosphine (10.09 g, 38.47 mmol) in DCM (150 mL) was added iodine (10.09 g, 39.75 mmol) at 25 °C. The mixture was stirred for 1 hr at 25 °C, then to the mixture a solution of benzyl 4-ethyl-4-(2- hydroxyethyl)piperidine-1-carboxylate (10.6 g, 32.74 mmol, Int-24c) in DCM (60 mL) was added. After being stirred for 12 hrs at 25 °C, the reaction mixture was diluted with water (300 mL), extracted with EA (100 mL) four times. The combined organic layers were washed with brine (100 mL) twice, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA=1/0 to 10/1) to afford benzyl 4- ethyl-4-(2-iodoethyl)iperidine-1-carboxylate (8.84 g, 22.03 mmol, _Int-24d). MS obsd. (ESI⁺) [(M+H)⁺]: 402.0. Step (e): benzyl 4-ethyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate 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) was dissolved in MeCN (40 mL) in darkness and stirred at 25 °C for 12 hrs. The reaction mixture was diluted with water (100 mL), extracted with EA (40 mL) three times. The combined organic layers were washed with brine (50 mL) twice, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA=1/0 to 3/1) to afford benzyl 4-ethyl-4- [2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (1002.0 mg, 2.25 mmol, Int-24e). MS obsd. (ESI⁺) [(M+H)⁺]: 446.2. Step (f): tert-butyl 3-[2-(1-benzyloxycarbonyl-4-ethyl-4-piperidyl)ethoxy]-4,4-difluoro- piperidine-1-carboxylate Int-24f Tert-butyl 3-[2-(1-benzyloxycarbonyl-4-ethyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine- 1-carboxylate (1030.0 mg, 2.02 mmol, Int-24f) was prepared in analogy to Intermediate 23, by replacing benzyl 4-methyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (Int-23b) with benzyl 4-ethyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (1070.49 mg, 2.4 mmol, _Int-24e). MS obsd. (ESI⁺) [(M-Boc+H]⁺)⁺]: 411.2. Step (g): tert-butyl 3-[2-(4-ethyl-4-piperidyl) ethoxy]-4,4-difluoro-piperidine-1-carboxylate Int-24 Tert-butyl 3-[2-(4-ethyl-4-piperidyl) ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int-24) was prepared in analogy to Intermediate 23, by replacing tert-butyl 3-[2-(1-benzyloxycarbonyl- 4-methyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine-1-carboxylate (1.0 g, 2.01 mmol, Int-23c) with tert-butyl 3-[2-(1-benzyloxycarbonyl-4-ethyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine-1- carboxylate (Int-24f). MS obsd. (ESI⁺) [(M+H)⁺]: 377.3. I_{ntermediate 30:} tert-butyl 3-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate Int-30 Step (a): 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]- 6-fluoro-pyridine-3-carboxylic acid Int-30a 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid (Int-30a, 1048.0 mg, 2.16 mmol) was prepared in analogy to Intermediate 31, by replacing 2,6-difluoronicotinic acid and 4-[3-(4-piperidyl)propyl]piperidine with 4,6-difluoropyridine-3-carboxylic acid and tert-butyl 4,4-difluoro-3-[3-(4- piperidyl)propyl]piperidine-1-carboxylate (_Int-15). MS obsd. (ESI⁺) [(M+H)⁺]: 486.3. Step (b): tert-butyl 3-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidyl]propyl]-4,4- difluoro-piperidine-1-carboxylate

Int-30 Tert-butyl 3-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine 1-carboxylate (Int-30, 902.0 mg, 1.86 mmol) was prepared in analogy to _{Intermediate 32}, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]- 6-fluoro-pyridine-3-carboxylic acid (Int-31) with 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3-carboxylic acid (Int-30a). MS obsd. (ESI⁺) [(M+Na)⁺]: 507.2. Intermediate 31: 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-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 To a solution of 4-[3-(4-piperidyl)propyl]piperidine (2.64 g, 12.57 mmol) in MeCN (20 mL) was added DIPEA (1621.72 mg, 12.57 mmol) (7087-68-5, Sigma Aldrich China) and 2,6- difluoronicotinic acid (1000.0 mg, 6.29 mmol) and the reaction mixture was stirred at 20 °C for 16 hrs. The mixture was acidified with 1N HCl (50 mL) to pH = 6 ~7. A large white precipitate was formed. The solid was collected by filtration. The filter cake was triturated with MeCN (50 mL) to afford 6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]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). Step (b): preparation of 2-(4-(3-(1-(tert-butoxycarbonyl)piperidin-4- yl)propyl)piperidin-1-yl)-6-fluoronicotinic acid Int-31 To a solution of 6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxylic acid (Int-31a, 1500.0 mg, 4.29 mmol) in methanol (20 mL) was added di-t-butyldicarbonate (936.86 mg, 4.29 mmol). The mixture was stirred for 2 hrs at 20 °C. The residue was purified by silica gel column (SiO2, 10% to 50% EA in PE) to afford 2-[4-[3-(1-tert-butoxycarbonyl-4- piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3-carboxylic acid (Int-31, 1.0 g, 2.22 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 450.2.¹H 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). Intermediate 32: N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]pyridine-3-carboxamide

Int-32 To a solution of 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-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) was added EDCI (2600.0 mg, 13.56 mmol) (25952-53-8, Accela ChemBio) at 0°C. After being stirred for 12 hrs at 36°C, the mixture was concentrated in vacuo. The residue was purified by reversed phase column (0.1% TFA in water, MeCN (55%- 85%)). The fractions was concentrated in vacuo to afford tert-butyl 4-[3-[1-(3-carbamoyl-6- fluoro-2-pyridyl)-4-piperidyl]propyl]piperidine-1-carboxylate (Int-32, 1.8 g, 4.01 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 449.3. Intermediate 33: 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-4- nitro-benzoic acid Int-33 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-4-nitro-benzoic acid (Int- ₃₃, 14.2 g, 29.8 mmol) was prepared in analogy to _{intermediate 31}, by replacing 2,6- difluoronicotinic acid with 2-fluoro-4-nitrobenzoic acid. MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 376.1. Intermediate 34: tert-butyl 4-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4- piperidyl]propyl]piperidine-1-carboxylate

Int-34 Tert-butyl 4-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]piperidine-1- carboxylate (Int-34, 1.0 g, 2.11 mmol) was prepared in analogy to Intermediate 32, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3- carboxylic acid (Int-31) with 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-4- nitro-benzoic acid (Int-33). MS obsd. (ESI⁺) [(M+H)⁺]: 475.3. Intermediate 35: 6-fluoro-4-[4-[3-(1-methyl-4-piperidyl)propyl]-1-piperidyl]pyridine- 3-carboxylic acid Int-35 6-Fluoro-4-[4-[3-(1-methyl-4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxylic acid (Int- 35, 10.0 g, 22.25 mmol) was prepared in analogy to Intermediate 31, by replacing 2,6- difluoronicotinic acid with 4,6-difluoropyridine-3-carboxylic acid. MS obsd. (ESI⁺) [(M+H)⁺]: 450.2.¹H 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). Intermediate 36: tert-butyl 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate Int-36 Tert-butyl 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidyl]propyl]piperidine-1- carboxylate (Int-36, 902 mg, 1.86 mmol) was prepared in analogy to Intermediate 32, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3- carboxylic acid (Int-31) with 6-fluoro-4-[4-[3-(1-methyl-4-piperidyl)propyl]-1- piperidyl]pyridine-3-carboxylic acid (Int-35). MS obsd. (ESI⁺) [(M+H)⁺]: 449.3. Intermediate-37: 3-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-5- fluoro-pyridine-2-carboxylic acid Int-37 3-[4-[3-(1-Tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-5-fluoro-pyridine-2- carboxylic acid (Int-37, 10.9 g, 24.25 mmol) was prepared in analogy to Intermediate 31, by replacing 2,6-difluoronicotinic acid with 3,5-difluoropyridine-2-carboxylic acid. MS obsd. (ESI⁺) [(M+H)⁺]: 450.4.¹H 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). Intermediate 38: 5-fluoro-3-[4-[3-(1-methyl-4-piperidyl)propyl]-1-piperidyl]pyridine- 2-carboxamide Int-38 Tert-butyl 4-[3-[1-(2-carbamoyl-5-fluoro-3-pyridyl)-4-piperidyl]propyl]piperidine-1- carboxylate (Int-38, 2.0 g, 4,46 mmol) was prepared in analogy to Intermediate 32, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3- carboxylic acid (Int-31) with 3-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-5- fluoro-pyridine-2-carboxylic acid (Int-37). MS obsd. (ESI⁺) [(M+H)⁺]: 449.2. Intermediate 39: 4-[4-[3-(1,4-dimethyl-4-piperidyl)propyl]-1-piperidyl]-6-methyl- pyridine-3-carboxamide Int-39 Step (a): Preparation of 4-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)propyl]-1- piperidyl]-6-fluoro-pyridine-3-carboxylic acid

Int-39a 4-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine- 3-carboxylic acid (Int-39a, 910 mg, 1.95 mmol) was prepared in analogy to Intermediate 31, by replacing 2, 6-difluoronicotinic acid with 4, 6-difluoropyridine-3-carboxylic acid. MS obsd. (ESI⁺)[(M+H)⁺]: 468.2. Step (b): preparation of tert-butyl 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4- piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate Int-39 Tert-butyl 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidyl]propyl]-4-fluoro- piperidine-1-carboxylate (Int-39, 850 mg, 1.85 mmol) was prepared in analogy to Int-32, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3- carboxylic acid (_Int-31) with 4-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)propyl]-1- piperidyl]-6-fluoro-pyridine-3-carboxylic acid (Int-39a). MS obsd. (ESI⁺)[(M+H)⁺]: 467.3. Intermediate 40: 2-[4-[2-fluoro-3-(1-methyl-4-piperidyl)propyl]-1-piperidyl]-6-methyl- pyridine-3-carboxamide

Int-40 Step (a): Preparation of ^tert-butyl 4-[2-[methoxy(methyl)amino]-2-^oxo- ethyl]piperidine-1-carboxylate Int-40a 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-piperidylacetic acid (10.0 g, 41.1 mmol) in EA (100 mL) was added T3P (30.63 g, 61.65 mmol) dropwise at 0 °C. After being stirred for 2 hrs at 0 °C, the mixture was diluted with EA (120 mL), washed with water (120 mL), sat. aq. NaHCO₃ (150 mL), 1N HCl (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to afford tert-butyl 4-[2-[methoxy(methyl)amino]-2-oxo- ethyl]piperidine-1-carboxylate (_Int-40a, 10.0 g, 34.92 mmol). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 187.1. Step (b): Preparation of tert-butyl 4-[2-oxo-3-(4-pyridyl)propyl]piperidine-1- carboxylate Int-40b To a solution of 4-methylpyridine (4.36 mL, 44.84 mmol) in THF (110 mL) was added n- BuLi (17.93 mL, 44.84 mmol) dropwise under N2 at -70 °C. The mixture was stirred for 2 hrs at -70 °C, 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 being stirred for 2 hrs at -70 °C, the reaction was poured into sat. aq. NH4Cl (50 mL), extracted with EA (60 mL) three times. The combined organic phase was washed with brine (40 mL). The organic layers were then separated and dried, concentrated in vacuo. The residue was purified by flash silica gel chromatography (SiO2, 5% EA to 30% EA in PE) to afford tert-butyl 4-[2-oxo-3-(4- pyridyl)propyl]piperidine-1-carboxylate (_Int-40b, 7.8 g, 24.5 mmol).¹H 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). Step (c): Preparation of tert-butyl 4-[2-hydroxy-3-(4-piperidyl)propyl]piperidine-1- carboxylate Int-40c A solution of tert-butyl 4-[2-oxo-3-(4-pyridyl)propyl]piperidine-1-carboxylate (Int-40b, 9.2 g, 28.89 mmol) in methanol (90 mL) was stirred at 20°C until becoming clear solution. Adjust the H2 back pressure regulator to 2.5 MPa, the flow rate of H2 to 30 ml/min, heated the fixed bed (10%Ru/SiO 2,5g) to 100°C. Then the solution was pumped into the reactor at a flow rate of 0.3 ml/min. After the reaction was finished, the reaction solution was concentrated in vacuo to afford a crude tert-butyl 4-[2-hydroxy-3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-40c, 1.7 g, 5.21 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 327.2. Step (d): Preparation of benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-hydroxy- propyl]piperidine-1-carboxylate Int-40d A solution of tert-butyl 4-[2-oxo-3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-40c, 1650.0 mg, 5.09 mmol) in MeCN (100 mL) was added N-(benzyloxycarbonyloxy)succinimide (2661.49 mg, 10.68 mmol) and stirred for 12 hrs at 20 °C. The mixture was concentrated in vacuo. The residue was purified by silica gel column (SiO2, 10% to 50% EA in PE). After concentration, benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-hydroxy-propyl]piperidine-1- carboxylate (_Int-40d, 2000.0 mg, 4.34 mmol) was obtained. MS obsd. (ESI⁺) [(M+Na)⁺]: 481.2. ¹H 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). Step (e): Preparation of benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-fluoro- propyl]piperidine-1-carboxylate Int-40e To a solution of benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-hydroxy- propyl]piperidine-1-carboxylate (Int-40d, 1200.0 mg, 2.61 mmol) in DCM (20 mL) was added DAST (0.52 mL, 3.91 mmol) (CAS: 38078-09-0, Shanghai Haohong Pharmaceutical Co.,Ltd) at -10 °C. After being stirred for 2 hat -10 °C, the mixture was poured into sat. aq. NaHCO3 (30 mL), extracted with EA (20 mL) twice. The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase Flash (0.1% TFA in water, MeCN (60~70%) to afford benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-fluoro-propyl]piperidine-1-carboxylate (_Int- 40e, 700.0 mg, 1.51 mmol) was obtained. MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 363.3. Step (f): Preparation of tert-butyl 4-[2-fluoro-3-(4-piperidyl)propyl]piperidine-1- carboxylate Int-40f To a solution of benzyl 4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-fluoro- propyl]piperidine-1-carboxylate (Int-40e, 700.0 mg, 1.51 mmol) in methanol (10 mL) was added Pd/C (200.0 mg) under N2. The suspension was degassed in vacuo and purged with H2 three times. The reaction mixture was stirred at 25 °C for 3 hrs under H₂ balloon. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford tert-butyl 4-[2-fluoro-3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-40f, 500.0 mg, 1.52 mmol), which was used in next step directly without further purification. Step (g): preparation of 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-fluoro-propyl]-1- piperidyl]-6-fluoro-pyridine-3-carboxylic acid Int-40g 2-[4-[3-(1-Tert-butoxycarbonyl-4-piperidyl)-2-fluoro-propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid (_Int-40g) was prepared in analogy to _{Intermediate 31}, by replacing 4-[3-(4-piperidyl)propyl]piperidine with tert-butyl 4-[2-fluoro-3-(4-piperidyl)propyl]piperidine- 1-carboxylate (Int-40f, 360 mg). MS obsd. (ESI⁺) [(M+H^)+]: 468.3. Step (h): preparation of tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate

Int-40 tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidyl]-2-fluoro-propyl]piperidine- 1-carboxylate (Int-40) was prepared in analogy to Intermediate 32, by replacing 2-[4-[3-(1-tert- butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3-carboxylic acid (_Int-31) with 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)-2-fluoro-propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid (Int-40f). tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate (_Int-40, 240 mg, 0.51 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 467.3. Intermediate 41: 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]-1- piperidyl]-4-nitro-benzoic acid Int-41 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro- benzoic acid (_Int-41, 190 mg, 0.37 mmol) was prepared in analogy to _{Intermediate 31}, by replacing 2,6-difluoronicotinic acid and 4-[3-(4-piperidyl)propyl]piperidine with 2-fluoro-4- nitrobenzoic acid and tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (_Int-15). MS obsd. (ESI⁺) [(M+H)⁺]: 512.2. Intermediate 42: tert-butyl 3-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]- 4,4-difluoro-piperidine-1-carboxylate Int-42 Tert-butyl 3-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (Int-42, 125 mg, 0.24 mmol) was prepared in analogy to Intermediate 32, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid (Int-31) with 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzoic acid (Int-41). MS obsd. (ESI⁺) [(M+H)⁺]: 511.3. Intermediate 43: 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-4- iodo-benzoic acid Int-43 2-[4-[3-(1-Tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-4-iodo-benzoic acid (Int- ₄₃, 650 mg, 1.12 mmol) was prepared in analogy to _{Intermediate 31}, by replacing 2,6- difluoronicotinic acid with 2-fluoro-4-iodobenzoic acid. MS obsd. (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). Intermediate 44: 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]-4- (difluoromethyl)-1-piperidyl]-6-fluoro-pyridine-3-carboxylic acid Int-44 4-[4-[3-(1-Tert-butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]-4-(difluoromethyl)-1- piperidyl]-6-fluoro-pyridine-3-carboxylic acid (Int-44, 330 mg, 0.62 mmol) was prepared in analogy to Intermediate 31, by replacing 2,6-difluoronicotinic acid and 4-[3-(4- piperidyl)propyl]piperidine with 4,6-difluoropyridine-3-carboxylic acid and tert-butyl 3-[3-[4- (difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Int-19). MS obsd. (ESI⁺) [(M+H)⁺]: 536.4. Intermediate 45: N-(2-chloro-4-pyridyl)-4-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1- piperidyl]-6-fluoro-pyridine-3-carboxamide Int-45 N-(2-chloro-4-pyridyl)-4-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxamide (Int-45, 391 mg, 0.73 mmol) was prepared in analogy to Intermediate 32, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid (Int-31) with 4-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3- piperidyl)propyl]-4-(difluoromethyl)-1-piperidyl]-6-fluoro-pyridine-3-carboxylic acid (Int-44). MS obsd. (ESI⁺) [(M+H)⁺]: 535.4. Intermediate 46: ^tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]ethoxy]- 4,4-difluoro-piperidine-1-carboxylate Step (a): 2-[4-[3-(1-tert-butoxycarbonyl-4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4- nitro-benzoic acid Int-46a To a solution of 2-fluoro-4-nitrobenzoic acid (587.72 mg, 3.17 mmol) in DMSO (12 mL) was added DIEA (1.89 mL, 11.55 mmol) and tert-butyl 4,4-difluoro-3-[3-(4- piperidyl)propyl]piperidine-1-carboxylate (1000.0 mg, 2.89 mmol, Int-16). After the reaction mixture being stirred at 110 °C for 36 hrs, the mixture was concentrated. The residue was purified by reversed flash (220 g, Flash Column Welch Ultimate XB_C1820-40 μm; 120 A, water (0.1% FA)-ACN, 80%, 80 mL/min) and then extracted with EA (120 mL) three times. The combined organic phase was washed with brine (120 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 2-[4-[3-(1-tert-butoxycarbonyl-4,4- difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzoic acid (620.0 mg, 1.21 mmol, Int-46a). MS obsd. (ESI⁺): 514.4 [(M+H)⁺]. Step (b): tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]ethoxy]-4,4-difluoro- piperidine-1-carboxylate Int-46 Tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]ethoxy]-4,4-difluoro- piperidine-1-carboxylate (620.0 mg, 1.21 mmol, Int-46) was prepared in analogy to _{Intermediate 32}, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]- 6-fluoro-pyridine-3-carboxylic acid (Int-31) with tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro- phenyl)-4-piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int-46a, 620.0 mg, 1.21 mmol) MS obsd. (ESI⁺) [(M+H)⁺]: 513.4. Intermediate 47: tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-methyl-4- piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate Int-47 To a solution of tert-butyl 4,4-difluoro-3-[2-(4-methyl-4-piperidyl)ethoxy]piperidine-1- carboxylate (720.0 mg, 1.99 mmol, Int-23) in NMP (10 mL) was added DIEA (1026.9 mg, 7.95 mmol) and 2-fluoro-4-nitro-benzamide (438.91 mg, 2.38 mmol). The reaction mixture was stirred at 110 °C for 12 hrs. The mixture was purified by reverse flash (120g Flash Column Welch Ultimate XB_C1820-40 μm; 120 A, water (0.1% FA)-ACN, 80%, 80 mL/min). The fraction was adjusted with sat.aq. NaHCO₃ to pH = 9 and concentrated in vacuo, extracted with EA (60mL) twice. The combined organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to afford tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)- 4-methyl-4-piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (520.0 mg, 0.99 mmol, _Int- 47). MS obsd. (ESI⁺) [(M+H)⁺]: 527.3. Intermediate 48: tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-ethyl-4- piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate Int-48 Tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-ethyl-4-piperidyl]ethoxy]-4,4-difluoro- piperidine-1-carboxylate (638.0 mg, 1.18 mmol, Int-48) was prepared in analogy to Intermediate 47, by replacing tert-butyl 4,4-difluoro-3-[2-(4-methyl-4- piperidyl)ethoxy]piperidine-1-carboxylate (Int-23) with tert-butyl 3-[2-(4-ethyl-4- piperidyl)ethoxy]-4,4-difluoro-piperidine-1-carboxylate (836.0 mg, 1.95 mmol, Int-24), MS obsd. (ESI⁺) [M+H]⁺: 541.4. Intermediate 49: ^tert-butyl 3-[2-[1-(2-carbamoyl-3-methyl-5-nitro-phenyl)-4- piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate

Int-49 Step (a): 2-chloro-6-methyl-4-nitro-benzonitrile Int-49a Solution 1: 2-chloro-6-methyl-4-nitro-aniline (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). The solution 1 was pumped by Pump 1 (Solution 1, Pump 1, 20 mL/min) to flow reactor 1 ( Glass (GL), Continues stirred tank reactor (CSTRs), 150 mL, 80 °C), and flow reactor 2 (Glasss(GL), Continues stirred tank reactor (CSTRs), 150 mL, 80 °C). The solution 2 was pumped by Pump 2 (Solution 2, Pump 2, 10 mL/min) to flow reactor 1 (flow reactor 1, Glass (GL), Continues stirred tank reactor (CSTRs), 150 mL, 80 °C), and flow reactor 2 (flow reactor 2, Glass (GL), Continues stirred tank reactor (CSTRs), 150 mL, 80 °C). The residence time of flow reactor 1 was 5 min. The residence time of flow reactor 2 was 5.000 min. The mixture was collected with a bottle. The Pump 1 and Pump 2 was started at the same time. The reaction mixture was collected after running 10 min. Take a sample for analysis after 10 min. Stop collecting the reaction mixture after 40 min. TLC (PE/EA=10/1, UV = 254 nm) showed the reactant 1 was consumed completely and two new spots was detected. The mixture was added H2O (500 mL) and extracted with ethyl acetate (400mL) three times. The combined organic phase was washed with brine (300 mL) twice, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/0 to 10/1) and concentrated in vacuo to afford 2-chloro-6-methyl-4-nitro-benzonitrile (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). Step (b): tert-butyl 3-[2-[1-(2-cyano-3-methyl-5-nitro-phenyl)-4-piperidyl]ethoxy]-4,4- difluoro-piperidine-1-carboxylate Int-49b To a solution of tert-butyl 4,4-difluoro-3-[2-(4-piperidyl)ethoxy]piperidine-1-carboxylate (4.0 g, 11.48 mmol) was added 2-chloro-6-methyl-4-nitro-benzonitrile (2482.55 mg, 12.63 mmol, Int-49a) and Cs2CO3 (11.2 mg, 34.44 mmol) in 1,4-Dioxane (60 mL). The mixture was stirred at 100 ℃ for 16 hrs. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/0 to 4/1) and concentrated in vacuo to afford tert-butyl 3-[2-[1-(2-cyano-3-methyl-5-nitro-phenyl)-4- piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (2.06 mg, 4.05 mmol, Int-49b). MS obsd. (ESI⁺) [(M-Boc+H)⁺]: 408.2. Step (c): tert-butyl 3-[2-[1-(2-carbamoyl-3-methyl-5-nitro-phenyl)-4 piperidyl]ethoxy]-4,4- difluoro-piperidine-1-carboxylate Int-49 To a solution of tert-butyl 3-[2-[1-(2-cyano-3-methyl-5-nitro-phenyl)-4-piperidyl]ethoxy]- 4,4-difluoro-piperidine-1-carboxylate (2060.0 mg, 4.05 mmol, _Int-49b) in DMSO (20 mL) was added K2CO3 (1.68 g, 12.15 mmol) and H2O2 (688.6 mg, 6.08 mmol) at 0 ℃. After being stirred at 25 ℃ for 16 hrs, the reaction mixture was added H2O (50 mL) and then extracted with ethyl acetate (40 mL) three times. The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/0 to 4/1) and concentrated in vacuo to afford tert-butyl 3-[2-[1-(2-carbamoyl-3-methyl-5-nitro-phenyl)-4- piperidyl] ethoxy]-4,4-difluoro-piperidine-1-carboxylate (550.0 mg, 1.04 mmol, Int-49). MS obsd. (ESI⁺) [(M+H)⁺]: 527.4. Intermediate 50: ^N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide Int-50 To a solution of 2-fluoro-4-nitrobenzoic acid (11.0 g, 59.42 mmol) in MeCN (100 mL) was added 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) at 0 °C. The mixture was heated to 45 °C and stirred at 45 °C for 2 hrs. The residue was diluted with H₂O (50 ml) and large purple solid was precipitated. The suspension was filtered. The filter cake was dried in vacuo to afford N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-50, 17.0 g, 57.5 mmol). MS obsd. (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). Intermediate 51: N-(6-bromo-5-methoxy-2-pyridyl)-2-fluoro-4-nitro-benzamide Int-51 N-(6-bromo-5-methoxy-2-pyridyl)-2-fluoro-4-nitro-benzamide (_Int-51, 700 mg, 1.89 mmol) was prepared in analogy to Intermediate 50, by replacing 2-amino-6-chloropyridine with 6-bromo-5-methoxy-pyridin-2-amine. MS obsd. (ESI⁺)[(M+H)⁺]: 370.0. Intermediate 52: ^N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro-benzamide Int-52 Step (a): preparation of 2,6-difluoro-4-nitro-benzoic acid Int-52a To a solution of 3,5-difluoronitrobenzene (5.0 g, 31.43 mmol) in THF (50 mL) was added LDA (18.86 mL, 37.71 mmol) at -78 °C dropwise. The mixture was stirred at -78 °C for 0.5h under N₂. Carbon dioxide (4.15 g, 94.29 mmol) (dry ice) was added to the mixture under N₂ in portions. After being stirred at -78 °C for 0.5 hr, the mixture was quenched by NH4Cl (200 mL) and extracted with EA (100 mL) times. The aqueous layer was acidified by HCl (1M) to pH=1~2 and extracted with EA (100 mL) three times. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the filtrated was concentrated in vacuo to give 2,6-difluoro-4-nitro-benzoic acid (Int-52a, 2270.0 mg, 11.18 mmol). Step (b): preparation of 2,6-difluoro-4-nitro-benzoyl chloride Int-52b To a solution of 2,6-difluoro-4-nitro-benzoic acid (2270.0 mg, 11.18 mmol) in DCM (30 mL) was added (COCl)₂ (2837.33 mg, 22.35 mmol) and 2,6-difluoro-4-nitro-benzoic acid (2270.0 mg, 11.18 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to give 2,6-difluoro-4-nitro-benzoyl chloride (Int- _52b, 2470.0 mg, 11.15 mmol), which was used in next step directly without further purification. Step (c): preparation of 2,6-difluoro-4-nitro-benzamide Int-52c 2,6-difluoro-4-nitro-benzoyl chloride (2470.0 mg, 11.15 mmol) was added to NH₃H₂O (30.0 mL, 11.15 mmol) at portion wise 0°C. The mixture was warmed to 25 °C and stirred at 25 °C for 1 hr. The mixture was diluted with H2O (50 mL) and extracted with EA (30 mL) three times. The combined organic layers were washed with brine (30 mL) three times, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo to give a crude. The crude was purified by column chromatography (SiO2, 35% EA in PE), followed by reversed flash (Welch Ultimate XB_C1820-40μm; 120 A, water (0.1% FA)-ACN, 27%, 100ml/min).2,6-difluoro-4- nitro-benzamide (_Int-52c, 1300.0 mg, 6.43 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 203.0. Step (d): preparation of N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro-benzamide Int-52 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) was added 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) at 25°C under N₂. The suspension was heated to 100 °C and stirred at 100 °C for 12 hrs under N2. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse flash (Welch Ultimate XB_C₁₈20-40μm; 120 A, water (0.1% FA)-ACN, 55%, 100ml/min). N-(6- chloro-2-pyridyl)-2,6-difluoro-4-nitro-benzamide (Int-52, 557.0 mg, 1.78 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 314.2. 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 To a solution of 2-fluoro-4-nitrobenzoic acid (10.0 g, 54.02 mmol) in DCM (100 mL) was added (COCl)₂ (13.71 g, 108.04 mmol) and DMF (394.9 mg, 5.4 mmol) at 0 °C. The reaction mixture was stirred at 20 ^oC for 2 hrs. Then the mixture was concentrated in vacuo. To the residue was added NH3.H2O (50.0 mL, 54.02 mmol) dropwise at 0 ^oC. After being stirred at 20 ^oC for 1 hr, the mixture was filtered and washed with EA (10 mL). The residue was dried in vacuo to afford 2-fluoro-4-nitro-benzamide (Int-53a, 4.20 g, 22.81 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 185.1. Step (b): preparation of ^N-(2-chloropyrimidin-4-yl)-2-fluoro-4-nitro-benzamide Int-53 N-(2-chloropyrimidin-4-yl)-2-fluoro-4-nitro-benzamide _(Int-53, 1.20 g, 4.05 mmol₎ was prepared in analogy to Intermediate 52, 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 obsd. (ESI⁺)[(M+H)⁺]: 297.0. Intermediate 54: preparation of N-(6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide Int-54 N-(6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-54, 4.4 g, 14.83 mmol) was prepared in analogy to Intermediate 50, by replacing 2-amino-6-chloropyridine with 2-amino-6- chloropyrazine. MS obsd. (ESI⁺) [(M+H)⁺]: 297.2. Intermediate 55: preparation of N-(2-chloro-4-pyridyl)-2-fluoro-4-nitro-benzamide Int-55 N-(2-chloro-4-pyridyl)-2-fluoro-4-nitro-benzamide (Int-55, 7.84 g, 26.52 mmol) was prepared in analogy to Intermediate 50, by replacing 2-amino-6-chloropyridine with 4-amino-2- chloropyridine. MS obsd. (ESI⁺) [(M+H)⁺]: 295.9. Intermediate 56: preparation of N-(3-chlorophenyl)-2-fluoro-4-nitro-benzamide Int-56 N-(3-bromophenyl)-2-fluoro-4-nitro-benzamide (Int-56, 3.37 g, 9.95 mmol) was prepared in analogy to Intermediate 50, by replacing 2-amino-6-chloropyridine with 3-bromo aniline. MS obsd. (ESI⁺) [(M+H)⁺]: 340.1. 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 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) was added azidotrimethylsilane (3.5 mL, 26.4 mmol) at 0 °C. After being stirred for 1 hr at 0 °C, the mixture was filtered and concentrated in vacuo to afford 1-azido-2-fluoro-4-nitro-benzene (Int-57a, 4.80 g, 26.36 mmol) in DMF, which was used in next step directly without further purification. Step (b): preparation of 2-chloro-6-[1-(2-fluoro-4-nitro-phenyl)triazol-4-yl]pyridine Int-57 To a solution of sodium L-ascorbate (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) was added 2-chloro-6-ethynyl-pyridine (3407.73 mg, 24.77 mmol). After being stirred for 3 hrs at 20 °C, the mixture was poured into water (400 mL) causing a large precipitate to form and the solid was collected by filtration. The filter cake was dried in vacuo to afford 2- chloro-6-[1-(2-fluoro-4-nitro-phenyl)triazol-4-yl]pyridine (6200.0 mg, 19.39 mmol). MS obsd. (ESI⁺) [(M+Na)⁺]: 341.9.¹H 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, 1 H), 7.81 (t, J = 8.0 Hz, 1 H), 7.34 (d, J = 7.6 Hz, 1H). Intermediate 58: N-(6-bromo-5-fluoro-2-pyridyl)-2-fluoro-4-nitro-benzamide Int-58 N-(6-bromo-5-fluoro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-58, 2.0 g, 5.59 mmol) was prepared in analogy to Intermediate 50, by replacing 2-amino-6-chloropyridine with 6-bromo- 5-fluoro-pyridin-2-amine. MS obsd. (ESI⁺) [(M+H)⁺]: 359.9. Intermediate 59: preparation of 4-bromo-2-fluoro-N-(3-sulfamoylphenyl)benzamide Int-59 To a solution of 3-aminobenzenesulfonamide (2000 mg, 11.61 mmol ) in pyridine (25 mL) was added 4-bromo-2-fluoro-benzoic acid (3.05 g, 13.94 mmol ) and EDCI.HCl (3.34 g, 17.42 mmol ) at rt. After being stirred for at 35°C for 12 hrs, the reactant mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-bromo-2-fluoro-N-(3-sulfamoylphenyl)benzamide (Int-59, 4.3 g,). MS obsd. (ESI⁺) [(M+H)⁺]: 188.0. Intermediate 70: 4-allyl-4-fluoro-piperidine Int-70 Step (a): Preparation of tert-butyl 4-allyl-4-fluoro-piperidine-1-carboxylate Int-70a To a solution of tert-butyl 4-allyl-4-hydroxy-piperidine-1-carboxylate (15.0 g, 62.16 mmol) in DCM (200 mL) was added DAST (9.85 mL, 74.59 mmol) dropwise at -60 °C under N2. The mixture was stirred for 2 hrs at -60 °C, then moved the dry-ice batch and warmed to 20 °C and stirred for 10 hrs at 20 °C under N₂. The mixture was poured into sat. aq. NaHCO₃ (300 mL), extracted with DCM (200 mL) twice. The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo to afford tert- butyl 4-allyl-4-fluoro-piperidine-1-carboxylate (Int-70a, 4.5 g, 18.49 mmol). MS obsd. (ESI⁺)[(M-F+H)⁺]: 168.0. Step (b): Preparation of 4-allyl-4-fluoro-piperidine Int-70 A solution of tert-butyl 4-allyl-4-fluoro-piperidine-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 hr. The mixture was concentrated in vacuo to afford 4-allyl-4-fluoro-piperidine (Int-70, 1.00 g, 3.89 mmol).¹H 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). Intermediate 71: 4-fluoro-4-vinyl-piperidine Int-71 Step (a): Preparation of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate Int-71a To a solution of (COCl)2 (8.98 g, 70.73 mmol) in DCM (200 mL) was added DMSO (11.05 g, 141.46 mmol) at -78 °C dropwise. The mixture was stirred at -78 °C for 0.5 hr. Then to the mixture was added tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (15.0 g, 64.3 mmol) in DCM (50 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hr. Then to the mixture was added TEA (32.55 g, 321.5 mmol) at -78 °C. After being stirred at 20 ^oC for 1 hr, the mixture was quenched with H2O (100 mL), extracted with DCM (200 mL) twice. The organic layer was washed with brine (100 mL) twice, dried over Na₂SO₄, filtered. The filtrate was concentrated in vacuo to afford tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1- carboxylate (Int-70a, 15.0 g, 64.3 mmol).¹H 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). Step (b): Preparation of tert-butyl 4-fluoro-4-vinyl-piperidine-1-carboxylate Int-71b To a solution of tert-butyl 4-fluoro-4-formyl-piperidine-1-carboxylate (Int-70a, 14.5 g, 62.7 mmol) in MeCN (200 mL) was added DBU (19.09 g, 125.39 mmol) and methyltriphenylphosphonium bromide (44.79 g, 125.39 mmol) at 20 ^oC. The reaction mixture was stirred at 80 °C for 12 hrs under N2. The mixture was concentrated in vacuo. The residue was purified by silica gel column (0 to 10% EA in PE) and concentrated in vacuo to afford tert- butyl 4-fluoro-4-vinyl-piperidine-1-carboxylate (_Int-70b, 5.0 g, 21.81 mmol).¹H NMR (400 MHz, CDCl3) δ = 5.96 - 5.85 (m, 1H), 5.37 - 5.26 (m, 1H), 5.17 (dd, J = 12.8 Hz, 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).¹⁹F NMR (376 MHz, CDCl₃) δ = -161.29. Step (c): Preparation of 4-fluoro-4-vinyl-piperidine Int-71 A solution of tert-butyl 4-fluoro-4-vinyl-piperidine-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 hr. The mixture was concentrated in vacuo to afford 4-fluoro-4-vinyl-piperidine (Int-71, 800.0 mg, 3.29 mmol).¹H 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). Intermediate 72: 4-vinylpiperidine Int-72 A solution of 1-BOC-4-vinyl-piperidine (2.00 g, 9.47 mmol) in TFA (3.0 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to afford 4-vinylpiperidine (Int-72, 2.10 g, 9.32 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 112.1. Intermediate 73: ^tert-butyl 4-allyl-3,3-difluoro-pyrrolidine-1-carboxylate Int-73 Step (a): preparation of tert-butyl 4-allyl-3,3-difluoro-pyrrolidine-1-carboxylate Int-73a To a solution of tert-butyl 3-allyl-4-oxo-pyrrolidine-1-carboxylate (2.50 g, 11.1 mmol) in DCM (50 mL) was added DAST (7.36 g, 33.29 mmol) dropwise at 20 °C. After being stirred at 20 °C for 12 hrs, the mixture was poured into sat. aq. NaHCO₃ (100 mL), extracted with DCM (100 mL). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (5% to 20% EA in PE) to afford tert-butyl 4-allyl-3,3-difluoro-pyrrolidine-1-carboxylate (_Int-73a, 1600.0 mg, 6.47 mmol). MS obsd. (ESI⁺) [(M-Bu+H)⁺]: 192.1.¹H NMR (400 MHz, 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). Step (b): Preparation of 4-allyl-3,3-difluoro-pyrrolidine Int-73 A solution of tert-butyl 4-allyl-3,3-difluoro-pyrrolidine-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 hr. The mixture was concentrated in vacuo to afford 4-allyl-3,3-difluoro-pyrrolidine (1.30 g, 4.98 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 148.0. Example 1 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: E_{DCI, Py TFA, DCM} _{Int-31 1.1} 1.2 Cs₂CO₃, Dioxane Cs₂CO₃, DMSO 1_{.3 Example 1} Step (a): preparation of ^tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro- 2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) To a solution of 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-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) was added EDCI (767.55 mg, 4.0 mmol). After being stirred for 16 hrs at 35°C, the reaction mixture was concentrated. The residue was purified by flash column chromatography (20% EA in isohexane) to afford tert-butyl 4-[3-[1-[3-[(6-chloro-2- pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 1.1, 800.0 mg, 1.43 mmol). MS obsd.(ESI⁺) [(M+H)⁺]: 560.3. Step (b): preparation of ^N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]pyridine-3-carboxamide (compound 1.2) To a solution of tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]- 4-piperidyl]propyl]piperidine-1-carboxylate (_{compound 1.1}, 800.0 mg, 1.43 mmol) in DCM (6 mL) was added TFA (0.74 mL, 9.65 mmol). After being stirred for 1 hr at 20 °C, the reaction mixture was concentrated in vacuo to afford N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2, 800 mg, 1.39 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 460.4. Step (c): preparation of 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 1.3) To a mixture of N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]pyridine-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 was added PEPPSI-Pd (40.0 mg) (CAS： 1612891-29-8, WuXi). The mixture was evacuated and backfilled with N₂ three times. After being stirred for 12 hrs at 80 °C under N2, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (30% EA in PE) to afford 15,18 2,6 9,14 12-fluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 1.3, 35.0 mg, 0.08 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 424.3. Step (d): preparation of 2-hydroxy-N-(8-oxo-1,7,13,15,29- pentazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 1) 15,18 2,6 9,14 To a mixture of 12-fluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 1.2, 35.0 mg, 0.05 mmol) and Caesium carbonate (0.04 mL, 0.1 mmol) in DMSO (0.5 mL) was added 2-hydroxyethanesulfonamide (12.41 mg, 0.1 mmol). After being stirred for 0.5 hr at 100 °C, the reaction mixture was taken up in EA (50 ml) and the organic phase was washed with water (50 mL) twice, sat.aq. brine (50 mL). The organic layers was separated and dried over anhydrous Na₂SO₄, concentrated in vacuo. The residue was then purified by prep-TLC (8% MeOH in DCM) to afford 2-hydroxy-N-(8-oxo-1,7,13,15,29- pentazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 1, 14.43 mg, 0.03 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 529.3.¹H 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). Example 2 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM x Padnt(pdhboas, o₂ ) dixane₃ Int-32 _{2.1 2.2} PEPPSI-Pd Cs₂CO₃, Dioxane Cs₂CO₃, DMSO 2.3 Example 2 Step (a): Preparation of ^tert-butyl 4-[3-[1-[3-[(2-chloropyrimidin-4-yl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 2.1) To a solution of 2,4-dichloropyrimidine (348.73 mg, 2.34 mmol) and tert-butyl 4-[3-[1-(3- carbamoyl-6-fluoro-2-pyridyl)-4-piperidyl]propyl]piperidine-1-carboxylate (_Int-32, 700.0 mg, 1.56 mmol) in 1,4-Dioxane (10 mL) was added Cs₂CO₃ (0.46 mL, 3.12 mmol), Pd₂(dba)₃ (142.9 mg, 0.16 mmol) and Xantphos (180.59 mg, 0.31 mmol). The mixture was evacuated and backfilled with N2 three times. After being stirred for 12 hrs at 80 °C under N2, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 40~70% EA in PE gradient @ 80 mL/min) to afford tert-butyl 4-[3-[1-[3-[(2-chloropyrimidin-4-yl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 2.1, 460.0 mg, 0.82 mmol). MS obsd. (ESI⁺) [(M+Na)⁺]: 583.2. Step (b): preparation of ^N-(2-chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 2.2) N-(2-chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 2.2}) was prepared in analogy to _{Example 1}, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[3-[(2-chloropyrimidin-4-yl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 2.1) in step (b). N-(2- chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 2.2, 430.0 mg, 0.93 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 461.2. Step (c): preparation of 12-fluoro-1,3,7,13,15,29- hexazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2,4,6(29),9,11,13-hexaen-8-one (compound 2.3) 15,18 2,6 9,14 12-Fluoro-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2,4,6(29),9,11,13-hexaen-8-one (Compound 2.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(2-chloropyrimidin-4-yl)-6-fluoro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 2.2, 430.0 mg, 0.93 mmol) in step (c).12-Fluoro-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2,4,6(29),9,11,13-hexaen-8-one (compound 2.3, 101.0 mg, 0.24 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 425.2.¹H 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).¹⁹F NMR (376 MHz, CDCl3) δ = -63.214. Step (d): preparation of 2-hydroxy-N-(8-oxo-1,3,7,13,15,29- 15,18 2,6 9,14 hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2,4,6(29),9,11,13-hexaen-12- yl)ethanesulfonamide (Example 2) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2,4,6(29),9,11,13-hexaen-12-yl)ethanesulfonamide (Example 2) was prepared in analogy to Example 1, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15,18 2,6 9,14 1.3) with 12-Fluoro-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2,4,6(29),9,11,13-hexaen-8-one (Compound 2.3) in step (c).2-Hydroxy-N-(8-oxo- 15,18 2,6 9,14 1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2,4,6(29),9,11,13-hexaen-12- yl)ethanesulfonamide (Example 2.11.18 mg, 0.02 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 530.2.¹H 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 = 8.0 Hz, 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). Example 3 N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 3) was prepared in analogy to _{Example 2}, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). N-(8- oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)ethanesulfonamide (Example 3, 14.43 mg, 0.03 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 514.4.¹H 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). Example 4 15,18 2,6 9,14 N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: K3PO4, CuI EDCI, Py N,N'-Dimethyl-1,2-cyclohexanediamine DMF I_{nt_43 4.1} PEPPSI-Pd TFA, DCM Cs₂CO₃, dioxane 4_{.2 4.3 Example 4} Step (a): Preparation of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-iodo- phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 4.1) Tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-iodo-phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 4.1) was prepared in analogy to Example 1, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid (Int-31) with (2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1- piperidyl]-4-iodo-benzoic acid (Int-43) in step (a). Tert-butyl 4-[3-[1-[2-[(6-chloro-2- pyridyl)carbamoyl]-5-iodo-phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 4.1, 2200.0 mg, 3.3 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 667.2. Step (b): Preparation of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5- (ethylsulfonylamino)phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 4.2) To a solution of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-iodo-phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (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) in DMF (7 mL). The mixture was evacuated and back-filled with nitrogen three times. The reaction vessel was sealed and heated in microwave at 130 °C for 5 hrs. The mixture was poured into water (50 mL), then extracted with EA (50 mL) three times. The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 30~70% EA in PE gradient @ 100 mL/min) to afford tert-butyl 4-[3-[1- [2-[(6-chloro-2-pyridyl)carbamoyl]-5-(2-hydroxyethylsulfonylamino)phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 4.2, 513.0 mg, 0.77 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 648.4. Step (c): Preparation of N-(6-chloro-2-pyridyl)-4-(ethylsulfonylamino)-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 4.3) N-(6-chloro-2-pyridyl)-4-(ethylsulfonylamino)-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (compound 4.3) was prepared in analogy to Example 1, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[(6-chloro- 2-pyridyl)carbamoyl]-5-(ethylsulfonylamino)phenyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 4.2) in step (b). N-(6-chloro-2-pyridyl)-4-(ethylsulfonylamino)-2-[4-[3- (4-piperidyl)propyl]-1-piperidyl]benzamide (compound 4.3, 490.0 mg, 0.89 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 548.2. Step (d): Preparation of N-(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 4) 15,18 2,6 9,14 N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide (Example 4) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 1.2}) with N-(6-chloro-2-pyridyl)-4-(ethylsulfonylamino)-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 4.3) in step (c). N-(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 4, 62.34 mg, 0.12 mmol) was obtained. MS obsd. (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). Example 5 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM x Padn 2t(pdhboas), 3 Int-32 _{5.1 5.2} PEPPSI-Pd Cs₂CO₃, dioxane Cs₂CO₃, DMSO 5_{.3 Example 5} Step (a): preparation of tert-butyl 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 5.1) Tert-butyl 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 5.1) was prepared in analogy to Example ₂, by replacing 2,4-dichloropyrimidine with 2,6-dichloropyrazine in step (a). tert-Butyl 4-[3-[1- [3-[(6-chloropyrazin-2-yl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 5.1, 240.0 mg, 0.43 mmol) was obtained. MS obsd. (ESI⁺) [(M+Na)⁺]: 583.2. Step (b): Preparation of N-(6-chloropyrazin-2-yl)-6-fluoro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 5.2) N-(6-chloropyrazin-2-yl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 5.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 5.1) in step (b). N-(6- chloropyrazin-2-yl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 5.2, 420.0 mg, 0.91 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 461.2. Step (c): Preparation of 12-fluoro-1,4,7,13,15,29- 15,18 2,6 9,14 hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 5.3) 15,18 2,6 9,14 12-Fluoro-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2,4,6(29),9,11,13-hexaen-8-one (_{Compound 5.3}) was prepared in analogy to _{Example 1}, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloropyrazin-2-yl)-6-fluoro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 5.2, 430.0 mg, 0.93 mmol) in 15,18 2,6 9,14 step (c).12-Fluoro-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one _{(compound 5.3,} 75.0 mg, 0.18 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 425.2. Step (d): preparation of 2-hydroxy-N-(8-oxo-1,4,7,13,15,29- 15,18 2,6 9,14 hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 5) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 5) was prepared in analogy to _{Example 1}, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _(compound 15,18 2,6 9,14 1.3) with 12-Fluoro-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2,4,6(29),9,11,13-hexaen-8-one (_{Compound 5.3}) in step (c).2-Hydroxy-N-(8-oxo- 1,4,7,13,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)ethanesulfonamide (Example 5, 17.34 mg, 0.03 mmol) was obtained. MS obsd. (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). Example 6 15,18 2,6 9,14 N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide 15,18 2,6 9,14 N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 6) was prepared in analogy to _{Example 5}, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). N-(8- 15,18 2,6 9,14 oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)ethanesulfonamide (Example 6, 11.59 mg, 0.02 mmol) was obtained. MS obsd. (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). Example 7 15,18 2,6 9,14 2-hydroxy-^N-(8-^oxo-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM P Cds₂ ₂(CdOba₃,)₂ d,io Xxaanntpehos Int-36 _{7.1 7.2} PEPPSI-Pd Cs₂CO₃, dioxane DMSO, Cs₂CO₃ 7.3 Example 7 Step (a): preparation of tert-butyl 4-[3-[1-[5-[(2-chloropyrimidin-4-yl)carbamoyl]-2- fluoro-4-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 7.1) tert-butyl 4-[3-[1-[5-[(2-chloropyrimidin-4-yl)carbamoyl]-2-fluoro-4-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 7.1) was prepared in analogy to Example 2, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (Int-32) with tert-butyl 4-[3-[1-(5-carbamoyl-2- fluoro-4-pyridyl)-4-piperidyl]propyl]piperidine-1-carboxylat (_Int-36) in step (a). tert-butyl 4-[3- [1-[5-[(2-chloropyrimidin-4-yl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 7.1, 1.0 g, 1.78 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 561.5. ¹H 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).¹⁹F NMR (376 MHz, CDCl3) δ = -60.734. Step (b): preparation of ^N-(2-chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 7.2) N-(2-chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 7.2}) was prepared in analogy to _{Example 1}, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[5-[(2-chloropyrimidin-4-yl)carbamoyl]-2- fluoro-4-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (Compound 7.1) in step (b). N-(2- chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 7.2, 800.0 mg, 1.74 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 461.3. Step (c): preparation of 12-fluoro-1,3,7,11,15,29- 15,18 2,6 9,14 hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 7.3) 15,18 2,6 9,14 12-Fluoro-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 7.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(2-chloropyrimidin-4-yl)-6-fluoro-4-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 7.2) in step (c).12-Fluoro- 15,18 2,6 9,14 1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 7.3, 190.0 mg, 0.45 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 425.3.¹H 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).¹⁹F NMR (376 MHz, CDCl3) δ = -62.278. Step (d): preparation of 2-hydroxy-N-(8-oxo-1,3,7,11,15,29- 15,18 2,6 9,14 hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 7) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (_{Example 7}) was prepared in analogy to Example 1, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15,18 2,6 9,14 1.3) with 12-fluoro-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 7.3) in step (d).2-Hydroxy-N-(8-oxo- 1,3,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)ethanesulfonamide (Example 7, 25.31 mg, 0.05 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 530.2. 1H 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). Example 8 15,18 2,6 9,14 N-(8-^oxo-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide 15,18 2,6 9,14 N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 8) was prepared in analogy to Example 7, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). N-(8- 15,18 2,6 9,14 oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)ethanesulfonamide (Example 8, 22.53 mg, 0.04 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 514.3.¹H NMR (400 MHz, CDCl₃): δ 9.53 (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). Example 9 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM TCFH, NMI MeCN Int-35 _{9.1 9.2} Cs₂CO₃, dixoane Cs₂CO₃, DMSO 9_{.3 Example 9} Step (a): preparation of tert-butyl 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro- 4-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 9.1) Tert-butyl 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 9.1) was prepared in analogy to Example 1, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid (_Int-31) with 4-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1- piperidyl]-6-fluoro-pyridine-3-carboxylic acid (Int-35) in step (a). Tert-butyl 4-[3-[1-[5-[(6- chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (_{compound 9.1}, 750.0 mg, 1.34 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 560.3. Step (b): preparation of N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1- piperidyl]pyridine-3-carboxamide (compound 9.2) N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 9.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2- fluoro-4-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (_{Compound 9.1}) in step (b). N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 9.2, 615.0 mg, 1.34 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 460.2. Step (c): preparation of 12-fluoro-1,7,11,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 9.3) 15,18 2,6 9,14 12-Fluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 9.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]- 1-piperidyl]pyridine-3-carboxamide (_{compound 9.2}) in step (c).12-Fluoro-1,7,11,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound _9.3, 120.0 mg, 0.28 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 424.2. Step (d): preparation of 2-hydroxy-N-(8-oxo-1,7,11,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9(14),10,12-hexaen-12- yl)ethanesulfonamide (Example 9) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide (Example 9) was prepared in analogy to Example 1, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15,18 2,6 9,14 1.3) with 12-fluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 9.3) in step (c).2-Hydroxy-N-(8-oxo-1,7,11,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9(14),10,12-hexaen-12- yl)ethanesulfonamide (Example 9, 14.86 mg, 0.03 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 529.2. 1H 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). Example 10 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM NaH, THF Int-36 _{10.1 10.2} PEPPSI-Pd dioxane, Cs₂CO₃ Cs₂CO₃, DMSO 10.3 Example 10 Step (a): preparation of tert-butyl 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (compound 10.1) tert-Butyl 4-[3-[1-[3-[(6-chloropyrazin-2-yl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 10.1) was prepared in analogy to Example 2, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (_Int-32) and 2,4-dichloropyrimidine with 6-methyl-4- [4-[3-(1-methyl-4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (Int-36) and 2,6- dichloropyrazine in step (a). tert-butyl 4-[3-[1-[5-[(6-chloropyrazin-2-yl)carbamoyl]-2-fluoro-4- pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (_{compound 10.2}, 700.0 mg, 1.25 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 561.3. Step (b): preparation of N-(6-chloropyrazin-2-yl)-6-fluoro-4-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 10.2) N-(6-chloropyrazin-2-yl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 10.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (_{compound 1.1)} with tert-butyl 4-[3-[1-[5-[(6-chloropyrazin-2-yl)carbamoyl]-2- fluoro-4-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (Compound 10.1) in step (b). N- (6-chloropyrazin-2-yl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (_{compound 10.2}, 500.0 mg, 1.08 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 461.2. Step (c): preparation of 12-fluoro-1,4,7,11,15,29- 15,18 2,6 9,14 hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 10.3) 15,18 2,6 9,14 12-Fluoro-1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 10.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 1.2}) with N-(6-chloropyrazin-2-yl)-6-fluoro-4-[4-[3-(4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 10.2) in step (c).12-Fluoro- 15,18 2,6 9,14 1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 10.3, 190.0 mg, 0.45 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 425.2.¹H 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). Step (d): preparation of 2-hydroxy-N-(8-oxo-1,4,7,11,15,29- 15,18 2,6 9,14 hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 10) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 10) was prepared in analogy to _{Example 1}, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound 15,18 2,6 9,14 1.3) with 12-fluoro-1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (_{compound 10.3)} in step (d).2-Hydroxy-N-(8-oxo- 15,18 2,6 9,14 1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (_{Example 10}, 25.31 mg, 0.05 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 530.3.¹H 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). Example 11 N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (_{Example 11}) was prepared in analogy to Example 10, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). N- (8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide (_{Example 11}.8.12 mg, 0.02 mmol) was obtained. MS obsd. (ESI⁺) [(M +H)⁺]: 514.3.¹H 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). Example 12 15,18 2,6 9,14 N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide 15,18 2,6 9,14 N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 12) was prepared in analogy to Example 1, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d). N-(8- 15,18 2,6 9,14 oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)ethanesulfonamide (Example 12, 28.21 mg, 0.06 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 513.2.¹H 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). Example 13 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme:

TFA, DCM Pd(dba), Xantphos Cs_{2 2} ₂CO₃, dioxane Int-39 _{13.1 13.2} PEPPSI-Pd Cs₂CO₃, DMSO Cs₂CO₃, dioxane 1_{3.3 Example 13} Step (a): preparation of tert-butyl 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro- 4-pyridyl]-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 13.1) Tert-butyl 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4- piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 13.1) was prepared in analogy to _{Example 2}, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (Int-32) with tert-butyl 4-[3-[1-(5-carbamoyl-2- fluoro-4-pyridyl)-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (Int-39) in step (a). Tert-butyl 4-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidyl]propyl]-4- fluoro-piperidine-1-carboxylate (_{compound 13.1}, 650.0 mg, 1.12 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 578.3. Step (b): preparation of N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-fluoro-4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 13.2) N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 13.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (Compound 13.1) in step (b). N- (6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-fluoro-4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 13.2}, 430.0 mg, 0.9 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 478.2. Step (c): preparation of 12,22-difluoro-1,7,11,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 13.3) 15,18 2,6 9,14 12,22-Difluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 13.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 1.2}) with N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-fluoro-4- piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 13.2) in step (c).12,22- 15,18 2,6 9,14 Difluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 13.3, 200.0 mg, 0.45 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 442.2. Step (d): preparation of ^N-(22-fluoro-8-^oxo-1,7,11,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2- hydroxy-ethanesulfonamide (Example 13) 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide (Example 13) was prepared in analogy to Example 1, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15,18 2,6 9,14 1.3) with 12,22-difluoro-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 13.3) in step (d). N-(22-fluoro-8-oxo-1,7,11,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 13, 30.07 mg, 0.06 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 547.3.¹H 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).¹⁹F NMR (376 MHz, CDCl3) δ = -137.45. Example 14 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM TCFH, NMI MeCN, Int-37 _{14.1 14.2} PEPPSI-Pd Cs₂CO₃, dioxane Cs₂CO₃, DMSO 1_{4.3 Example 14} Step (a): preparation of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-fluoro- 3-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 14.1) tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-fluoro-3-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 14.1) was prepared in analogy to Example 1, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6- fluoro-pyridine-3-carboxylic acid (Int-31) with 3-[4-[3-(1-tert-butoxycarbonyl-4- piperidyl)propyl]-1-piperidyl]-5-fluoro-pyridine-2-carboxylic acid (Int-37) in step (a). Tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-fluoro-3-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 14.1, 1.60 g, 2.86 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 560.2. Step (b): preparation of N-(6-chloro-2-pyridyl)-5-fluoro-3-[4-[3-(4-piperidyl)propyl]-1- piperidyl]pyridine-2-carboxamide (compound 14.2) N-(6-chloro-2-pyridyl)-5-fluoro-3-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-2- carboxamide (compound 14.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5- fluoro-3-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (_{Compound 14.1}) in step (b). N- (6-chloro-2-pyridyl)-5-fluoro-3-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-2-carboxamide (compound 14.2, 1450.0 mg, 2.11 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 460.3 Step (c): preparation of 12-fluoro-1,7,10,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 14.3) 15,18 2,6 9,14 12-fluoro-1,7,10,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 14.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-5-fluoro-3-[4-[3-(4-piperidyl)propyl]- 1-piperidyl]pyridine-2-carboxamide (compound 14.2) in step (c).12-fluoro-1,7,10,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 14.3, 35.0 mg, 0.08 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 424.2 Step (d): preparation of 2-hydroxy-^N-(8-^oxo-1,7,10,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9(14),10,12-hexaen-12- yl)ethanesulfonamide (Example 14) 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide (Example 14) was prepared in analogy to Example 1, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15,18 2,6 9,14 1.3) with 12-fluoro-1,7,10,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 14.3) in step (d).2-hydroxy-N-(8-oxo-1,7,10,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9(14),10,12-hexaen-12- yl)ethanesulfonamide (Example 14, 1.46 mg, 0.0 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 529.2.¹H 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). Example 15 15,18 2,6 9,14 N-(20-fluoro-8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd₂(dba)₂, Xantphos Cs₂CO₃, dioxane Int-40 _{15.1 15.2} PEPPSI-Pd Cs₂CO₃, dioxane Cs₂CO₃, DMSO 1_{5.3 Example 15} Step (a): preparation of tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro- 2-pyridyl]-4-piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate (compound 15.1) Tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]-2- fluoro-propyl]piperidine-1-carboxylate (_{compound 15.1}) was prepared in analogy to _Example 2, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (Int-32) with tert-butyl 4-[3-[1-(3-carbamoyl-6- fluoro-2-pyridyl)-4-piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate (_Int-40) in step (a). Tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]-2-fluoro- propyl]piperidine-1-carboxylate (compound 15.1, 120.0 mg, 0.21 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 578.4. Step (b): preparation of ^tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro- 2-pyridyl]-4-piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate (compound 15.2) tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]-2- fluoro-propyl]piperidine-1-carboxylate (_{compound 15.2}) was prepared in analogy to _Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[3-[(6-chloro- 2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate (Compound 15.1) in step (b). tert-Butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2- pyridyl]-4-piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate (compound 15.2, 90.0 mg, 0.16 mmol) was obtained which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 478.3. Step (c): preparation of 12,20-difluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15.3) 15,18 2,6 9,14 12,20-Difluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 15.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]-2-fluoro-propyl]piperidine-1-carboxylate (_{compound 15.2}) in 15,18 2,6 9,14 step (c).12,20-Difluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 15.3, 25.0 mg, 0.06 mmol) was obtained. MS obsd.(ESI⁺) [(M+H)⁺]: 442.3. Step (d): preparation of N-(20-fluoro-8-oxo-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2- hydroxy-ethanesulfonamide ⁽Example 15⁾ 15,18 2,6 9,14 N-(20-fluoro-8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide (_{Example 15}) was prepared in analogy to Example 1, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _1.3) 15,18 2,6 9,14 with 12,20-difluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 15.3) in step (d). N-(20-fluoro-8-oxo-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 15, 8.04 mg, 0.01 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 547.3. 1H 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). Example 20 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TCFH, NMI TFA, DCM MeCN 20.1 20.2 Int-33 PEPPSI-Pd B₂(OH)₄, 4,4 ^'-bipyridine TEA, DCM dioxane DMF 2_0.3 20.4 _20.5 LAH, THF Example 20 Step (a): preparation of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 20.1) To a solution of 2-amino-6-chloropyridine (3.24 g, 25.23 mmol) and 2-[4-[3-(1-tert- butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-4-nitro-benzoic acid (Int-33, 10.0 g, 21.03 mmol) in ACN (100 mL) was added TCFH (6784.7 mg, 24.18 mmol) and NMI (6042.39 mg, 73.59 mmol) at 0 °C. After being stirred at 45 °C for 8 hrs, then reaction mixture was poured into water (250 mL). The formed solid was collected by filtration and the cake was dried in vacuo to afford tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 20.1, 12.03 g, 20.52 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 586.4. Step (b): preparation of N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (compound 20.2) N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (_{compound 20.2}) was prepared in analogy to _{Example 1}, by replacing tert-butyl 4-[3-[1-[3-[(6- chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (_{compound 20.1}) in step (b). N-(6-chloro-2-pyridyl)- 4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (compound 20.2, 9900.0 mg, 20.37 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 486.2. Step (c): preparation of 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) 15,18 2,6 9,14 12-Nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one _{(compound 20.3)} was prepared in analogy to _{Example 1}, by replacing N-(6- chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (_{compound 20.2)} in step (c).12-Nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _20.3, 5.0 g, 11.12 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 450.2. Step (d): preparation of 12-amino-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) 15,18 2,6 9,14 To a solution of 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.3, 1250.0 mg, 2.78 mmol) in DMSO (50 mL) was added 4,4’-bipyridine (21.71 mg, 0.14 mmol) and B2(OH)4 (997.15 mg, 11.12 mmol). After being stirred at 20 °C for 0.1 hr, the mixture was poured into water (270 mL), then extracted with EA (300 mL) three times. The combined organic phase was washed with brine (500 mL) times, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to afford 12- 15,18 2,6 9,14 amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8- one _{(compound 20.4,} 1000.0 mg, 2.38 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 420.3. Step (e): preparation of methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) 15,18 2,6 9,14 To a solution of 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4, 2000.0 mg, 4.77 mmol) in DCM (20 mL) was added TEA (1.23 mL, 9.53 mmol) and methyl (chlorosulfonyl)acetate (1645.44 mg, 9.53 mmol) at 0 °C. After being stirred at 25 °C for 4 hrs. The result mixture was poured into water (270 mL), then extracted with DCM (300 mL) three times. The combined organic phase was washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 40 to 70% EA in PE gradient @ 100 mL/min) to afford methyl 2-[(8- 15,18 2,6 9,14 oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) (1.50 g, 2.7 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 556.3. Step (f): preparation of 2-hydroxy-^N-(8-^oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 20) To a solution of methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5, 1500.0 mg, 2.7 mmol) in THF (40 mL) was added LAH (1.62 mL, 4.05 mmol) at 0 °C. The mixture was evacuated and backfilled with N2 three times. After being stirred for 1 hr at 25 °C under N₂, the resultant mixture was quenched by 15% NaOH (15 mL) at 0 °C dropwise. The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlashSilica Flash Column, Eluent of 0% to 30% Methanol in Dichloromethane gradient @80 mL/min), then the crude product was purified by prep-HPLC (condition Phenomenex luna C18150*40mm* 15um, water (TFA)-ACN,22%-52%) to afford 2-hydroxy-N- 15,18 2,6 9,14 (8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 20, 385.86 mg, 0.73 mmol). MS obsd. (ESI+) [(M+H)⁺]: 529.2. ¹H 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). Example 21 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: PEPPSI-Pd DIEA, DMSO Cs₂CO₃, dioxane Int-54 21.1 21.2 B₂(OH) 4,4 ^'-bipyrid₄ine DMF TEA, DCM LAH, THF 21.3 21.4 Example 21 Step (a): preparation of N-(6-chloropyrazin-2-yl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]- 1-piperidyl]benzamide (compound 21.1) 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-piperidyl)propyl]piperidine (4432.14 mg, 21.07 mmol) in DMSO (30 mL) was added DIEA (3.21 mL, 19.45 mmol). After being stirred for 16 hrs at 25 °C, the resultant mixture was poured into water (150 mL), extracted with DCM (150 mL) three times. The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by prep-HPLC (condition Phenomenex luna C18150*40mm* 15um, water (TFA)-ACN, 35%-75%), then extracted with DCM (150 mL) three times. The combined organic phase was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo to afford N-(6-chloropyrazin-2-yl)-4-nitro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 21.1, 450.0 mg, 0.92 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 487.2. Step (b): preparation of 12-nitro-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 21.2) 15,18 2,6 9,14 12-Nitro-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 21.2) was prepared in analogy to Example 1, by replacing N-(6- chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2) with N-(6-chloropyrazin-2-yl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (compound 21.1) in step (c).12-nitro-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 21.2, 186.0 mg, 0.41 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 451.4. Step (c): preparation of 12-amino-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 21.3) 15,18 2,6 9,14 12-Amino-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 21.3) was prepared in analogy to Example 20, by replacing 12-nitro- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _{(compound 20.3)} 15,18 2,6 9,14 with 12-nitro-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (_{compound 21.2)} in step (d).12-Amino-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _(compound 21.3, 40.0 mg, 0.1 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 421.2. Step (d): preparation of methyl 2-[(8-oxo-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 21.4) 15,18 2,6 9,14 Methyl 2-[(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 21.4) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) with 12-amino-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _21.3) in step (e). Methyl 2-[(8-oxo-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 21.4, 35.0 mg, 0.06 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 557.3. Step (e): preparation of 2-hydroxy-N-(8-oxo-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 21) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 21) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(8-oxo-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (_{compound 21.4}) in step (f).2-Hydroxy-N-(8-oxo-1,4,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (_{Example 21}, 3.47 mg, 0.01 mmol) was obtained. MS obsd. (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). Example 22 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd₂(dba), Xantphos Cs₂CO₃,₂ dioxane Int-34 _{22.1 22.2} _{PEPPSI-Pd 4,4} B _'-2b( iO pH y_r) i_{4dine TEA, DCM} Cs DMF o₂CO dixane₃ 22.3 22.4 22.5 LAH, THF Example 22 Step (a): preparation of tert-butyl 4-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5- nitro-phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 22.1) tert-butyl 4-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 22.1) was prepared in analogy to _{Example 2}, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (Int-32) with tert-butyl 4-[3-[1-(2-carbamoyl-5-nitro- phenyl)-4-piperidyl]propyl]piperidine-1-carboxylate (Int-34) in step (a). Tert-butyl 4-[3-[1-[2- [(2-chloropyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 22.1, 600.0 mg, 1.02 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 587.3. Step (b): preparation of N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 22.2) N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (compound 22.2) was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6- chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (_{compound 1.1)} with tert-butyl 4-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]- 4-piperidyl]propyl]piperidine-1-carboxylate (Compound 22.1) in step (b). N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (_{compound 22.2}, 500.0 mg, 1.03 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 487.2. Step (c): preparation of 12-nitro-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 22.3) 15,18 2,6 9,14 12-Nitro-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 22.3) was prepared in analogy to Example 1, by replacing N-(6- chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2) with N-(2-chloropyrimidin-4-yl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (compound 22.2) in step (c).12-Nitro-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 22.3, 200.0 mg, 0.44 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 451.2. Step (d): preparation of 12-amino-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 22.4) 15,18 2,6 9,14 12-Amino-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 22.4) was prepared in analogy to Example 20, by replacing 12-nitro- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _{(compound 20.3)} 15,18 2,6 9,14 with 12-nitro-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one _{(compound 22.3)} in step (d).12-Amino-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound 22.4, 190.0 mg, 0.45 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 421.2. Step (e): preparation of methyl 2-[(8-oxo-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 22.5) 15,18 2,6 9,14 Methyl 2-[(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 22.5) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) with 12-amino-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _22.4) in step (e). Methyl 2-[(8-oxo-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 22.5, 250.0 mg, 0.45 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 557.2. Step (f): preparation of 2-hydroxy-N-(8-oxo-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 22) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 22) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(8-oxo-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate _{(compound 22.5}) in step (f).2-hydroxy-N-(8-oxo-1,3,7,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide _{(Example 22}, 48.27 mg, 0.09 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 529.3.¹H 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). Example 23 15,18 2,6 9,14 2-hydroxy-^N-(8-^oxo-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: PEPPSI-Pd DIEA, DMSO dioxane, Cs₂CO₃ Int-55 23.1 23.2 B ^' ₂(OH) 4,4-bipyridine LAH, THF D^MF TEA, DCM 23.3 23.4 Example 23 Step (a): preparation of N-(2-chloro-4-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide N-(2-chloro-4-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (compound 23.1) was prepared in analogy to Example 21 by replacing N-(6-chloropyrazin-2- yl)-2-fluoro-4-nitro-benzamide (Int-54) with N-(2-chloro-4-pyridyl)-2-fluoro-4-nitro-benzamide (_Int-55) in step (a). N-(2-chloro-4-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (compound 23.1, 3500.0 mg, 7.2 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 486.3. Step (b): preparation of 12-nitro-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 23.2) 15,18 2,6 9,14 12-Nitro-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (_{compound 23.2}) was prepared in analogy to Example 1, by replacing N-(6- chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2) with N-(2-chloro-4-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (_{compound 23.1}) in step (c).12-Nitro-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 23.2) (160.0 mg, 0.36 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 450.3 Step (c): preparation of 12-amino-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 23.3) 15,18 2,6 9,14 12-Amino-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 23.3) was prepared in analogy to Example 20, by replacing 12-nitro- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _{(compound 20.3)} 15,18 2,6 9,14 with 12-nitro-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (_{compound 23.2}) in step (d).12-Amino-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound 23.3, 150.0 mg, 0.36 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 420.3. Step (d): preparation of methyl 2-[(8-oxo-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 23.4) 15,18 2,6 9,14 Methyl 2-[(8-oxo-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 23.4) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) with 12-amino-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15,18 2,6 9,14 23.3) in step (e). Methyl 2-[(8-oxo-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 23.4, 150.0 mg, 0.27 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 556.4. Step (e): preparation of 2-hydroxy-N-(8-oxo-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 23) 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 23) was prepared in analogy to _{Example 20}, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(8-oxo-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 23.4) in step (f).2-hydroxy-N-(8-oxo-1,3,7,15- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 23, 27.49 mg, 0.05 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 528.2.¹H 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). Example 24 2-hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM TCFH, NMI MeCN Int-33 _{24.1 24.2} B PEPPSI-Pd 4,4 ^'-b₂(OH) ipyrid₄ine d C_is_o _2xC_anO_e _{3 DMF} ^{TEA, DCM} 2_4.3 24.4 _24.5 LAH THF Example 24 Step (a): preparation of tert-butyl 4-[3-[1-[2-[(6-bromo-5-methoxy-2- pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 24.1) Tert-butyl 4-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate _{(compound 24.1)} was prepared in analogy to Example 20, by replacing 2-amino-6-chloropyridine with 6-bromo-5-methoxy-pyridin-2-amine in step (a). Tert-butyl 4-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 24.1, 1.5 g, 2.27 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 662.1. Step (b): preparation of N-(6-bromo-5-methoxy-2-pyridyl)-4-nitro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 24.2) N-(6-bromo-5-methoxy-2-pyridyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (_{compound 24.2}) was prepared in analogy to _{Example 1}, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[(6-bromo- 5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (Compound 24.1) in step (b). N-(6-bromo-5-methoxy-2-pyridyl)-4-nitro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 24.2, 1.27 g, 2.27 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 562.2. Step (c): preparation of 3-methoxy-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 24.3) 15,18 2,6 9,14 3-Methoxy-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 24.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 1.2}) with N-(6-bromo-5-methoxy-2-pyridyl)-4-nitro-2-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 24.2) in step (c).3-Methoxy-12-nitro- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 24.3, 400.0 mg, 0.83 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 480.3. Step (d): preparation of 12-amino-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 24.4) 15,18 2,6 9,14 12-Amino-3-methoxy-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 24.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one _{(compound 20.3)} with 3-methoxy-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound _24.3) in step (d).12-Amino-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 24.4,180.0 mg, 0.4 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 450.3. Step (e): preparation of methyl 2-[(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 24.5) 15,18 2,6 9,14 Methyl 2-[(3-methoxy-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 24.5) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one _{(compound 20.4)} with 12-amino-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound _24.4) in step (e). Methyl 2-[(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 24.5, 50.0 mg, 0.09 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 586.2. Step (f): preparation of 2-hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 24) 2-Hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 24) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 24.5) in step (f).2-Hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 24, 8.67 mg, 0.02 mmol). MS obsd. (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 = 8.8 Hz, 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). Example 25 15,18 2,6 9,14 N-(10-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: Cs₂CO₃, PEPPSI-Pd DIEA, DMSO 1,4-dioxane Int-54 _{25.1 25.2} B(OH ,₂4 ^' ) 4 -bip₄yridine LAH DMF TEA, DCM THF 25.3 25.4 Example 25 Step (a): preparation of N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-6-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 25.1) N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-6-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (compound 25.1) was prepared in analogy to Example 21, by replacing N-(6-chloropyrazin-2- yl)-2-fluoro-4-nitro-benzamide (_Int-52) with N-(6-chloro-2-pyridyl)-2,6-difluoro-4-nitro- benzamide (Int-54) in step (a). N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-6-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 25.1, 895.0 mg, 1.78 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 504.2. Step (b): preparation of 10-fluoro-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 25.3) 15,18 2,6 9,14 10-Fluoro-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 25.2) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-6-[4-[3-(4- piperidyl)propyl]-1-piperidyl]benzamide (compound 25.1) in step (c).10-Fluoro-12-nitro- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 25.2, 85.0 mg, 0.18 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 468.2 Step (c): preparation of 12-amino-10-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 25.3) 15,18 2,6 9,14 12-Amino-10-fluoro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 25.3) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 10-fluoro-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 25.2) in step (d).12-Amino-10-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 25.3, 79.0 mg, 0.18 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 438.3 Step (d): preparation of methyl 2-[(10-fluoro-8-^oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 25.4) 15,18 2,6 9,14 Methyl 2-[(10-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 25.4) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) with 12-amino-10-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 25.3) in step (e). Methyl 2-[(10-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 25.4, 103.0 mg, 0.18 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 574.4. Step (e): preparation of N-(10-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 25) 15,18 2,6 9,14 N-(10-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide (Example 25) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(10-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 25.4) in step (f). N-(10-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (_{Example 25}, 11.79 mg, 0.02 mmol) was obtained. MS obsd. (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). Example 26 17,20 2,6 7,10 11,16 N-(24-fluoro-1,8,9,10,17,32-hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta- 2(32),3,5,7(31),8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme:

Int-1 TFA/DCM DIEA, DMSO Int-57 26.1 26.2 B( 4,4 ^'-b₂OH) ip ₄ PEPPSI-Pd yridine Cs₂CO DMF TEA, DCM dioxane₃ _26.3 26.4 _26.5 LAH THF Example 26 Step (a): preparation of tert-butyl 4-[3-[1-[2-[4-(6-chloro-2-pyridyl)triazol-1-yl]-5- nitro-phenyl]-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (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), tert-butyl 4-fluoro-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (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 hrs. The mixture was concentrated in vacuo. The residue was purified by reversed flash (Welch Ultimate XB_C1820-40μm; 120 A, water (0.1% FA)-ACN, 95%, 100ml/min) to afford tert-butyl 4-[3-[1-[2-[4-(6-chloro-2-pyridyl)triazol-1-yl]-5-nitro-phenyl]-4-piperidyl]propyl]-4- fluoro-piperidine-1-carboxylate (_{compound 26.1}, 362.0 mg, 0.58 mmol). MS obsd. (ESI⁺) [(M- Boc+H)⁺]: 528.3. Step (b): preparation of 2-chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1- piperidyl]-4-nitro-phenyl]triazol-4-yl]pyridine (compound 26.2) 2-Chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1-piperidyl]-4-nitro-phenyl]triazol-4- yl]pyridine (compound 26.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[4-(6-chloro-2-pyridyl)triazol-1-yl]-5- nitro-phenyl]-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (Compound 26.1) in step (b).2-Chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1-piperidyl]-4-nitro-phenyl]triazol-4- yl]pyridine (_{compound 26.2}, 304.0 mg, 0.58 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 528.3. Step (c): preparation of 24-fluoro-14-nitro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3) 17,20 2,6 7,10 11,16 24-Fluoro-14-nitro-1,8,9,10,17,32-hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta- 2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with 2-chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1- piperidyl]-4-nitro-phenyl]triazol-4-yl]pyridine (compound 26.2, 430.0 mg, 0.93 mmol) in step 17,20 2,6 7,10 11,16 (c).24-Fluoro-14-nitro-1,8,9,10,17,32-hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta- 2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3, 260.0 mg, 0.53 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 492.3. Step (d): preparation of 24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- amine (compound 26.4) 17,20 2,6 7,10 11,16 24-Fluoro-1,8,9,10,17,32-hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta- 2(32),3,5,7(31),8,11,13,15-octaen-14-amine (compound 26.4) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) with 24-fluoro-14-nitro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaene (compound 26.3) in step (d).24-Fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- amine (compound 26.4, 244.0 mg, 0.53 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 462.4. Step (e): preparation of methyl 2-[(24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- yl)sulfamoyl]acetate (compound 26.5) Methyl 2-[(24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- yl)sulfamoyl]acetate (compound 26.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one _{(compound 20.4)} with 24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- amine (compound 26.4) in step (e). Methyl 2-[(24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- yl)sulfamoyl]acetate (compound 26.5, 156.0 mg, 0.26 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 598.3. Step (f): preparation of ^N-(24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- yl)-2-hydroxy-ethanesulfonamide (Example 26) 17,20 2,6 7,10 11,16 N-(24-fluoro-1,8,9,10,17,32-hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta- 2(32),3,5,7(31),8,11,13,15-octaen-14-yl)-2-hydroxy-ethanesulfonamide (Example 26) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- yl)sulfamoyl]acetate (compound 26.5) in step (f). N-(24-fluoro-1,8,9,10,17,32- 17,20 2,6 7,10 11,16 hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta-2(32),3,5,7(31),8,11,13,15-octaen-14- yl)-2-hydroxy-ethanesulfonamide (Example 26, 26.38 mg, 0.05 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 570.3.¹H 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). Example 27 N-(22-fluoro-18-methyl-8-oxo-1,7,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-7 TFA DIEA, DMSO DCM Int-50 _{27.1 27.2} PEPPSI-Pd B 4,4 ^'-₂(OH) bipyri₄ dine Cs₂CO DMF TEA, DCM dioxane₃ _27.3 27.4 _27.5 LAH, THF Example 27 Step (a): preparation of benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-methyl-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 27.1) A mixture of N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-50, 392.61 mg, 1.33 mmol), benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (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 hrs. The mixture was diluted with H2O (100 mL), extracted with EA (80 mL) three times. The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column (10% to 50% EA in PE) and concentrated in vacuo to afford benzyl 4-[3-[1-[2-[(6-chloro-2- pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4-piperidyl]propyl]-4-fluoro-piperidine-1- carboxylate (compound 27.1, 610.0 mg, 0.94 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 652.3. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]-4- methyl-1-piperidyl]-4-nitro-benzamide (compound 27.2) A solution of benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl- 4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 27.1, 580.0 mg, 0.89 mmol) in TFA (5.0 mL, 0.89 mmol) was stirred at 80 °C for 1 hrs. The mixture was concentrated in vacuo. The residue was purified by reversed phase flash (0.1% FA) to afford N-(6-chloro-2- pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]-4-methyl-1-piperidyl]-4-nitro-benzamide (compound 27.2, 410.0 mg, 0.79 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 518.2. Step (c): preparation of 22-fluoro-18-methyl-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 27.3) 15,18 2,6 9,14 22-Fluoro-18-methyl-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 27.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]- 4-methyl-1-piperidyl]-4-nitro-benzamide (compound 27.2) in step (c).22-fluoro-18-methyl-12- 15,18 2,6 9,14 nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 27.3, 210.0 mg, 0.44 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 482.2. Step (d): preparation of 12-amino-22-fluoro-18-methyl-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one ⁽compound 27.4) 15,18 2,6 9,14 12-amino-22-fluoro-18-methyl-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 27.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 22-fluoro-18-methyl-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 27.3) in step (d).12-Amino-22-fluoro-18-methyl-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 27.4, 150.0 mg, 0.33 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 452.3. Step (e): preparation of methyl 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate ⁽compound 27.5⁾ Methyl 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 27.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 12-amino-22-fluoro-18-methyl-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 27.4) in step (e). Methyl 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 27.5, 50.0 mg, 0.09 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 588.4. Step (f): preparation of ^N-(22-fluoro-18-methyl-8-^oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 27) 15,18 2,6 9,14 N-(22-fluoro-18-methyl-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide (Example 27) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(22-fluoro-18-methyl-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 27.5) in step (f). N-(22-fluoro-18-methyl-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 27, 21.24 mg, 0.04 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 560.3.¹H 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).¹⁹F NMR (376 MHz, CDCl₃) δ = -130.95. Example 28 2-hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]ethanesulfonamide The titled compound was synthesized according to the following scheme:

Int-5 TFA, DCM DIEA, DMSO Int-50 _{28.1 28.2} PEPPSI-Pd B 4,4 ^'-₂(OH) bipyri₄ dine Cs₂CO TEA, DCM DMF dioxane₃ _28.3 28.4 _28.5 LAH, THF Example 28 Step (a): preparation of ^tert-butyl 4-[2-[[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine-1-carboxylate (compound 28.1) Tert-butyl 4-[2-[[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(trifluoromethyl)- 4-piperidyl]amino]ethyl]piperidine-1-carboxylate (compound 28.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1- carboxylate (Int-7) with tert-butyl 4-[2-[[4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine- 1-carboxylate (Int-5) in step (a). Tert-butyl 4-[2-[[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine-1-carboxylate (compound 28.1, 1050.0 mg, 1.6 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 655.2. Step (b): preparation of ^N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[2-(4- piperidyl)ethylamino]-4-(trifluoromethyl)-1-piperidyl]benzamide (compound 28.2) N-(6-chloro-2-pyridyl)-4-nitro-2-[4-[2-(4-piperidyl)ethylamino]-4-(trifluoromethyl)-1- piperidyl]benzamide (_{compound 28.2}) was prepared in analogy to _{Example 1}, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 4-[2-[[1-[2-[(6- chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(trifluoromethyl)-4- piperidyl]amino]ethyl]piperidine-1-carboxylate Compound 28.1) in step (b). N-(6-chloro-2- pyridyl)-4-nitro-2-[4-[2-(4-piperidyl)ethylamino]-4-(trifluoromethyl)-1-piperidyl]benzamide (compound 28.2, 889.0 mg) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 555.2. Step (c): preparation of 12-nitro-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.3) 12-Nitro-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4- [3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (_{compound 1.2}) with N-(6-chloro- 2-pyridyl)-4-nitro-2-[4-[2-(4-piperidyl)ethylamino]-4-(trifluoromethyl)-1-piperidyl]benzamide (compound 28.2) in step (c).12-Nitro-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.3, 332.0 mg, 0.64 mmol) was obtained by concentration. MS obsd. (ESI⁺) [(M+H)⁺]: 519.3. Step (d): preparation of 12-amino-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.4) 12-amino-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.4) was prepared in analogy to Example 20, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) with 12-nitro-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.3) in step (d).12-Amino-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.4, 310.0 mg, 0.63 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 489.2. Step (e): preparation of methyl 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 28.5) Methyl 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 28.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 12-amino-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 28.4) in step (e). Methyl 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 28.5, 482.0 mg, 0.77 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 625.3. Step (f): preparation of 2-hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]ethanesulfonamide (Example 28) 2-Hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]ethanesulfonamide (Example 28) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[[8-oxo-18-(trifluoromethyl)- 15,18 2,6 9,14 1,7,15,19,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 28.5) in step (f).2-Hydroxy-N-[8-oxo-18-(trifluoromethyl)- 15,18 2,6 9,14 1,7,15,19,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]ethanesulfonamide (_{Example 28}, 51.67 mg, 0.09 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 597.3.¹H 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 = 8.4 Hz, 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). Example 29 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-1 TFA, DCM DIEA, DMSO Int-50 _{29.1 29.2} B PEPPSI-Pd 4,4 ^'-₂(OH) bipyri₄dine Cs₂CO DMF TEA, DCM dioxane₃ _29.3 29.4 _29.5 LAH, THF Example 29 Step (a): preparation of tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 29.1) Tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]- 4-fluoro-piperidine-1-carboxylate (compound 29.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (_Int-7) with tert-butyl 4-fluoro-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-1) in step (a). Tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4- fluoro-piperidine-1-carboxylate (compound 29.1, 900.0 mg, 1.49 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 604.4. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1- piperidyl]-4-nitro-benzamide (compound 29.2) N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1-piperidyl]-4-nitro- benzamide (compound 29.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (_{compound 1.1}) with tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (Compound 29.1) in step (b). N- (6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 29.2, 650.0 mg, 1.29 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 504.3. Step (c): preparation of 22-fluoro-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 29.3) 15,18 2,6 9,14 22-Fluoro-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 29.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]- 1-piperidyl]-4-nitro-benzamide (compound 29.2) in step (c).22-Fluoro-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 29.3, 320.0 mg, 0.68 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 468.2. Step (d): preparation of 12-amino-22-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 29.4) 15,18 2,6 9,14 12-Amino-22-fluoro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 29.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 22-fluoro-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 29.3) in step (d).12-Amino-22-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 29.4, 240.0 mg, 0.55 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 438.2. Step (e): preparation of methyl 2-[(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 29.5) 15,18 2,6 9,14 Methyl 2-[(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 29.5) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one _{(compound 20.4)} with 12-amino-22-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 29.4) in step (e). Methyl 2-[(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 29.5, 50.0 mg, 0.09 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 574.3. Step (f): preparation of N-(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 29) 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide (_{Example 29}) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 29.5) in step (f). N-(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 29, 15.21 mg, 0.03 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 546.3.¹H NMR (400 MHz, 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 = 2.0 Hz, 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). 1⁹F NMR (376 MHz, DMSO-d₆) δ = -134.70. Example 30 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29- tetrazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13-hexaen-8-one The titled compound was synthesized according to the following scheme: K₂CO₃ TEA, DCM DMF 2_{9.4 30.1 Example 30} Step (a): preparation of ^N-(22-fluoro-8-^oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)propane-1- sulfonamide (compound 30.1) 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)propane-1-sulfonamide (compound 30.1) was prepared in analogy to Example 20, by replacing 12-amino-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) and methyl (chlorosulfonyl)acetate with 12-amino-22-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 29.4) and 3-chloropropanesulfonyl chloride in step (e). N-(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)propane-1- sulfonamide (compound 30.1, 70.0 mg, 0.12 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 578.2. Step (b): preparation of 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (Example 30) A mixture of N-(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)propane-1- sulfonamide (compound 30.1, 60.0 mg, 0.1 mmol), K2CO3 (43.03 mg, 0.31 mmol) in DMF (2.0 mL) was stirred at 50 °C for 2 hrs. The mixture was poured into water (20 mL), then extracted with DCM (20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (Phenomenex luna C18150*40mm* 15um, water (0.1% FA)-MeCN, 42% to 72% MeCN in H₂O, 10 min) and lyophilized to afford 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22- fluoro-1,7,15,29-tetrazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (_{Example 30}, 25.44 mg, 0.05 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 542.4.¹H 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).¹⁹F NMR (376 MHz, DMSO-d6) δ = -134.59. Example 31 15,18 2,6 9,14 N-(22-fluoro-8-^oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: TEA, DCM c_{ompound 29.4 Example 31} 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 31) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) and methyl (chlorosulfonyl)acetate with 12- 15,18 2,6 9,14 amino-22-fluoro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (_{compound 29.4}) and ethanesulfonyl chloride in step (e). N-(22-fluoro-8-oxo- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (_{Example 31}, 6.86 mg, 0.01 mmol) was obtained. MS obsd. (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).¹⁹F NMR (376 MHz, DMSO-d6) δ = -134.70. Example 32 N-[18-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy- ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-4 TFA DIEA, DMSO Int-50 _{32.1 32.2} B PEPPSI-Pd ,4 ^'-₂(OH) 4 bipyrid₄ine Cs₂CO₃ DMF TEA, DCM dioxane 3_2.3 32.4 _32.5 LAH, THF Example 32 Step (a): preparation of benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-(difluoromethyl)-4-piperidyl]propyl]piperidine-1-carboxylate (32.1) Benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4- piperidyl]propyl]piperidine-1-carboxylate (compound 32.1) was prepared in analogy to Example 27, by replacing benzyl 4-[3-[4-(difluoromethyl)-4-piperidyl]propyl]piperidine-1- carboxylate (_Int-7) with tert-butyl 4-[2-[[4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine- 1-carboxylate (Int-4) in step (a). Benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-(difluoromethyl)-4-piperidyl]propyl]piperidine-1-carboxylate (compound 32.1, 650.0 mg, 0.97 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 670.2. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 32.2) N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4-piperidyl)propyl]-1-piperidyl]-4- nitro-benzamide (compound 32.2) was prepared in analogy to Example 27, by replacing benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4-piperidyl]propyl]-4- fluoro-piperidine-1-carboxylate (compound 27.1) with Benzyl 4-[3-[1-[2-[(6-chloro-2- pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4-piperidyl]propyl]piperidine-1- carboxylate _{(compound 32.1)} in step (b). N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 32.2, 350.0 mg, 0.65 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 536.2. Step (c): preparation of 18-(difluoromethyl)-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 32.3⁾ 15,18 2,6 9,14 18-(Difluoromethyl)-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (_{compound 32.3}) was prepared in analogy to _{Example 1}, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (_{compound 32.2}) in step (c).18- 15,18 2,6 9,14 (Difluoromethyl)-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 32.3, 130.0 mg, 0.26 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 500.3. Step (d): preparation of 12-amino-18-(difluoromethyl)-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 32.4) 15,18 2,6 9,14 12-Amino-18-(difluoromethyl)-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (_{compound 32.4}) was prepared in analogy to _{Example 20}, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (_{compound 20.3}) with 18-(difluoromethyl)-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound _32.3) in step (d).12-Amino-18-(difluoromethyl)-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound 32.4, 100.0 mg, 0.21 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 470.3. Step (e): preparation of methyl 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 32.5) Methyl 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (_{compound 32.5}) was prepared in analogy to _{Example 20}, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 12-amino-18-(difluoromethyl)-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound 32.4) in step (e). Methyl 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 32.5, 40.0 mg, 0.07 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 606.3. Step (f): preparation of ^N-[18-(difluoromethyl)-8-^oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy- ethanesulfonamide ⁽Example 32⁾ 15,18 2,6 9,14 N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy-ethanesulfonamide (_{Example 29}) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[[18-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 32.5) in step (f). N-[18-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy- ethanesulfonamide (Example 32, 3.88 mg, 0.01 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 578.3.¹H 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).¹⁹F NMR (376 MHz, CDCl₃) δ = - 128.34. Example 33 N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-16 TFA, DCM DIEA, DMSO Int-50 _{33.1 33.2} B(OH) PEPPSI-Pd 4,4 ^'-₂bipyri₄dine Cs dio₂CO xane₃ DMF TEA, DCM 3_3.3 33.4 _33.5 LAH, THF Example 33 Step (a): preparation of tert-butyl 3-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (compound 33.1) Tert-butyl 3-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]ethoxy]- 4,4-difluoro-piperidine-1-carboxylate (compound 33.1) was prepared in analogy to Example ₂₇, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (Int-7) with tert-butyl 4,4-difluoro-3-[2-(4-piperidyl)ethoxy]piperidine-1-carboxylate (Int-16) in step (a). Tert-butyl 3-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (compound 33.1, 820.0 mg, 1.31 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 624.3. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3- piperidyl)oxy]ethyl]-1-piperidyl]-4-nitro-benzamide (compound 33.2) N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3-piperidyl)oxy]ethyl]-1-piperidyl]-4-nitro- benzamide (compound 33.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (_{compound 1.1)} with tert-butyl 3-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Compound 33.1) in step (b). N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3-piperidyl)oxy]ethyl]-1-piperidyl]-4-nitro- benzamide _{(compound 33.2,} 520.0 mg, 0.99 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 524.1 Step (c): preparation of 18,18-difluoro-4-nitro-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 33.3) 10,14 15,19 2,7 18,18-difluoro-4-nitro-20-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-8-one (Compound 33.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[2-[(4,4-difluoro-3- piperidyl)oxy]ethyl]-1-piperidyl]-4-nitro-benzamide (compound 33.2) in step (c).18,18- 10,14 15,19 2,7 Difluoro-4-nitro-20-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-8-one (Compound 33.3, 550.0 mg) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 488.1.¹H 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). Step (d): preparation of 4-amino-18,18-difluoro-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 33.4) 4-Amino-18,18-difluoro-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 33.4) was prepared in analogy to Example 20, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _20.3) with 18,18-difluoro-4-nitro-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (Compound 33.3) in step (d).4-Amino-18,18-difluoro-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 33.4, 530.0 mg, 1.16 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 458.2. Step (e): preparation of methyl 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (compound 33.5) Methyl 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (compound 33.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18-difluoro-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 33.4)in step (e). Methyl 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (compound 33.5, 420.0 mg, 0.71 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 594.2. Step (f): preparation of ^N-(18,18-difluoro-8-^oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 33) N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (Example 33) was prepared in analogy to Example 20, by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(18,18-difluoro-8-oxo-20-oxa- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (compound 33.5) in step (f). N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide _{(Example 33,} 64.03 mg, 0.11 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 566.3.¹H 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). Example 34 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: PEPPSI-Pd DIEA, DMSO Cs dio₂CO xane₃ Int-56 34.1 34.2 B 4,4 ^'-₂(OH) bipyri₄dine LAH, THF DMF TEA, DCM 34.3 34.4 Example 34 Step (a): preparation of ^N-(3-bromophenyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (compound 34.1) N-(3-bromophenyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (compound _34.1) was prepared in analogy to _{Example 21}, 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-piperidyl)propyl]-1-piperidyl]benzamide (compound 34.1, 2844.0 mg, 5.37 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 531.3.¹H 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). Step (b): preparation of 12-nitro-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 34.2) 15,18 2,6 9,14 12-Nitro-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 34.2) was prepared in analogy to Example 1, by replacing N-(6-chloro-2- pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (_compound 1.2) with N-(3-bromophenyl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide 15,18 2,6 9,14 (compound 34.1) in step (c).12-Nitro-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 34.2, 478.0 mg, 1.07 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 449.2. Step (c): preparation of 12-amino-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 34.3) 15,18 2,6 9,14 12-Amino-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 34.3) was prepared in analogy to Example 20, by replacing 12-nitro- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _{(compound 20.3)} 15,18 2,6 9,14 with12-nitro-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (_{compound 34.2} in step (d).12-Amino-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _(compound 34.3, 425.0 mg, 1.02 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 419.3. Step (d): preparation of methyl 2-[(8-oxo-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 34.4) 15,18 2,6 9,14 Methyl 2-[(8-oxo-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate (compound 34.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) with 12-amino-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 15,18 2,6 9,14 34.3) in step (e). methyl 2-[(8-oxo-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 34.4, 265.0 mg, 0.48 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 555.3. Step (e): preparation of 2-hydroxy-N-(8-oxo-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 34) 15,18 2,6 9,14 2-Hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 34) was prepared in analogy to _{Example 20}, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(8-oxo-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 34.4) in step (f).2-Hydroxy-N-(8-oxo-1,7,15- 15,18 2,6 9,14 triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 34, 30.03 mg, 0.06 mmol) was obtained. MS obsd. (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). Example 35 10,14 15,19 2,7 N-(18,18-difluoro-8-^oxo-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-15 TFA, DCM DIEA, DMSO Int-50 _{35.1 35.2} PEPPSI-Pd B₂(OH)₄ Cs₂CO 4,4 ^'-bipyridine dioxane_{3 DMF TEA, DCM} 35.3 35.4 35.5 LAH, THF Example 35 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 35.1) Tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]- 4,4-difluoro-piperidine-1-carboxylate (compound 35.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (_Int-7) with tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (_Int-15) in step (a). Tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 35.1, 650.0 mg, 1.04 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 622.2. Step (b): preparation of N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1- piperidyl]pyridine-3-carboxamide (compound 35.2) N-(6-chloro-2-pyridyl)-6-fluoro-4-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 35.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (_{Compound 35.1}) in step (b). N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 35.2, 610.0 mg, 1.17 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 522.2. Step (c): preparation of 18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 35.3) 10,14 15,19 2,7 18,18-Difluoro-4-nitro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 35.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 35.2) in step (c).18,18-Difluoro- 10,14 15,19 2,7 4-nitro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen- 8-one (compound 35.3) (520.0 mg, 1.07 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 486.2. Step (d): preparation of 4-amino-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 35.4) 10,14 15,19 2,7 4-Amino-18,18-difluoro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 35.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 35.3) in step (d).4-Amino-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 35.4, 200.0 mg, 0.44 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 456.2. Step (e): preparation of methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 35.5) Methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 35.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 35.4) in step (e). Methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 35.5, 250.0 mg, 0.42 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 592.1. Step (f): preparation of N-(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 35) 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide (Example 35) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[[(E)-3-[4-[3-[1-[(E)- aminomethyliminomethyl]-4,4-difluoro-3-piperidyl]propyl]-1-piperidyl]but-2- enyl]sulfamoyl]acetate (compound 35.5) in step (f). N-(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (Example 35, 48.39 mg, 0.09 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 564.3.¹H 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). Example 35A and Example 35b 2-hydroxy-N-[(19S)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 35A and Example 35B) Example 35A and Example 35B Separation of compound of Example 35 by SFC afforded Example 35A (faster eluting, 19.59 mg) and Example 35B (slower eluting, 16.23 mg) with column DAICEL CHIRALPAK IG (250mm*30mm, 10um), CO2-EtOH (0.1%NH3H2O), 40%, 150ml/min). Example 35A (faster eluting): 19.59 mg, 0.03 mmol. MS obsd. (ESI⁺) [(M+H)⁺]: 564.3. 1H 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). Example 35B (slower eluting): 16.23 mg, 0.03 mmol. MS obsd. (ESI⁺) [(M+H)⁺]: 564.3. ¹H 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 = 2.0 Hz, 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). Example 36 N-[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy- ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-2 TFA, DCM DIEA, DMSO Int-50 _{36.1 36.2} PEPPSI-Pd B 4,4 ^'-₂(OH) bipyri₄dine Cs dio₂CO xane₃ DMF TEA, DCM 36.3 36.4 36.5 LAH, THF Example 36 Step (a): preparation of ^tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4-(difluoromethyl)piperidine-1-carboxylate (compound 36.1) Tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]- 4-(difluoromethyl)piperidine-1-carboxylate (compound 36.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1- carboxylate (Int-7) with tert-butyl 4-(difluoromethyl)-4-[3-(4-piperidyl)propyl]piperidine-1- carboxylate (Int-2) in step (a). Tert-butyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4-(difluoromethyl)piperidine-1-carboxylate _{(compound 36.1}, 600.0 mg, 0.94 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 636.4. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4- piperidyl]propyl]-1-piperidyl]-4-nitro-benzamide (compound 36.2) N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4-piperidyl]propyl]-1-piperidyl]-4- nitro-benzamide (compound 36.2) was prepared in analogy to Example 1, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[(6-chloro- 2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4-(difluoromethyl)piperidine-1- carboxylate (Compound 36.1) in step (b). N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4- piperidyl]propyl]-1-piperidyl]-4-nitro-benzamide (compound 36.2, 430.0 mg, 0.8 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 536.2. Step (c): preparation of 22-(difluoromethyl)-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 36.3) 15,18 2,6 9,14 22-(Difluoromethyl)-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 36.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-[4-(difluoromethyl)-4- piperidyl]propyl]-1-piperidyl]-4-nitro-benzamide (compound 36.2) in step (c).22- 15,18 2,6 9,14 (Difluoromethyl)-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 36.3, 120.0 mg, 0.24 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 500.2. Step (d): preparation of 12-amino-22-(difluoromethyl)-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 36.4) 15,18 2,6 9,14 12-Amino-22-(difluoromethyl)-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 36.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 22-(difluoromethyl)-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 36.3) in step (d).12-Amino-22-(difluoromethyl)-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 36.4, 60.0 mg, 0.13 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 470.2. Step (e): preparation of methyl 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 36.5) Methyl 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 36.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 12-amino-22-(difluoromethyl)-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 36.4) in step (e). Methyl 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (compound 36.5, 40.0 mg, 0.07 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 606.3. Step (f): preparation of N-[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy- ethanesulfonamide (Example 36) 15,18 2,6 9,14 N-[22-(difluoromethyl)-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy-ethanesulfonamide (Example 36) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate (_{compound 36.5)} in step (f). N-[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy- ethanesulfonamide (_{Example 36}, 18.74 mg, 0.03 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 578.3.¹H 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).¹⁹F NMR (376 MHz, DMSO-d6) δ = -128.87. Example 37 N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-17 TFA, DCM DIEA, DMSO Int-50 _{37.1 37.2} B PEPPSI-Pd 4 ^'-₂(OH) 4, bipyri₄dine Cs dio₂CO xane₃ DMF TEA, DCM 37.3 37.4 LAH, THF Example 37 Step (a): preparation of tert-butyl 4-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]ethoxy]-3,3-difluoro-pyrrolidine-1-carboxylate (compound 37.1) Tert-butyl 4-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]ethoxy]- 3,3-difluoro-pyrrolidine-1-carboxylate (compound 37.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (_Int-7) with tert-butyl 3,3-difluoro-4-[2-(4-piperidyl)ethoxy]pyrrolidine-1-carboxylate (_Int-17) in step (a). Tert-butyl 4-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]ethoxy]-3,3-difluoro-pyrrolidine-1-carboxylate (compound 37.1, 1012.0 mg, 1.66 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 610.2. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[2-(4,4-difluoropyrrolidin-3- yl)oxyethyl]-1-piperidyl]-4-nitro-benzamide (compound 37.2) N-(6-chloro-2-pyridyl)-2-[4-[2-(4,4-difluoropyrrolidin-3-yl)oxyethyl]-1-piperidyl]-4-nitro- benzamide (_{compound 37.2}) was prepared in analogy to _{Example 1}, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[2-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]ethoxy]-3,3-difluoro-pyrrolidine-1-carboxylate (_{Compound 37.1}) in step (b). N-(6-chloro-2-pyridyl)-2-[4-[2-(4,4-difluoropyrrolidin-3-yl)oxyethyl]-1-piperidyl]-4-nitro- benzamide (compound 37.2, 845.0 mg, 1.66 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 510.1. Step (c): preparation of 17,17-difluoro-4-nitro-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 37.3) 10,14 15,18 2,7 17,17-Difluoro-4-nitro-19-oxa-1,9,15,28-tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa- 2,4,6,10,12,14(28)-hexaen-8-one (compound 37.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 1.2}) with N-(6-chloro-2-pyridyl)-2-[4-[2-(4,4-difluoropyrrolidin-3- yl)oxyethyl]-1-piperidyl]-4-nitro-benzamide (compound 37.2) in step (c).17,17-Difluoro-4- 10,14 15,18 2,7 nitro-19-oxa-1,9,15,28-tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)- hexaen-8-one (compound 37.3, 614.0 mg, 1.3 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 474.2 Step (d): preparation of 4-amino-17,17-difluoro-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-8-one ⁽compound 37.4⁾ 4-Amino-17,17-difluoro-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 37.4) was prepared in analogy to Example 20, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) with17,17-difluoro-4-nitro-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 37.3) in step (d).4-Amino-17,17-difluoro-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 37.4, 543.0 mg, 1.22 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 444.3. Step (e): preparation of methyl 2-[(17,17-difluoro-8-^oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate ⁽compound 37.5⁾ Methyl 2-[(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate (compound 37.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-17,17-difluoro-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 37.4) in step (e). Methyl 2-[(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate (compound 37.5, 416.0 mg, 0.72 mmol) was obtained which was used in next step directly. MS obsd. (ESI⁺) [(M+H)⁺]: 580.3. Step (f): preparation of N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (Example 37) N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (_{Example 37}) was prepared in analogy to _{Example 20}, by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[(17,17-difluoro-8-oxo-19-oxa- 10,14 15,18 2,7 1,9,15,28-tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate (_{compound 37.5}) in step (f). N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (_{Example 37}, 37.37 mg, 0.07 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 552.2.¹H NMR (400 MHz, DMSO-d6) δ = 11.04 (br. s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.63-7.57 (m, 2H), 7.12(s, 1H), 7.03 (dd, J1 = 2 Hz, J2 = 8.8 Hz, 1H), 6.40 (dd, J1 = 2 Hz, J2=6.8 Hz, 1H), 5.06 (dd, J₁ = 2.4 Hz, J₂ = 12.8 Hz, 1H), 3.98 (dd, J₁ = 4 Hz, J₂ = 12.4Hz, 1H), 3.86 - 3.79 (m, 2H), 3.76 (t, J = 6.8Hz, 2H), 3.70 - 3.68 (m, 2H), 3.36 - 3.34 (m, 2H), 3.29 (m, 2H), 3.00 (d, J = 11.6 Hz, 1H), 2.87 (t, J = 10.4 Hz, 1H), 2.44 - 2.38 (m, 2H), 1.91 - 1.81 (m, 2H), 1.75 - 1.26 (m, 6H). Example 37A and Example 37B 2-hydroxy-N-[(18S)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide ^and 2-hydroxy-^N-[(18^R)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide (Example 37A ^and Example 37B)

Example 37A ^and Example 37B Separation of compound of Example 37 by SFC afforded Example 37A (faster eluting, 34.08 mg) and Example 37B (slower eluting, 37.72 mg) with column DAICEL CHIRALPAK IG (250mm*30mm, 10um), CO₂-EtOH (0.1%NH₃H₂O), 40%, 150ml/min). Example 37A (faster eluting): 34.08 mg, 0.06 mmol. MS obsd. (ESI⁺) [(M+H)⁺]: 552.4.¹H NMR (400 MHz, DMSO-d6) δ = 11.35 (br. s 1H), 7.71 (d, J = 8.4Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 5.06 (d, J = 12.4 Hz, 1H), 3.97 (d, J = 9.6 Hz, 1H), 3.82 (t, J = 13.2 Hz, 2H), 3.73 - 3.67 (m, 4H), 3.27 - 3.20 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2.97 (d, J = 10.8 Hz, 1H), 2.88 (t, J = 11.2 Hz, 1H), 2.35 - 2.33 (m, 1H), 1.90 - 1.84 (m, 2H), 1.74 - 1.59 (m, 4H), 1.28 - 1.23 (m, 2H). E_{xample 37B} (slower eluting): 37.72 mg, 0.07 mmol. MS obsd. (ESI⁺) [(M+H)⁺]: 552.3. ¹H NMR (400 MHz, DMSO-d6) δ = 11.57 (br. s, 1H), 7.65 - 7.61 (m, 2H), 7.54 (t, J = 8 Hz, 1H), 6.70 - 6.66 (m, 2H), 6.34 (d, J = 7.6 Hz, 1H), 5.08 (d, J = 13.6 Hz, 1H), 4.00 (d, J = 1.6 Hz, 1H), 3.85 - 3.79 (m, 2H), 3.71 - 3.68 (m, 4H), 3.21 (d, J = 8.8 Hz, 2H), 2.94 - 2.88 (m, 4H), 2.33 (t, J = 11.6 Hz, 1H), 1.97 - 1.86 (m, 2H), 1.76 - 1.71 (m, 3H), 1.61 - 1.59 (m, 1H), 1.29 - 1.24 (m, 2H). Example 39 N-(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM DIEA, DMSO Int-42 3_{9.1 39.2} B PEPPSI-Pd ₂(OH) 4,4 ^'-bipyri₄dine CsCO dio₂xane_{3 DMF TEA, DCM} _39.3 39.4 _39.5 LAH, THF Example 39 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5- nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 39.1) Tert-butyl 3-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 39.1) was prepared in analogy to _{Example 2}, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (Int-32) with tert-butyl 3-[3-[1-(2-carbamoyl-5-nitro- phenyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Int-42) in step (a). Tert-butyl 3-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4- difluoro-piperidine-1-carboxylate (compound 39.1, 115.0 mg, 0.18 mmol) was obtained. MS obsd. (ESI⁺) [(M-C4H8+H)⁺]: 623.2. Step (b): preparation of N-(2-chloropyrimidin-4-yl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 39.2) N-(2-chloropyrimidin-4-yl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro- benzamide (compound 39.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(2-chloropyrimidin-4-yl)carbamoyl]-5- nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Compound 39.1) in step (b). N-(2-chloropyrimidin-4-yl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4- nitro-benzamide (compound 39.2, 96.0 mg, 0.18 mmol) was obtained. MS obsd. (ESI⁺) [(M+Na)⁺]: 523.2. Step (c): preparation of 18,18-difluoro-4-nitro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 39.3) 10,14 15,19 2,7 18,18-Difluoro-4-nitro-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 39.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 1.2}) with N-(2-chloropyrimidin-4-yl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 39.2) in step (c).18,18-Difluoro- 10,14 15,19 2,7 4-nitro-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)- hexaen-8-one (compound 39.3, 30.0 mg, 0.06 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 487.4. Step (d): preparation of 4-amino-18,18-difluoro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 39.4) 10,14 15,19 2,7 4-Amino-18,18-difluoro-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 39.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 18,18-difluoro-4-nitro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 39.3) in step (d).4-Amino-18,18-difluoro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 39.4, 28.0 mg, 0.06 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 457.3. Step (e): preparation of methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 39.5) Methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 39.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18-difluoro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 39.4) in step (e). Methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 39.5, 36.0 mg, 0.06 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 593.2. Step (f): preparation of ^N-(18,18-difluoro-8-^oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 39) 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide (Example 39) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 39.5) in step (f). N-(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 39, 5.78 mg, 0.01 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 565.2.¹H NMR (400 MHz, DMSO-d₆) δ = 11.56 (br. s, 1H), 10.24 (br. s, 1H), 8.31 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.10 (s, 1H), 7.03 (dd, J = 8.4 Hz, J2 = 2.0 Hz, 1H), 4.15 - 4.05 (m, 1H), 4.00 - 3.92 (m, 1H), 3.75 (t, J = 6.4 Hz, 2H), 3.67 - 3.62 (m, 2H), 3.35 (t, J = 6.4 Hz, 2H), 3.20 - 3.05 (m, 2H), 2.79 - 2.59 (m, 2H), 2.06 - 1.83 (m, 5H), 1.79 - 1.50 (m, 6H), 1.43 - 1.28 (m, 3H). Example 40 N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd 2(dba 3), Xantphos Cs₂ CO,₂ dioxane Int-42 _{40.1 40.2} PEPPSI-Pd B 4,4 ^'-₂(OH) bipyri₄dine Cs dio₂CO xane₃ DMF TEA, DCM 4_0.3 40.4 _40.5 LAH, THF Example 40 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(2-chloro-6-methyl-pyrimidin-4- yl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 40.1) Tert-butyl 3-[3-[1-[2-[(2-chloro-6-methyl-pyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 40.1) was prepared in analogy to Example 2, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (_Int-32) and 2, 4-dichloropyrimidine with tert-butyl 3- [3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Int-42) and 2, 4-dichloro-6-methyl-pyrimidine in step (a). Tert-butyl 3-[3-[1-[2-[(2-chloro-6- methyl-pyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine- 1-carboxylate (compound 40.1, 270.0 mg, 0.42 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 637.4. Step (b): preparation of ^N-(2-chloro-6-methyl-pyrimidin-4-yl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 40.2) N-(2-chloro-6-methyl-pyrimidin-4-yl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1- piperidyl]-4-nitro-benzamide (compound 40.2) was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(2-chloro- 6-methyl-pyrimidin-4-yl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (Compound 40.1) in step (b). N-(2-chloro-6-methyl-pyrimidin-4-yl)-2- [4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 40.2, 275.0 mg, 0.42 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 537.2. Step (c): preparation of 18,18-difluoro-12-methyl-4-nitro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 40.3) 18,18-Difluoro-12-methyl-4-nitro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 40.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4- [3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2) with N-(2-chloro- 6-methyl-pyrimidin-4-yl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro- benzamide (_{compound 40.2}) in step (c).18,18-Difluoro-12-methyl-4-nitro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_compound 40.3, 120.0 mg, 0.24 mmol) was obtained. MS obsd. (ESI+) [(M+H)+]: 501.2. Step (d): preparation of 4-amino-18,18-difluoro-12-methyl-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 40.4) 4-Amino-18,18-difluoro-12-methyl-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_compound _40.4) was prepared in analogy to _{Example 20}, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _(compound 20.3) with 18,18-difluoro-12-methyl-4-nitro-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_compound 40.3) in step (d).4-Amino-18,18-difluoro-12-methyl-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_compound 40.4, 112.0 mg, 0.24 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 471.2. Step (e): preparation of methyl 2-[(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 40.5) Methyl 2-[(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 40.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18-difluoro-12-methyl-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 40.4) in step (e). Methyl 2-[(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 40.5, 144.0 mg, 0.24 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 607.3. Step (f): preparation of N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 40) N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 40) was prepared in analogy to _{Example 20}, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[(18,18-difluoro-12-methyl-8- 10,14 15,19 2,7 oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen- 4-yl)sulfamoyl]acetate (_{compound 40.5}) in step (f). N-(18,18-difluoro-12-methyl-8-oxo- 10,14 15,19 2,7 1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)-2-hydroxy-ethanesulfonamide (Example 40, 27.42 mg, 0.05 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 579.3.¹H NMR (400 MHz, DMSO-d6) δ = 11.40 (br. s, 1H), 10.21 (br. s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.12 - 7.00 (m, 2H), 4.94 (br. s, 1H), 4.23 - 3.97 (m, 2H), 3.79 - 3.70 (m, 3H), 3.67 - 3.55 (m, 1H), 3.39 - 3.34 (m, 2H), 3.22 - 3.05 (m, 2H), 2.79 - 2.61 (m, 2H), 2.30 (s, 3H), 2.03 - 1.82 (m, 5H), 1.75- 1.42 (m, 7H), 1.37 - 1.28 (m, 2H). Example 40A and Example 40B 2-hydroxy-^N-[(19^S)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide ^and 2-hydroxy-^N-[(19^R)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 40A and Example 40B) Example 40A and Example 40B Separation of Example 40 by SFC afforded Example 40A (faster eluting, 98.8 mg) and Example 40B (slower eluting, 90.77 mg) with Column: (s, s) WHELK-O1 (250mm*30mm, 10um)); Condition: CO₂-MeOH (0.1% NH₃H₂O)), B%: 30-30%; Flow Rate (mL/min): 120)). Example 40A (faster eluting): MS obsd. (ESI⁺) [(M+H)⁺]: 579.2. 1H NMR (400 MHz, DMSO-d6) δ = 11.42 (br. s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.07 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.27 - 4.08 (m, 1H), 4.05 - 3.90 (m, 1H), 3.80 - 3.69 (m, 3H), 3.67 - 3.56 (m, 1H), 3.36 - 3.33 (m, 2H), 3.22 - 3.16 (m, 1H), 3.10 - 3.03 (m, 1H), 2.80 - 2.61 (m, 2H), 2.29 (s, 3H), 2.04 - 1.85 (m, 5H), 1.73- 1.41 (m, 7H), 1.37 - 1.28 (m, 2H). Example 40B (slower eluting): MS obsd. (ESI⁺) [(M+H)⁺]: 579.2. 1H NMR (400 MHz, DMSO-d₆) δ = 11.41 (br. s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.07 (s, 1H), 7.02 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 4.24 - 4.09 (m, 1H), 4.06 - 3.89 (m, 1H), 3.79 - 3.68 (m, 3H), 3.64 - 3.52 (m, 1H), 3.35 - 3.32 (m, 2H), 3.23 - 3.15 (m, 1H), 3.10 - 3.02 (m, 1H), 2.81 - 2.70 (m, 1H), 2.69 - 2.60 (m, 1H), 2.29 (s, 3H), 2.05 - 1.84 (m, 5H), 1.73- 1.41 (m, 7H), 1.35 - 1.26 (m, 2H). Example 41 2-hydroxy-N-(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-18 TFA, DCM DIEA, DMSO Int-50 _{41.1 41.2} PEPPSI-Pd B 4,4 ^'-₂(OH) bipyrid₄ine CsC dio₂ O xane_{3 DMF TEA, DCM} _41.3 41.4 _41.5 LAH, THF Example 41 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-fluoro-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 41.1) Tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-fluoro-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 41.1) was prepared in analogy to _{Example 27}, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4- piperidyl)propyl]piperidine-1-carboxylate (Int-7) with tert-butyl 4,4-difluoro-3-[3-(4-fluoro-4- piperidyl)propyl]piperidine-1-carboxylate (Int-18) in step (a). Tert-butyl 3-[3-[1-[2-[(6-chloro-2- pyridyl)carbamoyl]-5-nitro-phenyl]-4-fluoro-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (compound 41.1, 178.0 mg, 0.28 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 640.4. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-4-fluoro-1-piperidyl]-4-nitro-benzamide (compound 41.2) N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-4-fluoro-1-piperidyl]-4- nitro-benzamide (compound 41.2) was prepared in analogy to Example 1, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(6-chloro- 2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-fluoro-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (_{Compound 41.1}) in step (b). N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-4-fluoro-1-piperidyl]-4-nitro-benzamide (compound 41.2, 150.0 mg, 0.28 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 540.3. Step (c): preparation of 18,18,23-trifluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-8-one (compound 41.3) 10,14 15,19 2,7 18,18,23-Trifluoro-4-nitro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-8-one (compound 41.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine- 3-carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-4-fluoro-1-piperidyl]-4-nitro-benzamide (compound 41.2, in step (c). 10,14 15,19 2,7 18,18,23-Trifluoro-4-nitro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-8-one (compound 41.3, 113.0 mg, 0.22 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 504.2. Step (d): preparation of 4-amino-18,18,23-trifluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-8-one (compound 41.4) 10,14 15,19 2,7 4-Amino-18,18,23-trifluoro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-8-one (compound 41.4) was prepared in analogy to Example 20, 15,18 2,6 9,14 by replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) with 18,18,23-trifluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-8-one (_{compound 41.3)} in step (d).4-Amino-18,18,23-trifluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-8-one (_{compound 41.4}, 106.0 mg, 0.22 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 474.3. Step (e): preparation of methyl 2-[(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 41.5) Methyl 2-[(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 41.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18,23-trifluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-8-one (compound 41.4) in step (e). Methyl 2-[(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 41.5, 128.0 mg, 0.21 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M-tBu+H)⁺]: 610.4. Step (f): preparation of 2-hydroxy-N-(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide (Example 41) 2-Hydroxy-N-(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide (_{Example 41}) was prepared in analogy to _{Example 20}, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[(18,18,23-trifluoro-8-oxo- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (_{compound 41.5}) in step (f).2-Hydroxy-N-(18,18,23-trifluoro-8-oxo- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide (Example 41, 7.76 mg, 0.01 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 582.3.¹H NMR (400 MHz, DMSO-d6): δ 11.12(br. s, 1H), 10.14 (br. s, 1H), 7.94 ((d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.05 (dd, J₁=2.0 Hz, J₂ = 8.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.10(s, 1H), 4.08 (d, J = 13.2 Hz, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.63 - 3.59 (m, 1H), 3.44 (d, J = 12.4 Hz, 1H), 3.36 - 3.35 (m, 2H), 3.28 - 3.10 (m, 2H), 3.25 - 2.95 (m, 2H), 2.88 - 2.83 (m, 1H), 2.43 - 2.33 (m, 2H), 2.18 - 1.91 (m, 4H), 1.77 - 1.67 (m, 2H), 1.62 - 1.4 (m, 4H). Example 41A and example 41B 2-hydroxy-^N-[(19^S)-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide ^and 2-hydroxy-^N-[(19^R)-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 41A and Example 41B) Example 41A and Example 41B Separation of Example 41 by SFC afforded Example 41A (faster eluting, 94.86 mg) and _{Example 41B} (slower eluting, 100.8 mg) with column: ChiralPak IH, 250*50mm, 10um (250mm*50mm, 10um), Condition: CO₂-EtOH(0.1%NH₃H₂O), B%: 40-40%; FlowRate(ml/min): 150. E_{xample 41A} (faster eluting): MS obsd. (ESI⁺) [(M+H)⁺]: 582.2.¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (br. s, 1H), 10.22 - 10.07 (m, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.05 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 4.92 (br. s 1H), 4.14-4.06 (m, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.62 - 3.59 (m, 1H), 3.45 (d, J = 13.2 Hz, 2H), 3.26 - 3.19 (m, 1H), 3.16 – 3.14 (m, 1H), 3.05 - 2.95 (m, 2H), 2.88 – 2.82 (m, 1H), 2.47 – 2.33 (m, 2H), 2.17 - 1.71 (m, 7H), 1.67 - 1.44 (m, 4H). Example 41B (slower eluting): MS obsd. (ESI⁺)[(M+H)⁺]: 582.2. 1H NMR (400 MHz, DMSO-d₆): δ 11.12(br. s, 1H), 10.25 – 9.95 (m, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.05 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 4.94 (br. s 1H), 4.10-4.06 (m, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.65 - 3.55 (m, 1H), 3.45 (d, J = 13.2 Hz, 2H), 3.37 - 3.33 (m, 1H), 3.25 - 3.12 (m, 1H), 3.08 - 2.94 (m, 2H), 2.90 – 2.81 (m, 1H), 2.44 - 2.27 (m, 2H), 2.19 - 1.71 (m, 7H), 1.65 - 1.43 (m, 4H). Example 42 N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl]-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-19 TFA, DCM DIEA, DMSO Int-50 _{42.1 42.2} B₂(OH) PEPPSI-Pd 4,4 ^'-bipyri₄dine Cs dio₂CO xane_{3 DMF TEA, DCM} 42.3 42..4 42..5 LAH, THF Example 42 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 42.1) Tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)- 4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 42.1) was prepared in analogy to _{Example 27}, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4- piperidyl)propyl]piperidine-1-carboxylate (Int-7) with tert-butyl 3-[3-[4-(difluoromethyl)-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Int-19) in step (a). Tert-butyl 3-[3-[1- [2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4-piperidyl]propyl]-4,4- difluoro-piperidine-1-carboxylate (compound 42.1, 90.0 mg, 0.13 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 672.3. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4,4- difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4,4-difluoro-3-piperidyl)propyl]-1- piperidyl]-4-nitro-benzamide (compound 42.2) was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(6-chloro- 2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (_{Compound 42.1}) in step (b). N-(6-chloro-2-pyridyl)-2-[4- (difluoromethyl)-4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 42.2, 80.0 mg, 0.14 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 572.3. Step (c): preparation of 23-(difluoromethyl)-18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.3) 23-(Difluoromethyl)-18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4- [3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2) with N-(6-chloro- 2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro- benzamide (compound 42.2) in step (c).23-(Difluoromethyl)-18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.3, 45.0 mg, 0.08 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 536.3.¹H NMR (400 MHz, CDCl3) δ = 11.06 (br. s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 8.07 - 8.04 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 5.79 (t, J = 56.4 Hz, 1H), 3.95 - 3.82 (m, 2H), 3.59 - 3.50 (m, 2H), 3.32 - 3.13 (m, 4H), 2.42 - 2.28 (m, 1H), 2.16 - 1.92 (m, 8H), 1.75 - 1.65 (m, 2H), 1.51 - 1.45 (m, 2H) Step (d): preparation of 4-amino-23-(difluoromethyl)-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.4) 4-Amino-23-(difluoromethyl)-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.4) was prepared in analogy to Example 20, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) with 23-(difluoromethyl)-18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.3) in step (d).4-amino-23-(difluoromethyl)-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.4, 45.0 mg, 0.09 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 506.3. Step (e): preparation of methyl 2-[[23-(difluoromethyl)-18,18-difluoro-8-^oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]sulfamoyl]acetate (compound 42.5) Methyl 2-[[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]sulfamoyl]acetate (compound 42.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-23-(difluoromethyl)-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 42.4) in step (e). Methyl 2-[[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]sulfamoyl]acetate (compound 42.5, 55.0 mg, 0.09 mmol) was obtained. MS obsd. (ESI⁺[(M+H)⁺].): 642.3 Step (f): preparation of N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl]-2- hydroxy-ethanesulfonamide (Example 42) N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl]-2- hydroxy-ethanesulfonamide (Example 42) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[[23-(difluoromethyl)-18,18- 10,14 15,19 2,7 difluoro-8-oxo-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)- hexaen-4-yl]sulfamoyl]acetate (_{compound 42.5}, in step (f). N-[23-(difluoromethyl)-18,18- 10,14 15,19 2,7 difluoro-8-oxo-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl]-2-hydroxy-ethanesulfonamide (Example 42, 9.79 mg, 0.02 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 614.3. 1H NMR (400 MHz, DMSO-d6) δ = 11.36 (br. s, 1H), 10.16 (br. s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 2.4, 8.8 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.25 (t, J = 55.6 Hz, 1H), 5.06 - 4.85 (m, 1H), 3.96 - 3.82 (m, 1H), 3.75 (t, J = 6.4 Hz, 3H), 3.54 - 3.42 (m, 2H), 3.32 - 3.15 (m, 2H), 3.10 - 2.87 (m, 4H), 2.24 - 2.08 (m, 3H), 2.03 - 1.88 (m, 2H), 1.84 - 1.74 (m, 2H), 1.62 - 1.21 (m, 6H). Example 42A and Example 42B 2-hydroxy-N-[(19S)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide ^and 2-hydroxy-^N-[(19^R)-23-(difluoromethyl)-18,18-difluoro-8-oxo- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 42A ^and Example 42B) Example 42A and Example 42B Separation of Example 42 by SFC afforded Example 42A (faster eluting, 63.79 mg) and Example 42B (slower eluting, 71.74 mg) with Column: DAICEL CHIRALCEL OD (250mm*30mm, 10 um), Condition: CO2-i-PrOH (0.1% NH3H2O), B%: 35-35%; FlowRate (ml/min): 150). Example 42A (faster eluting): MS obsd. (ESI⁺) [(M+H)⁺]: 614.2.¹H NMR (400 MHz, DMSO-d6): δ 11.36 (br. s, 1H), 10.22 - 10.08 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.05 (dd, J₁ = 2.0 Hz, J₂ = 8.4 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.25 (t, J = 56.0 Hz, 1H), 5.08 - 4.86 (m, 1H), 3.93- 3.85 (m, 1H), 3.75 (t, J = 6.8 Hz, 3H), 3.52 - 3.40 (m, 2H), 3.35 (s, 2H), 3.10 - 2.88 (m, 4H), 2.25 - 2.03 (m, 5H), 1.92 - 1.88 (m, 1H), 1.79 (d, J = 12.8 Hz, 2H), 1.56 - 1.38 (m, 4H), 1.33 - 1.23 (m, 1H). Example 42B: (slower eluting): MS obsd. (ESI⁺) [(M+H)⁺]: 614.2.¹H NMR (400 MHz, DMSO-d6): δ 11.36 (br. s, 1H), 10.24 - 10.10 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.05 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.25 (t, J = 55.6 Hz, 1H), 5.03 - 4.87 (m, 1H), 3.93 - 3.85 (m, 1H), 3.75 (t, J = 6.4 Hz, 3H), 3.50 - 3.40 (m, 2H), 3.56 - 3.34 (m, 2H), 3.13 - 2.88 (m, 4H), 2.23 - 1.97 (m, 5H), 1.94 - 1.88 (m, 1H), 1.79 (d, J = 13.6 Hz, 2H), 1.56 - 1.36 (m, 4H), 1.21 - 1.19 (m, 1H). Example 44 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd₂(dba), Xantphos CsCO ₂ _{2 3}, dioxane Int-46 44.1 44.2 PEPPSI-Pd Cs dio₂CO xane₃ Cs₂CO₃, DMSO 44.3 Example 44 Step (a): preparation of tert-butyl 3-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro- 4-pyridyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 44.1) Tert-butyl 3-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidyl]propyl]- 4,4-difluoro-piperidine-1-carboxylate (compound 44.1) was prepared in analogy to Example 2, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2-pyridyl)-4-piperidyl]propyl]piperidine- _{1-carboxylate (Int-32) and 2, 4-dichloropyrimidine with} ^{tert-butyl 3-[3-[1-(5-carbamoyl-2-} fluoro-4-pyridyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Int-30) and 2, 6- dichloropyridine in step (a). Tert-butyl 3-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4- pyridyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 44.1, 575.0 mg, 0.96 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 596.4. . Step (b): N-(6-chloro-2-pyridyl)-4-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]- 6-fluoro-pyridine-3-carboxamide (compound 44.2) N-(6-chloro-2-pyridyl)-4-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxamide (compound 44.2) was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[5-[(6-chloro- 2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (_{Compound 44.1}) in step (b). N-(6-chloro-2-pyridyl)-4-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3-carboxamide (compound 44.2, 474.0 mg, 0.96 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 496.3. Step (c): preparation of 4,18,18-trifluoro-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 44.3) 10,14 15,19 2,7 4,18,18-Trifluoro-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (_{compound 44.3}) was prepared in analogy to _{Example 1}, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-4-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3-carboxamide (_{compound 44.2}, in step (c). 10,14 15,19 2,7 4,18,18-trifluoro-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 44.3, 439.0 mg, 0.96 mmol) was obtained, which was used in next step directly without further purification. MS obsd. (ESI⁺) [(M +H)⁺]: 460.3. Step (d): preparation of N-(18,18-difluoro-8-oxo-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 44) 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide _{(Example 44)} was prepared in analogy to Example 1, by replacing 12-fluoro-1,7,13,15,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _1.3) 10,14 15,19 2,7 with 4,18,18-trifluoro-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one _{(compound 44.3)} in step (d). N-(18,18-difluoro-8-oxo- 10,14 15,19 2,7 1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)-2-hydroxy-ethanesulfonamide (Example 44, 70.07 mg, 0.12 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 565.3.¹H NMR (400 MHz, DMSO-d6): 10.01 (br. s, 1H), 8.14 - 8.02 (m, 1H), 7.61 - 7.54 (m, 2H), 6.59 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 4.89 - 4.75 (m, 1H), 4.18 (d, J = 10.8 Hz, 1H), 3.76 (t, J = 6.8 Hz, 2H), 3.71 - 3.68 (m, 1H), 3.58 (d, J = 12.8 Hz, 1H), 3.46 - 3.43 (m, 3H), 2.78 (t, J = 12.0 Hz, 2H), 2.11 - 1.80 (m, 6H), 1.72 - 1.65 (m, 2H), 1.51 - 1.48 (m, 2H), 1.42 - 1.23 (m, 6H). Example 45 N-[23-(difluoromethyl)-18,18-difluoro-8-^oxo-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl]-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd₂(dba)₂, Xantphos Cs₂CO₃, dioxane Int-45 _{45.1 45.2} PEPPSI-Pd Cs dio₂CO xane₃ Cs₂CO₃, DMSO 45.3 Example 45 Step (a): preparation of tert-butyl 3-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro- 4-pyridyl]-4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 45.1) Tert-butyl 3-[3-[1-[5-[(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4- (difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 45.1) was prepared in analogy to Example 2, by replacing tert-butyl 4-[3-[1-(3-carbamoyl-6-fluoro-2- pyridyl)-4-piperidyl]propyl]piperidine-1-carboxylate (_Int-32) and 2, 4-dichloropyrimidine with tert-butyl 4-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]piperidine-1-carboxylate (Int-45) and 2, 6-dichloropyridine in step (a). Tert-butyl 3-[3-[1-[5-[(6-chloro-2- pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (compound 45.1, 80.0 mg, 0.12 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 646.3 Step (b): preparation of ^N-(6-chloro-2-pyridyl)-4-[4-(difluoromethyl)-4-[3-(4,4- difluoro-3-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3-carboxamide (compound 45.2) N-(6-chloro-2-pyridyl)-4-[4-(difluoromethyl)-4-[3-(4,4-difluoro-3-piperidyl)propyl]-1- piperidyl]-6-fluoro-pyridine-3-carboxamide (compound 45.2) was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2- pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[5- [(6-chloro-2-pyridyl)carbamoyl]-2-fluoro-4-pyridyl]-4-(difluoromethyl)-4-piperidyl]propyl]-4,4- difluoro-piperidine-1-carboxylate (Compound 45.1) in step (b). N-(6-chloro-2-pyridyl)-4-[4- (difluoromethyl)-4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3- carboxamide (_{compound 45.2}, 60.0 mg, 0.11 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 546.3. Step (c): preparation of 23-(difluoromethyl)-4,18,18-trifluoro-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 45.3) 23-(Difluoromethyl)-4,18,18-trifluoro-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_compound 45.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4- [3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2) with N-(6-chloro- 2-pyridyl)-4-[4-(difluoromethyl)-4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxamide (_{compound 45.2}) in step (c).23-(Difluoromethyl)-4,18,18-trifluoro- 10,14 15,19 2,7 1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_{compound 45.3}, 80.0 mg, 0.16 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 510.3. Step (d): preparation of N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl]-2- hydroxy-ethanesulfonamide (Example 45) N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl]-2-hydroxy- ethanesulfonamide (Example 45) was prepared in analogy to Example 1, by replacing 12- 15,18 2,6 9,14 fluoro-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 1.3) with 23-(difluoromethyl)-4,18,18-trifluoro-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 45.3) in step (c). N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl]-2-hydroxy- ethanesulfonamide (Example 45, 5.95 mg, 0.01 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 615.3.¹H NMR (400 MHz, CHLOROFORM-d) δ = 9.07 (br s, 1H), 8.33 (br s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 - 7.50 (m, 1H), 6.65 (s, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.69 (t, J = 16.0 Hz, 1H), 4.35 - 4.18 (m, 1H), 4.17 - 4.08 (m, 2H), 3.70 - 3.62 (m, 1H), 3.61 - 3.53 (m, 1H), 3.51 - 3.44 (m, 1H), 3.43 - 3.31 (m, 4H), 3.13 - 3.01 (m, 2H), 2.20 - 2.11 (m, 2H), 2.08 - 2.00 (m, 3H), 1.98 - 1.90 (m, 2H), 1.82 - 1.73 (m, 2H), 1.43 - 1.30 (m, 3H), 1.29 - 1.09 (m, 2H). Example 46 N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme:

Int-22 TFA, DCM DIEA, DMSO Int-50 _{46.1 46.2} PEPPSI-Pd B₂(OH)₄, 4,4 ^'-bipyridine Cs₂CO_3, dioxane DMF TEA, DCM 4_6.3 46.4 _46.5 LAH, THF Example 46 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-methyl-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 46.1) Tert-butyl 3-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 46.1) was prepared in analogy to _{Example 27}, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4- piperidyl)propyl]piperidine-1-carboxylate (Int-7) with tert-butyl 4-[2-[[4-(trifluoromethyl)-4- piperidyl]amino]ethyl]piperidine-1-carboxylate (Int-22) in step (a). Tert-butyl 3-[3-[1-[2-[(6- chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate _{(compound 46.1,} 398.0 mg, 0.63 mmol) was obtained. MS obsd. (ESI⁺) [M+H]⁺: 636.3. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-4-methyl-1-piperidyl]-4-nitro-benzamide (compound 46.2) N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-4-methyl-1-piperidyl]-4- nitro-benzamide (compound 46.2) was prepared in analogy to Example 1, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(6-chloro- 2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (Compound 46.1) in step (b). N-(6-chloro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-4-methyl-1-piperidyl]-4-nitro-benzamide (compound 46.2, 325.0 mg, 0.61 mmol) was obtained. MS obsd. (ESI⁺) [M+H]+: 536.4. Step (c): preparation of 18,18-difluoro-23-methyl-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.3) 18,18-Difluoro-23-methyl-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4- [3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (_{compound 1.2}) with N-(6-chloro- 2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-4-methyl-1-piperidyl]-4-nitro-benzamide (compound 46.2) in step (c).18,18-Difluoro-23-methyl-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.3, 351.0 mg, 0.7 mmol) was obtained. MS obsd. (ESI⁺) [M+H]⁺: 500.3. Step (d): preparation of 4-amino-18,18-difluoro-23-methyl-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.4) 4-Amino-18,18-difluoro-23-methyl-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.4) was prepared in analogy to Example 20, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) with 18,18-difluoro-23-methyl-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.3) in step (d).4-Amino-18,18-difluoro-23-methyl-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.4, 145.0 mg, 0.31 mmol) was obtained. MS obsd. (ESI⁺) [M+H]⁺: 470.4. Step (e): preparation of methyl 2-[(18,18-difluoro-23-methyl-8-^oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate ⁽compound 46.5⁾ Methyl 2-[(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 46.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18-difluoro-23-methyl-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 46.4) in step (e). Methyl 2-[(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 46.5, 142.0 mg, 0.23 mmol) was obtained. MS obsd. (ESI⁺) [M+H]⁺: 606.4. Step (f): preparation of N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 46) N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (_{Example 46)} was prepared in analogy to _{Example 20}, by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[(18,18-difluoro-23-methyl-8-oxo- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (_{compound 46.5}) in step (f). N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (_{Example 46}, 23.55 mg, 0.04 mmol) was obtained. MS obsd. (ESI⁺) [M+H]⁺: 578.3.¹H NMR (400 MHz, Chloroform-d) δ = 11.46 (br. s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 - 7.50 (m, 1H), 7.21 - 7.18 (m, 1H), 6.99 (dd, J = 2.0, 8.4 Hz, 1H), 6.76 (s, 1H), 6.39 (d, J = 8.4 Hz, 1H), 4.29 - 4.03 (m, 3H), 3.71 - 3.56 (m, 1H), 3.53 - 3.38 (m, 2H), 3.34 (t, J = 5.2 Hz, 2H), 3.19 - 3.06 (m, 2H), 3.04 - 2.94 (m, 1H), 2.84 (t, J = 12.4 Hz, 1H), 2.59 - 2.32 (m, 2H), 2.25 - 2.07 (m, 3H), 1.91 - 1.77 (m, 1H), 1.74 - 1.65 (m, 1H), 1.54 - 1.45 (m, 4H), 1.41 - 1.21 (m, 3H), 1.04 (s, 3H). Example 46A and Example 46B 2-hydroxy-N-[(19S)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide ^and 2-hydroxy-^N-[(19^R)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 46A ^and Example 46B) Example 46A and Example 46B Separation of compound of Example 46 by SFC afforded Example 46A (faster eluting, 20.71 mg) and Example 46B (slower eluting, 17.13 mg) with column: ((s, s) WHELK-O1 (250mm*30mm, 10um), IPA+ACN (0.05%DEA) 55% in CO2. Example 46A (faster eluting): 20.71 mg, 0.04 mmol. MS obsd. (ESI⁺) [M+H]⁺: 578.3.¹H NMR (400 MHz, DMSO-d₆) δ = 11.49 (br. s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.19 - 7.12 (m, 1H), 7.05 (dd, J = 1.6, 8.8 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 4.16 - 4.01 (m, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.62 - 3.46 (m, 2H), 3.44 - 3.33 (m, 3H), 3.08 - 2.97 (m, 2H), 2.96 - 2.87 (m, 1H), 2.80 (t, J = 12.0 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.18 - 1.95 (m, 4H), 1.84 - 1.66 (m, 1H), 1.63 - 1.52 (m, 1H), 1.51 - 1.39 (m, 4H), 1.32 (d, J = 12.8 Hz, 1H), 1.24 (s, 1H), 1.02 (s, 3H). Example 46B (slower eluting): 17.13 mg, 0.03 mmol. MS obsd. (ESI⁺) [M+H]⁺: 578.3.¹H NMR (400 MHz, DMSO-d₆) δ = 11.47 (br. s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.21 - 7.12 (m, 1H), 7.05 (dd, J = 1.6, 8.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.05 (d, J = 12.0 Hz, 1H), 3.75 (t, J = 6.4 Hz, 2H), 3.61 - 3.45 (m, 2H), 3.43 - 3.34 (m, 3H), 3.07 - 2.95 (m, 2H), 2.95 - 2.86 (m, 1H), 2.84 - 2.74 (m, 1H), 2.39 - 2.26 (m, 1H), 2.18 - 1.95 (m, 4H), 1.83 - 1.67 (m, 1H), 1.63 - 1.51 (m, 1H), 1.50 - 1.38 (m, 4H), 1.36 - 1.27 (m, 1H), 1.26 - 1.17 (m, 1H), 1.01 (s, 3H). Example 47 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme:

Int-15 TFA, DCM DIEA, DMSO Int-55 _{47.1 47.2} PEPPSI-Pd B₂(OH)₄, ^' dio₂ 4,4-bipyridine CsCO xane₃ DMF TEA, DCM 47.3 47..4 47..5 LAH, THF Example 47 Step (a): preparation of ^tert-butyl 3-[3-[1-[2-[(2-chloro-4-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 47.1) Tert-butyl 3-[3-[1-[2-[(2-chloro-4-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]- 4,4-difluoro-piperidine-1-carboxylate (compound 47.1) was prepared in analogy to Example ₂₇, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (Int-7) and N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-50) with tert-butyl 4,4- difluoro-3-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-15) and N-(2-chloro-4-pyridyl)- 2-fluoro-4-nitro-benzamide (_Int-55) in step (a). Tert-butyl 3-[3-[1-[2-[(2-chloro-4- pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 47.1, 401.0 mg, 0.64 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 622.4. Step (b): preparation of N-(2-chloro-4-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 47.2) N-(2-chloro-4-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro- benzamide (compound 47.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(2-chloro-4-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (Compound 47.1) in step (b). N-(2-chloro-4-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 47.2, 315.0 mg, 0.6 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 522.3. Step (c): preparation of 18,18-difluoro-4-nitro-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 47.3) 10,14 15,19 2,7 18,18-Difluoro-4-nitro-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 47.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(2-chloro-4-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 47.2) in step (c).18,18-Difluoro- 10,14 15,19 2,7 4-nitro-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen- 8-one (compound 47.3, 106.0 mg, 0.22 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 486.3. Step (d): preparation of 4-amino-18,18-difluoro-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 47.4) 10,14 15,19 2,7 4-Amino-18,18-difluoro-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 47.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 18,18-difluoro-4-nitro-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 47.3) in step (d).4-Amino-18,18-difluoro-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 47.4, 180.0 mg, 0.4 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 456.3. Step (e): preparation of methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 47.5) Methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 47.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18-difluoro-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 47.4) in step (e). methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 47.5, 150.0 mg, 0.25 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 592.3. Step (f): preparation of ^N-(18,18-difluoro-8-^oxo-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 47) 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide (Example 47) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 47.5) in step (f). N-(18,18-difluoro-8-oxo-1,9,13,15- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (Example 47, 5.79 mg, 0.01 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 564.3.¹H NMR (400 MHz, DMSO-d₆) δ = 10.57 (br. s, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.74 (dd, J = 1.2, 5.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.92 (dd, J = 2.0, 8.4 Hz, 1H), 6.68 (s, 1H), 4.75 - 4.44 (m, 1H), 3.92 - 3.79 (m, 1H), 3.74 (t, J = 6.4 Hz, 2H), 3.36 (d, J = 2.4 Hz, 1H), 3.31 - 3.27 (m, 2H), 3.25 - 3.17 (m, 2H), 3.09 - 2.97 (m, 1H), 2.77 - 2.66 (m, 1H), 2.64 - 2.52 (m, 2H), 2.00 - 1.80 (m, 4H), 1.70 - 1.49 (m, 5H), 1.43 - 1.25 (m, 3H), 1.23 - 1.08 (m, 2H). Example 48 10,14 15,19 2,7 N-(18,18-difluoro-8-^oxo-1,3,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,3,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide was prepared in analogy to Example 44, by replacing tert-butyl 4-[3-[1-(5-carbamoyl-2-methyl-4-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxylate (Int-36) with tert-butyl 4-[3-[1-(3-carbamoyl-6- methyl-2-pyridyl)-4-piperidyl]propyl]piperidine-1-carboxylate (Int-32). MS obsd. (ESI⁺)[(M+H)⁺]: 565.4.¹H NMR (400 MHz, DMSO-d6) δ = 10.74 (s, 1H), 10.16 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 4.10 - 4.01 (m, J = 11.3 Hz, 1H), 3.81 - 3.79 (m, J = 3.6 Hz, 1H), 3.77 - 3.72 (m, 4H), 3.66 - 3.60 (m, 2H), 3.58 - 3.53 (m, 1H), 3.40 - 3.31 (m, 1H), 2.85 - 2.70 (m, 2H), 2.15 - 1.85 (m, 5H), 1.78 - 1.61 (m, 2H), 1.55 - 1.27 (m, 7H). Example 49 2-hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29- tetrazapentacyclo[21.2.2.1^10,14.1^15,19.0^2,7]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-15 TFA, DCM DIEA, DMSO Int-58 _{49.1 49.2} PEPPSI-Pd B₂(OH)₄, 4,4 ^'-bipyridine Cs dio₂CO xane₃ DMF TEA, DCM 49.3 49.4 49..5 LAH, THF Example 49 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(6-bromo-5-fluoro-2-pyridyl)carbamoyl]- 5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 49.1) Tert-butyl 3-[3-[1-[2-[(6-bromo-5-fluoro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 49.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4- piperidyl)propyl]piperidine-1-carboxylate (Int-7) and N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro- benzamide (Int-50) with tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1- carboxylate (_Int-15) and N-(6-bromo-5-fluoro-2-pyridyl)-2-fluoro-4-nitro-benzamide (_Int-58) in step (a). Tert-butyl 3-[3-[1-[2-[(6-bromo-5-fluoro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 49.1, 650.0 mg, 0.95 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 686.2. Step (b): preparation of N-(6-bromo-5-fluoro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 49.2) N-(6-bromo-5-fluoro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4- nitro-benzamide (compound 49.2) was prepared in analogy to Example 1, by replacing tert- butyl-4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(6-bromo- 5-fluoro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (Compound 49.1) in step (b). N-(6-bromo-5-fluoro-2-pyridyl)-2-[4-[3-(4,4-difluoro- 3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 49.2, 550.0 mg, 0.94 mmol) was obtained. MS obsd. (ESI+) [(M+H)+]: 586.1. Step (c): preparation of 13,18,18-trifluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 49.3) 10,14 15,19 2,7 13,18,18-trifluoro-4-nitro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 49.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (_{compound 1.2}) with N-(6-bromo-5-fluoro-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 49.2) in step (c).13,18,18- 10,14 15,19 2,7 trifluoro-4-nitro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)- hexaen-8-one (compound 49.3, 165.0 mg, 0.33 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 504.2. Step (d): preparation of 4-amino-13,18,18-trifluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 49.4) 10,14 15,19 2,7 4-Amino-13,18,18-trifluoro-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 49.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 13,18,18-trifluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 49.3) in step (d).4-Amino-13,18,18-trifluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 49.4, 155.0 mg, 0.33 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 474.3. Step (e): preparation of methyl 2-[(13,18,18-trifluoro-8-^oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 49.5) Methyl 2-[(13,18,18-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 49.5) was prepared in analogy to Example 20, by replacing 12- 15,18 2,6 9,14 amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8- one (compound 20.4) with 4-amino-13,18,18-trifluoro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 49.4) in step (e). Methyl 2-[(13,18,18-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 49.5, 199.0 mg, 0.33 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 610.2. Step (f): preparation of 2-hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29- tetrazapentacyclo[21.2.2.1^10,14.1^15,19.0^2,7]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide (Example 49) 2-hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29- tetrazapentacyclo[21.2.2.1^10,14.1^15,19.0^2,7]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide (Example 49) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(13,18,18-trifluoro-8-oxo- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (_{compound 49.5}) in step (f).2-hydroxy-N-(13,18,18-trifluoro-8-oxo- 1,9,15,29-tetrazapentacyclo[21.2.2.1^10,14.1^15,19.0^2,7]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide (Example 49, 40.04 mg, 0.07 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 582.2.¹H NMR (400 MHz, DMSO-d6) δ = 11.63 (br. s, 1H), 10.18 (br. s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.72 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 1H), 7.54 (q, J = 8.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.06 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 4.96 (br. s, 1H), 3.99 - 3.75 (m, 4H), 3.63 - 3.39 (m, 2H), 3.37 - 3.34 (m, 2H), 3.19 - 3.12 (m, 2H), 2.80 - 2.63 (m, 2H), 2.17 - 1.89 (m, 5H), 1.74- 1.65 (m, 3H), 1.61- 1.44 (m, 6H). Example 50 N-(18,18-difluoro-8-^oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: I_{nt-20 TFA, DCM} Int-50 5_{0.1 50.2} PEPPSI-Pd 2₃ B xane ₂(OH)₄, 4,4 ^'-bipyridine CsCO, dio DMF TEA, DCM 50.3 50..4 50..5 LAH, THF Example 50 Step (a): preparation of tert-butyl 1-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound 50.1) Tert-butyl 1-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]- 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound 50.1) was prepared in analogy to _{Example 27}, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4- piperidyl)propyl]piperidine-1-carboxylate (Int-7) with tert-butyl 6,6-difluoro-1-[3-(4- piperidyl)propyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int-20) in step (a). Tert-butyl 1-[3- [1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate (compound 50.1, 420.0 mg, 0.68 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 620.3. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-[3-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-1-yl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 50.2) N-(6-chloro-2-pyridyl)-2-[4-[3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-1-yl)propyl]-1- piperidyl]-4-nitro-benzamide;2,2,2-trifluoroacetic acid (compound 50.2) was prepared in analogy to _{Example 1}, by replacing tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6- fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 1- [3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate (_{Compound 50.1}) in step (b). N-(6-chloro-2-pyridyl)-2- [4-[3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-1-yl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 50.2, 419.0 mg, 0.66 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 520.2. Step (c): preparation of 18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 50.3) 10,14 15,19 2,7 17,19 18,18-Difluoro-4-nitro-1,9,15,29-tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-8-one (_{compound 50.3}) was prepared in analogy to _{Example 1}, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-[3-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-1-yl)propyl]-1-piperidyl]-4-nitro-benzamide (_{compound 50.2)} in step 10,14 15,19 2,7 17,19 (c).18,18-Difluoro-4-nitro-1,9,15,29-tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-8-one (_{compound 50.3}, 200.0 mg, 0.41 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 484.2. Step (d): preparation of 4-amino-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 50.4) 10,14 15,19 2,7 17,19 4-Amino-18,18-difluoro-1,9,15,29-tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-8-one (compound 50.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 18,18-difluoro-4-nitro-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (_{compound 50.3)} in step (d).4-amino-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (_{compound 50.4}, 136.0 mg, 0.3 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 454.2. Step (e): preparation of methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (compound 50.5) Methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (compound 50.5) was prepared in analogy to Example 20, by replacing 12- 15,18 2,6 9,14 amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8- one _{(compound 20.4)} with 4-amino-18,18-difluoro-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (_{compound 50.4}) in step (e). Methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (_{compound 50.5}, 176.0 mg, 0.3 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 590.2. Step (f): preparation of N-(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 50) 10,14 15,19 2,7 17,19 N-(18,18-difluoro-8-oxo-1,9,15,29-tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide (_{Example 50}) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate (compound 50.5) in step (f). N-(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 50, 42.63 mg, 0.08 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 562.3.¹H NMR (400 MHz, DMSO-d₆) δ = 11.80 (br. s, 1H), 10.15 (br. s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.05 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 4.93 (br. s, 1H), 3.95 - 3.85 (m, 1H), 3.75 (t, J = 6.4 Hz, 2H), 3.54 - 3.44 (m, 1H), 3.37 - 3.33 (m, 2H), 3.31 - 3.26 (m, 2H), 3.06 - 2.99 (m, 1H), 2.90 - 2.81 (m, 1H), 2.61 - 2.53 (m, 1H), 2.42 - 2.36 (m, 1H), 2.01 - 1.91 (m, 1H), 1.82 - 1.56 (m, 6H), 1.44 - 1.34 (m, 4H). Example 51 2-hydroxy-N-(8-oxo-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: I_{nt-21 TFA, DCM} Int-50 _{51.1 51.2} PEPPSI-Pd B₂(OH)₄, 4,4 ^'-bipyridine C di^so₂x^Ca^One_{3 DMF} TEA, DCM 5_1.3 51..4 _51..5 LAH, THF Example 51 Step (a): preparation of tert-butyl 2-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro- phenyl]-4-piperidyl]propyl]morpholine-4-carboxylate (compound 51.1) Tert-butyl 2-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]morpholine-4-carboxylate (compound 51.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1- carboxylate (_Int-7) with tert-butyl 2-[3-(4-piperidyl)propyl]morpholine-4-carboxylate (_Int-21) in step (a). Tert-butyl 2-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]morpholine-4-carboxylate (compound 51.1, 220.0 mg, 0.37 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 588.4. Step (b): preparation of N-(6-chloro-2-pyridyl)-2-[4-(3-morpholin-2-ylpropyl)-1- piperidyl]-4-nitro-benzamide (compound 51.2) N-(6-chloro-2-pyridyl)-2-[4-(3-morpholin-2-ylpropyl)-1-piperidyl]-4-nitro-benzamide (compound 51.2) was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6- chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 2-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]morpholine-4-carboxylate (_{Compound 51.1}) in step (b). N-(6-chloro-2- pyridyl)-2-[4-(3-morpholin-2-ylpropyl)-1-piperidyl]-4-nitro-benzamide (compound 51.2, 220.0 mg, 0.45 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 488.3. Step (c): preparation of 4-nitro-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 51.3) 10,14 15,19 2,7 4-Nitro-18-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 51.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-chloro-2-pyridyl)-2-[4-(3-morpholin-2-ylpropyl)-1- piperidyl]-4-nitro-benzamide (_{compound 51.2)} in step (c).4-Nitro-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_compound _51.3, 100.0 mg, 0.22 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 452.2. Step (d): preparation of 4-amino-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 51.4) 10,14 15,19 2,7 4-Amino-18-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 51.4) was prepared in analogy to Example 20, by 15,18 2,6 9,14 replacing 12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 20.3) with 4-nitro-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound _51.3 10,14 15,19 2,7 ) in step (d).4-Amino-18-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-8-one (compound 51.4, 80.0 mg, 0.19 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 422.2. Step (e): preparation of methyl 2-[(8-oxo-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 51.5) 10,14 15,19 2,7 Methyl 2-[(8-oxo-18-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)sulfamoyl]acetate _{(compound 51.5)} was prepared in analogy to _{Example 20} 15,18 2,6 9,14 , by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) with 4-amino-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one _(compound 51.4) in step (e). Methyl 2-[(8-oxo-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 51.5, 100.0 mg, 0.18 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 558.3. Step (f): preparation of 2-hydroxy-^N-(8-^oxo-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)ethanesulfonamide (Example 51) 10,14 15,19 2,7 2-Hydroxy-N-(8-oxo-18-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)ethanesulfonamide _{(Example 51)} was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(8-oxo-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 51.5) in step (f).2-Hydroxy-N-(8-oxo-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)ethanesulfonamide (Example 51, 19.45 mg, 0.04 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 530.3.¹H NMR (400 MHz, CDCl₃) δ = 11.99 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.09 - 6.93 (m, 2H), 6.33 (d, J = 8.4 Hz, 1H), 4.83 (d, J = 12.8 Hz, 1H), 4.14 (t, J = 4.8 Hz, 2H), 4.03 - 3.90 (m, 1H), 3.76 - 3.66 (m, 1H), 3.65 - 3.56 (m, 1H), 3.51 (d, J = 12.4 Hz, 1H), 3.34 (t, J = 5.2 Hz, 2H), 3.29 - 3.17 (m, 3H), 2.93 - 2.75 (m, 3H), 2.71 - 2.54 (m, 1H), 2.27 - 2.06 (m, 2H), 1.92 - 1.75 (m, 3H), 1.72 - 1.63 (m, 2H), 1.57 - 1.41 (m, 4H). Example 52 N-(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-15 TFA, DCM NaH, THF, Int-51 _{52.1 52.2} PEPPSI-Pd B₂(OH)₄, 4,4 ^'-bipyridine C_s2CO₃, Dioxane DMF TEA, DMF 5_2.3 52..4 _52..5 LAH, THF Example 52 Step (a): preparation of tert-butyl 3-[3-[1-[2-[(6-bromo-5-methoxy-2- pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (compound 52.1) Tert-butyl 3-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 52.1) was prepared in analogy to _{Example 27}, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4- piperidyl)propyl]piperidine-1-carboxylate (Int-7) and N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro- benzamide (Int-50) with tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1- carboxylate (_Int-15) and N-(6-bromo-5-methoxy-2-pyridyl)-2-fluoro-4-nitro-benzamide (_Int-51) in step (a). Tert-butyl 3-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxylate (compound 52.1, 840.0 mg, 1.21 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 696.2. Step (b): preparation of N-(6-bromo-5-methoxy-2-pyridyl)-2-[4-[3-(4,4-difluoro-3- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 52.2) N-(6-bromo-5-methoxy-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4- nitro-benzamide (_{compound 52.2}) was prepared in analogy to _{Example 1}, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(6-bromo- 5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (Compound 52.1) in step (b). N-(6-bromo-5-methoxy-2-pyridyl)-2-[4-[3-(4,4- difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 52.2, 340.0 mg) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 598.1 Step (c): preparation of 18,18-difluoro-13-methoxy-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 52.3) 18,18-Difluoro-13-methoxy-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 52.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4- [3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (_{compound 1.2}) with N-(6-bromo- 5-methoxy-2-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 52.2) in step (c).18,18-Difluoro-13-methoxy-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 52.3, 160.0 mg, 0.31 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 516.3. Step (d): preparation of 4-amino-18,18-difluoro-13-methoxy-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 52.4) 4-Amino-18,18-difluoro-13-methoxy-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one _(compound _52.4) was prepared in analogy to _{Example 20}, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _(compound 20.3) with18,18-difluoro-13-methoxy-4-nitro-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (_compound 52.3) in step (d).4-Amino-18,18-difluoro-13-methoxy-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 52.4, 150.0 mg, 0.31 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 486.3. Step (e): preparation of methyl 2-[(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 52.5) Methyl 2-[(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate _{(compound 52.5)} was prepared in analogy to _{Example 20}, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-18,18-difluoro-13-methoxy-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one (compound 52.4) in step (e). Methyl 2-[(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 52.5, 190.0 mg, 0.31 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 622.2. Step (f): preparation of ^N-(18,18-difluoro-13-methoxy-8-^oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 52) N-(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 52) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(18,18-difluoro-13-methoxy- 10,14 15,19 2,7 8-oxo-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate (compound 52.5) in step (f). N-(18,18-difluoro-13-methoxy-8-oxo- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)- 2-hydroxy-ethanesulfonamide (Example 52, 39.66 mg, 0.07 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 594.2.¹H NMR (400 MHz, DMSO-d6) δ = 11.59 (br. s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.06 (dd, J₁ = 8.8 Hz, J2 = 2.0 Hz, 1H), 4.17 - 3.93 (m, 2H), 3.76 (s, 3H), 3.75 (t, J = 6.4 Hz, 2H), 3.36 - 3.33 (m, 2H), 3.32 - 3.30 (m, 2H), 3.16 - 3.10 (m, 2H), 2.77 - 2.65 (m, 2H), 2.18 - 1.81 (m, 5H), 1.76- 1.42 (m, 9H). Example 53 N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide The titled compound was synthesized according to the following scheme:

Int-1 TFA, DCM DIEA, DMSO Int-51 _{53.1 53.2} B₂(OH) 4, 4 ^'- ₄ PEPPSI-Pd bipyridine Cs₂CO_{3 DMF TEA, DCM} dioxane 5_3.3 53.4 _53.5 LAH, THF Example 53 Step (a): preparation of ^tert-butyl 4-[3-[1-[2-[(6-bromo-5-methoxy-2- pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 53.1) Tert-butyl 4-[3-[1-[2-[(6-bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 53.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4-piperidyl)propyl]piperidine-1- carboxylate (Int-7) and N-(6-chloro-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-50) with ^tert- butyl 4-fluoro-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-1) and N-(6-bromo-5- methoxy-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-51) in step (a). Tert-butyl 4-[3-[1-[2-[(6- bromo-5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4-fluoro- piperidine-1-carboxylate _{(compound 53.1}, 900.0 mg, 1.33 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 680.3. Step (b): preparation of N-(6-bromo-5-methoxy-2-pyridyl)-2-[4-[3-(4-fluoro-4- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 53.2) N-(6-bromo-5-methoxy-2-pyridyl)-2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1-piperidyl]-4- nitro-benzamide (compound 53.2) was prepared in analogy to Example 1, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (_{compound 1.1)} with tert-butyl 4-[3-[1-[2-[(6-bromo- 5-methoxy-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-piperidyl]propyl]-4-fluoro-piperidine-1- carboxylate (Compound 53.1) in step (b). N-(6-bromo-5-methoxy-2-pyridyl)-2-[4-[3-(4-fluoro- 4-piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 53.2, 750.0 mg, 1.3 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 580.2. Step (c): preparation of 22-fluoro-3-methoxy-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 53.3) 15,18 2,6 9,14 22-Fluoro-3-methoxy-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 53.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3- carboxamide (compound 1.2) with N-(6-bromo-5-methoxy-2-pyridyl)-2-[4-[3-(4-fluoro-4- piperidyl)propyl]-1-piperidyl]-4-nitro-benzamide (compound 53.2) in step (c).22-Fluoro-3- 15,18 2,6 9,14 methoxy-12-nitro-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-8-one (compound 53.3, 420.0 mg, 0.84 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 498.3. Step (d): preparation of 12-amino-22-fluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 53.4) 12-Amino-22-fluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 53.4) was prepared in analogy to Example 20, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 20.3) with 22-fluoro-3-methoxy-12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _53.3) in step (d).12-Amino-22-fluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound _53.4, 160.0 mg, 0.34 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 468.3. Step (e): preparation of methyl 2-[(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 53.5) Methyl 2-[(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 53.5) was prepared in analogy to Example 20, by replacing 12- 15,18 2,6 9,14 amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8- one (compound 20.4) with 12-amino-22-fluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 53.4) in step (e). Methyl 2-[(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 53.5, 100.0 mg, 0.17 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 604.3. Step (f): preparation of N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 53) 15,18 2,6 9,14 N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide (Example 53) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 53.5) in step (f). N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (_{Example 53}, 48.92 mg, 0.08 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 576.4.¹H NMR (400 MHz, DMSO-d₆) δ = 10.90 (br. s, 1H), 10.11 (br. s, 1H), 7.86 - 7.80 (m 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 3.87 - 3.80 (m, 2H), 3.79 (s, 3H), 3.75 (t, J = 6.4 Hz, 2H), 3.32 (t, J = 6.4 Hz, 2H), 3.21 - 3.13 (m, 4H), 2.70 - 2.61 (m, 2H), 2.33 - 2.16 (m, 2H), 1.72 - 1.53 (m, 9H), 1.49 - 1.43 (m, 2H), 1.25 - 1.16 (m, 2H).¹⁹F NMR (376 MHz, CDCl3) δ = -140.94. Example 54 N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)methanesulfonamide To a solution of 12-Amino-22-fluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_compound 53.4, 40.0 mg, 0.09 mmol) in DCM (2 mL) was added Py (13.53 mg, 0.17 mmol) and methanesulfonic anhydride (17.88 mg, 0.1 mmol) at 0 °C. After being stirred at 25 °C for 1 hr, the mixture was quenched with H₂O (20 mL) and extracted with DCM (10 mL) three times. The combined organic layers was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (Column: Phenomenex luna C18 150*25mm* 10um; Condition: water (FA)-MeCN; B%: 20-50%; FlowRate (ml/min): 25) and lyophilized to afford N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)methanesulfonamide (_{Example 54}, 31.94 mg, 0.06 mmol). MS obsd. (ESI⁺)[(M+H)⁺]: 546.4. ¹H NMR (400 MHz, DMSO-d6) δ = 10.87 (br. s, 1H), 10.13 (br. s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 3.87 - 3.80 (m, 2H), 3.78 (s, 3H), 3.23 - 3.12 (m, 4H), 3.08 (s, 3H), 2.70 - 2.62 (m, 2H), 2.31 - 2.16 (m, 2H), 1.76 - 1.53 (m, 9H), 1.50 - 1.41 (m, 2H), 1.24 - 1.15 (m, 2H).¹⁹F NMR (376 MHz, CDCl3) δ = -140.89. Example 60 N-(17,17-difluoro-8-oxo-1,9,15,28-tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa- 2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme:

Int-72 Int-73 Grabbs' 2nd PEPPSI-Pd DCM, 40 C, 16 hrs DIEA, DMSO Cs io₂CO d xane₃ Int-50 60.1 60.2 Pd/C, H₂ TEA, DCM 6_{0.3 60.4 60.5} LAH Example 60 Step (a): preparation of ^N-(6-chloro-2-pyridyl)-4-nitro-2-(4-vinyl-1- piperidyl)benzamide (compound 60.1) N-(6-chloro-2-pyridyl)-4-nitro-2-(4-vinyl-1- piperidyl)benzamide (compound 60.1) was prepared in analogy to Example 27, by replacing benzyl 4-fluoro-4-[3-(4-methyl-4- piperidyl)propyl]piperidine-1-carboxylate (Int-7) with 4-vinylpiperidine (Int-72) in step (a). N- (6-chloro-2-pyridyl)-4-nitro-2-(4-vinyl-1-piperidyl)benzamide (compound 60.1, 1100.0 mg, 2.84 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 387.1. Step (b): preparation of ^N-[6-(4-allyl-3,3-difluoro-pyrrolidin-1-yl)-2-pyridyl]-4-nitro- 2-(4-vinyl-1-piperidyl)benzamide (compound 60.2) N-[6-(4-allyl-3,3-difluoro-pyrrolidin-1-yl)-2-pyridyl]-4-nitro-2-(4-vinyl-1- piperidyl)benzamide _{(compound 60.2)} was prepared in analogy to _{Example 21}, by replacing N- (6-chloropyrazin-2-yl)-4-nitro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]benzamide (compound 21.1) with N-(6-chloro-2-pyridyl)-4-nitro-2-(4-vinyl-1-piperidyl)benzamide (compound 60.1) and 4-allyl-3,3-difluoro-pyrrolidine (_Int-73) in step (b). N-[6-(4-allyl-3,3-difluoro-pyrrolidin-1- yl)-2-pyridyl]-4-nitro-2-(4-vinyl-1-piperidyl)benzamide (compound 60.2, 720.0 mg, 1.45 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 498.3. Step (c): preparation of (20Z)-17,17-difluoro-4-nitro-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28),20-heptaen-8-one (compound 60.3) To a solution of N-[6-(4-allyl-3,3-difluoro-pyrrolidin-1-yl)-2-pyridyl]-4-nitro-2-(4-vinyl-1- piperidyl)benzamide (compound 60.2, 400.0 mg, 0.8 mmol) in DCM (4.0 L) was added Grabs' 2nd (136.51 mg, 0.16 mmol) (CAS: 246047-72-3, Sinocompound) at 20 °C. The mixture was degassed and purged with N2 for three times. After being stirred at 40 °C for 12 hrs under N2, the mixture was concentrated in vacuo. The residue was purified by silica gel column (5% to 20% EA in PE) to afford (20Z)-17,17-difluoro-4-nitro-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28),20-heptaen-8-one (compound 60.3, 160.0 mg, 0.34 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 470.2. Step (d): preparation of 4-amino-17,17-difluoro-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 60.4) To a solution of (20Z)-17,17-difluoro-4-nitro-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28),20-heptaen-8-one (compound 60.3, 150.0 mg, 0.32 mmol) in THF (20 mL) was added Pd/C (50.0 mg, 10% loaded on active carbon) under N2. After being stirred at 25 °C for 4 hrs under H2 balloon (15 psi), the mixture was filtered through celite, washed with DCM (50 mL). The combined filtrate was concentrated in vacuo to afford 4-amino-17,17-difluoro-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 60.4, 130.0 mg, 0.29 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 442.2 Step (e): preparation of methyl 2-[(17,17-difluoro-8-^oxo-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate (compound 60.5) Methyl 2-[(17,17-difluoro-8-oxo-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate (compound 60.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 4-amino-17,17-difluoro-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-8-one (compound 60.4) in step (e). Methyl 2-[(17,17-difluoro-8-oxo-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate (compound 60.5, 150.0 mg, 0.26 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 578.3. Step (f): preparation of N-(17,17-difluoro-8-oxo-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (Example 60) N-(17,17-difluoro-8-oxo-1,9,15,28-tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa- 2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide (Example 60) was prepared in analogy to _{Example 20}, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(17,17-difluoro-8-oxo-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl)sulfamoyl]acetate (compound 60.5) in step (f). N-(17,17-difluoro-8-oxo-1,9,15,28- tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (Example 60, 30.08 mg, 0.05 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 550.3.¹H NMR (400 MHz, DMSO-d6) δ = 10.89 (br. s, 1H), 10.13 (br. s, 1H), 7.86 (d, J = 12.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 5.11 - 4.83 (m, 1H), 4.76 (d, J = 12.0 Hz, 1H), 3.90 - 3.79 (m, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.43 - 3.35 (m, 3H), 3.05 (d, J = 12.0 Hz, 1H), 2.86 (t, J = 12.0 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.36 - 2.23 (m, 1H), 2.00 - 1.76 (m, 2H), 1.74 - 1.60 (m, 3H), 1.58 - 1.39 (m, 3H), 1.39 - 1.26 (m, 2H), 1.17 - 1.05 (m, 1H). Example 61 N-(18,22-difluoro-8-^oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: Int-70 Int-71 Grubbs-II DIEA, DMSO DIEA, NMP DCM Int-53 61.1 61.2 B(OH) 4,4 ^'-₂bipyri₄dine DMF TEA, DCM 61.3 61.4 61.5 LAH, THF Example 61 Step (a): preparation of N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-fluoro-4- nitro-benzamide (compound 61.1) N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-fluoro-4-nitro-benzamide (compound 61.1) was prepared in analogy to Example 21, by replacing N-(6-chloropyrazin-2-yl)-2-fluoro-4- nitro-benzamide (Int-54) and 4-[3-(4-piperidyl)propyl]piperidine with N-(6-chloro-2-pyridyl)-2- fluoro-4-nitro-benzamide (Int-53) and 4-allyl-4-fluoro-piperidine (Int-70) in step (a). N-[2-(4- allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-fluoro-4-nitro-benzamide (_{compound 61.1}, 1200.0 mg, 2.97 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 404.2. Step (b): preparation of N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-(4-fluoro- 4-vinyl-1-piperidyl)-4-nitro-benzamide (compound 61.2) N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-(4-fluoro-4-vinyl-1-piperidyl)-4-nitro- benzamide (compound 61.2) was prepared in analogy to Example 21, by replacing N-(6- chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-54) and 4-[3-(4-piperidyl)propyl]piperidine with N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-fluoro-4-nitro-benzamide (_compound 61.1) and 4-fluoro-4-vinyl-piperidine (Int-71) in step (a). N-[2-(4-allyl-4-fluoro-1- piperidyl)pyrimidin-4-yl]-2-(4-fluoro-4-vinyl-1-piperidyl)-4-nitro-benzamide (compound 61.2, 520.0 mg, 1.01 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 513.2. Step (c): preparation of (19Z)-18,22-difluoro-12-nitro-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one (compound 61.3) (19Z)-18,22-difluoro-12-nitro-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one (_{compound 60.3}) was prepared in analogy to _{Example 60}, by replacing N-[6-(4-allyl-3,3- difluoro-pyrrolidin-1-yl)-2-pyridyl]-4-nitro-2-(4-vinyl-1-piperidyl)benzamide (compound 60.2) with N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-(4-fluoro-4-vinyl-1-piperidyl)-4-nitro- benzamide _{(compound 61.2)} in step (c). (19Z)-18,22-difluoro-12-nitro-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one (compound 60, 100.0 mg, 0.21 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 485.3. Step (d): preparation of 12-amino-18,22-difluoro-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 61.4) 12-amino-18,22-difluoro-1,3,7,15,29-pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one _{(compound 61.4)} was prepared in analogy to _{Example 60}, by replacing (20Z)-17,17-difluoro-4-nitro-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28),20-heptaen-8-one (compound 60.3) with (19Z)-18,22-difluoro-12-nitro-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one _{(compound 61.3)}in step (d).12-amino-18,22-difluoro-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 61.4, 60.0 mg, 0.13 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 457.2. Step (e): preparation of methyl 2-[(18,22-difluoro-8-^oxo-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 61.5) Methyl 2-[(18,22-difluoro-8-oxo-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 61.5) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one (compound 20.4) with 12-amino-18,22-difluoro-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 61.4) in step (e). Methyl 2-[(18,22-difluoro-8-oxo-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 61.5, 40.0 mg, 0.07 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 593.3. Step (f): preparation of N-(18,22-difluoro-8-oxo-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2- hydroxy-ethanesulfonamide (Example 61) N-(18,22-difluoro-8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide (Example 61) was prepared in analogy to _{Example 20}, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate _{(compound 20.5)} with methyl 2-[(18,22-difluoro-8-oxo-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 61.5) in step (f). N-(18,22-difluoro-8-oxo-1,3,7,15,29- pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 61, 6.12 mg, 0.01 mmol) was obtained. MS obsd. (ESI⁺)[(M+H)⁺]: 565.3.¹H NMR (400 MHz, DMSO-d6) δ = 10.73 (br. s, 1H), 10.15 (br. s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 4.52 - 4.40 (m, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.35 (t, J = 6.4 Hz, 2H), 3.30 - 3.25 (m, 2H), 3.05 - 2.97 (m, 2H), 2.96 - 2.87 (m, 2H), 2.08 - 1.89 (m, 6H), 1.78 - 1.65 (m, 4H), 1.55 - 1.33 (m, 4H).¹⁹F NMR (376 MHz, DMSO-d6) δ = -129.04, -144.09. Example 62 N-(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide The titled compound was synthesized according to the following scheme:

Int-70 PEPPSI-Pd DIEA dioxane,Cs₂CO₃ Int-51 62.1 62.2 G_rubbs-II ^{Pd/C, H} ₂ TEA, DCM DCN 6_2.3 62.4 _62.5 LAH, THF Example 62 Step (a): preparation of ^N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2- fluoro-4-nitro-benzamide (compound 62.1) N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2-fluoro-4-nitro-benzamide (compound 62.1) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6- fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (_{compound 1.2}) with N- (6-bromo-5-methoxy-2-pyridyl)-2-fluoro-4-nitro-benzamide (Int-51) and 4-allyl-4-fluoro- piperidine (Int-70) in step (c). N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2- fluoro-4-nitro-benzamide (_{compound 62.1}, 540.0 mg, 1.25 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 433.2. Step (b): preparation of N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2-(4- fluoro-4-vinyl-1-piperidyl)-4-nitro-benzamide (compound 62.2) N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2-(4-fluoro-4-vinyl-1-piperidyl)- 4-nitro-benzamide (compound 62.2) was prepared in analogy to Example 21, by replacing N- (6-chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-54) and 4-[3-(4- piperidyl)propyl]piperidine with N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2- fluoro-4-nitro-benzamide (compound 62.1) and 4-fluoro-4-vinyl-piperidine (Int-71) in step (a). N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2-(4-fluoro-4-vinyl-1-piperidyl)-4- nitro-benzamide _{(compound 62.2,} 390.0 mg, 0.72 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 542.3. Step (c): preparation of (19Z)-18,22-difluoro-3-methoxy-12-nitro-1,7,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one (compound 62.3) (19Z)-18,22-difluoro-3-methoxy-12-nitro-1,7,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one _{(compound 62.3)} was prepared in analogy to _{Example 60}, by replacing N-[6-(4-allyl-3,3- difluoro-pyrrolidin-1-yl)-2-pyridyl]-4-nitro-2-(4-vinyl-1-piperidyl)benzamide (compound 60.2) with N-[6-(4-allyl-4-fluoro-1-piperidyl)-5-methoxy-2-pyridyl]-2-(4-fluoro-4-vinyl-1-piperidyl)- 4-nitro-benzamide _{(compound 62.2)} in step (c). (19Z)-18,22-difluoro-3-methoxy-12-nitro- 1,7,15,29-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one (compound 62.3, 240.0 mg, 0.47 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 514.3. Step (d): preparation of 12-amino-18,22-difluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 62.4) 12-Amino-18,22-difluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (compound 62.4) was prepared in analogy to Example 60, by replacing (20Z)-17,17-difluoro-4-nitro- 10,14 15,18 2,7 1,9,15,28-tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28),20-heptaen-8-one (compound 60.3) with (19Z)-18,22-difluoro-3-methoxy-12-nitro-1,7,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13,19-heptaen-8-one _{(compound 62.3)} in step (d).12-Amino-18,22-difluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one (_{compound 62.4,} 220.0 mg, 0.45 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 486.2. Step (e): preparation of methyl 2-[(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 62.5) Methyl 2-[(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (_{compound 62.5}) was prepared in analogy to _{Example 20}, by replacing 15,18 2,6 9,14 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 8-one _{(compound 20.4)} with 12-amino-18,22-difluoro-3-methoxy-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one _(compound 62.4) in step (e). Methyl 2-[(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 62.5, 120.0 mg, 0.19 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 622.4. Step (f): preparation of N-(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 62) N-(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 62) was prepared in analogy to Example 20, by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen- 12-yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(18,22-difluoro-3-methoxy-8-oxo- 1,7,15,29-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (_{compound 62.5)} in step (f). N-(18,22-difluoro-3-methoxy-8-oxo- 15,18 2,6 9,14 1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2- hydroxy-ethanesulfonamide _{(Example 62,} 17.18 mg, 0.03 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 594.3.¹H NMR (400 MHz, DMSO-d₆) δ = 10.68 (br. s, 1H), 7.78 (dd, J = 8.4 Hz, J = 1.2 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.00 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.78 (s, 3H), 3.75 (t, J = 6.4 Hz, 2H), 3.32 (t, J = 6.4 Hz, 2H), 3.22 - 3.05 (m, 4H), 2.95 - 2.84 (m, 2H), 2.25 - 1.89 (m, 4H), 1.84 - 1.61 (m, 6H), 1.57 - 1.47 (m, 2H), 1.22 - 1.07 (m, 2H). Example 65 2-hydroxy-N-(7-oxo-1,8,15,29-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme:

DMF Boc₂O 65.1 65.2 B(OH ,4 ^'-b₂ ) 4 ipyrid₄ine DMF TCFH, NMI, MeCN 6_{5.3 65.4 65.5 65.6} LAH, THF TEA, DCM 65.7 65.8 Example 65 Step (a): preparation of N-[(2,4-dimethoxyphenyl)methyl]-3-iodo-4-nitro-aniline (compound 65.1) A mixture of 2,4-dimethoxybenzylamine (1.24 mL, 8.24 mmol), 4-fluoro-2-iodo-1-nitro- benzene (2.00 g, 7.49 mmol), K2CO3 (3.10 g, 22.47 mmol) in DMF (30 mL) was stirred at 100 °C for 12 hrs. The mixture was diluted with H₂O (100 mL), extracted with EA (100 mL) three times. The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase flash (0.1% FA in water, MeCN) and lyophilized to afford N-[(2,4-dimethoxyphenyl)methyl]-3-iodo- 4-nitro-aniline (compound 65.1, 3.0 g, 7.24 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 415.0. Step (b): preparation of N-[(2,4-dimethoxyphenyl)methyl]-4-nitro-3-[4-[3-(4- piperidyl)propyl]-1-piperidyl]aniline (compound 65.2) A mixture of 4-[3-(4-piperidyl)propyl]piperidine (761.81 mg, 3.62 mmol), K₂CO₃ (1.50 g, 10.86 mmol), N-[(2,4-dimethoxyphenyl)methyl]-3-iodo-4-nitro-aniline (compound 65.1, 1.50 g, 3.62 mmol), Pd2(dba)3 (331.81 mg, 0.36 mmol), Xantphos (209.54 mg, 0.36 mmol) in 1,4- Dioxane (20 mL) was degassed and purged with N₂ three times. After being stirred at 100 °C for 12 hrs under N₂, the mixture was filtered through celite, washed with EA (100 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column (5% to 30% EA in PE) to afford N-[(2,4-dimethoxyphenyl)methyl]-4-nitro-3-[4-[3-(4-piperidyl)propyl]-1- piperidyl]aniline (compound 65.2, 1.50 g, 3.02 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 497.3. Step (c): preparation of tert-butyl 4-[3-[1-[5-[(2,4-dimethoxyphenyl)methylamino]-2- nitro-phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 65.3) A mixture of di-t-butyldicarbonate (527.33 mg, 2.42 mmol), N-[(2,4- dimethoxyphenyl)methyl]-4-nitro-3-[4-[3-(4-piperidyl)propyl]-1-piperidyl]aniline (_compound 65.2, 1.20 g, 2.42 mmol) and TEA (244.61 mg, 2.42 mmol) in DCM (20 mL) was stirred at 20 °C for 2 hrs. The mixture was concentrated in vacuo. The residue was purified by silica gel column (10% to 30% EA in PE) and concentrated in vacuo to afford tert-butyl 4-[3-[1-[5-[(2,4- dimethoxyphenyl)methylamino]-2-nitro-phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 65.3, 1.20 g, 2.01 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 597.5. Step (d): preparation of tert-butyl 4-[3-[1-[2-amino-5-[(2,4- dimethoxyphenyl)methylamino]phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 65.4) To a solution of tert-butyl 4-[3-[1-[5-[(2,4-dimethoxyphenyl)methylamino]-2-nitro-phenyl]- 4-piperidyl]propyl]piperidine-1-carboxylate (_{compound 65.3}, 700.0 mg, 1.17 mmol) in DMSO (30 mL) was added 4,4’-bipyridine (9.16 mg, 0.06 mmol) at 20 °C. A solution of B2(OH)4 (420.65 mg, 4.69 mmol) in DMSO (5.0 mL) was added to the mixture dropwise over 5 min at 20 °C. After being stirred at 20 °C for 6 mins, the mixture was poured into water (100 mL), then extracted with EA (200 mL). The organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo to afford tert-butyl 4-[3-[1- [2-amino-5-[(2,4-dimethoxyphenyl)methylamino]phenyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 65.4, 620.0 mg, 1.09 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 567.5. Step (e): preparation of tert-butyl 4-[3-[1-[2-[(6-chloropyridine-2-carbonyl)amino]-5- [(2,4-dimethoxyphenyl)methylamino]phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 65.5) To a mixture of 6-chloropyridine-2-carboxylic acid (166.78 mg, 1.06 mmol), tert-butyl 4- [3-[1-[2-amino-5-[(2,4-dimethoxyphenyl)methylamino]phenyl]-4-piperidyl]propyl]piperidine-1- carboxylate (_{compound 65.4}, 600.0 mg, 1.06 mmol) and NMI (434.57 mg, 5.29 mmol) in MeCN (15 mL) was added TCFH (891.06 mg, 3.18 mmol) at 0 °C. After being stirred for 4 hrs at 25 °C, the mixture was diluted with H2O (30 mL), extracted with EA (30 mL) three times. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (10% to 30% EA in PE) to afford tert-butyl 4-[3-[1-[2-[(6- chloropyridine-2-carbonyl)amino]-5-[(2,4-dimethoxyphenyl)methylamino]phenyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 65.5, 560.0 mg, 0.79 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 706.5. Step (f): preparation of N-[4-amino-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]phenyl]-6- chloro-pyridine-2-carboxamide (compound 65.6) A solution of tert-butyl 4-[3-[1-[2-[(6-chloropyridine-2-carbonyl)amino]-5-[(2,4- dimethoxyphenyl)methylamino]phenyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 65.5, 560.0 mg, 0.79 mmol) in DCM (20 mL) and TFA (4.0 mL) was stirred for 2 hrs at 20 °C. The mixture was concentrated in vacuo. The residue was diluted with H₂O (50 mL), basified with solid NaHCO₃ to pH = 8, extracted with EA (100 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo to afford N-[4-amino-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]phenyl]-6-chloro- pyridine-2-carboxamide (compound 65.6, 350.0 mg, 0.77 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 456.3. Step (g): preparation of 12-amino-1,8,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-7-one (compound 65.7) A mixture of N-[4-amino-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]phenyl]-6-chloro- pyridine-2-carboxamide (_{compound 65.6}, 350.0 mg, 0.77 mmol), Cs₂CO₃ (750.19 mg, 2.3 mmol) and PEPPSI-Pd (65.82 mg, 0.08 mmol) in 1,4-Dioxane (300 mL) was degassed under N₂ for three times. After being stirred for 12 hrs at 100 °C under N2, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (10% to 30% _{EA in PE) to afford} 15,18 2,6 9,14 12-amino-1,8,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-7-one (compound 65.7, 120.0 mg, 0.29 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 420.3.¹H NMR (400 MHz, DMSO-d6) δ = 9.84 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 8.4 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 6.30 (dd, J = 8.4 Hz, J = 2.8 Hz, 1H), 4.95 (s, 2H), 3.92 - 3.82 (m, 2H), 3.27 - 3.19 (m, 2H), 2.97 (d, J = 10.8 Hz, 2H), 2.47 - 2.41 (m, 2H), 1.94 - 1.79 (m, 5H), 1.73 - 7.62 (m, 3H), 1.55 - 1.46 (m, 4H), 1.43 - 1.36 (m, 4H). Step (h): preparation of methyl 2-[(7-oxo-1,8,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 65.8) Methyl 2-[(7-oxo-1,8,15,29-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)sulfamoyl]acetate (compound 65.8) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-8-one (compound 20.4) with ^{12-amino-1,8,15,29-} 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-7-one (compound 65.7, 100.0 mg, 0.24 mmol) in step (e). Methyl 2-[(7-oxo-1,8,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 65.8, 45.0 mg, 0.08 mmol) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 556.3. Step (i): preparation of 2-hydroxy-N-(7-oxo-1,8,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 65) 2-hydroxy-N-(7-oxo-1,8,15,29-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide _{(Example 65)} was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (compound 20.5) with methyl 2-[(7-oxo-1,8,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)sulfamoyl]acetate (_{compound 65.8)} in step (f).2-Hydroxy-N-(7-oxo-1,8,15,29- tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide (Example 65, 19.37 mg, 0.04 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 528.3. ¹H NMR (400 MHz, DMSO-d6) δ = 10.03 (br. s, 1H), 9.58 (br. s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 4.91 (t, J = 5.6 Hz, 1H), 3.93 - 3.81 (m, 2H), 3.78 - 3.68 (m, 2H), 3.26 - 3.18 (m, 4H), 3.06 - 2.99 (m, 2H), 2.57 - 2.52 (m, 2H), 1.97 - 1.79 (m, 5H), 1.73 - 1.61 (m, 3H), 1.58 - 1.48 (m, 4H), 1.47 - 1.34 (m, 4H). Example 70 N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide

The titled compound was synthesized according to the following scheme: CMBP DIEA, MeCN toluene I_{nt-59 70.1 70.2} CuI, MNPMO K₃PO₄, DMSO E_{xample 70} _{Step (a): preparation of} 4-bromo-2-[4-(4-hydroxybutyl)-1-piperidyl]-N-(3- ^{sulfamoylphenyl)benzamide} _{(compound 70.1)} To a solution of 4-bromo-2-fluoro-N-(3-sulfamoylphenyl)benzamide (Int-59, 500 mg, 1.34 mmol ) in acetonitrile (10 mL) was added 4-(4-piperidyl -butanol (210.68 mg, 1.34 mmol ) and DIEA (0.7 mL, 4.02 mmol ) at rt. After being stirred for 4 hrs at 140°C under microwave irradiation, the reaction mixture was concentrated. The crude material was purified by flash _{chromatography on silica gel to obtain} ^{4-bromo-2-[4-(4-hydroxybutyl)-1-piperidyl]-N-(3-} sulfamoylphenyl)benzamide (compound 70.1, 880 mg). MS obsd. (ESI⁺) [(M+H)⁺]: 510.1. Step (b): preparation of 4-bromo-15,15-dioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-8-one _(compound 70.2) To a solution of 4-bromo-2-[4-(4-hydroxybutyl)-1-piperidyl]-N-(3- ^{sulfamoylphenyl)benzamide} (compound 70.1, 200 mg, 391.82 µmol) in tetrahydrofuran (10 mL) toluene (30 mL) was added CMBP (411.15 µL, 1.57 mmol) at rt. After being stirred at 115°C for 2 h under microwave irradiation, the reaction mixture was concentrated to dryness. The crude material was subjected to flash chromatography on silica gel to obtain 4-bromo-15,15- dioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13- hexaen-8-one (compound 70.2, 140 mg). MS obsd. (ESI⁺) [(M+H)⁺]: 492.2. Step (c): N-(8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl)ethanesulfonamide (Example 70) To a solution of 4-bromo-15,15-dioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-8-one (80 mg, _{compound 70.2}, 162.46 µmol) in DMSO (1.2 mL) was added ethanesulfonamide (53.2 mg, 487.38 µmol), MNPMO (20.7 mg, 64.98 µmol), copper (I) iodide (6.19 mg, 32.49 µmol), tripotassium phosphate (103.46 mg, 487.38 µmol) at rt. After being stirred for 3 hrs at 120°C, the mixture was diluted with EA (30 mL), washed with sat. aq. NH₄Cl (3 mL), water (10 mL) and brine (10 mL) three times, dried with anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude material was purified by prep-HPLC to afford N-(8,15,15- trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13- hexaen-4-yl)ethanesulfonamide (Example 70, 3.2 mg). MS obsd. (ESI⁺) [(M+H)⁺]: 521.3. 1H NMR (400 MHz,CDCl3) δ = 11.70 (s, 1H), 8.82 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.45 - 7.36 (m, 1H), 7.12 (d, J = 1.9 Hz, 1H), 6.95 (dd, J = 1.9, 8.5 Hz, 1H), 6.82 (s, 1H), 4.57 (t, J = 6.2 Hz, 1H), 3.34 (q, J = 5.8 Hz, 2H), 3.27 - 3.15 (m, 4H), 2.79 (br t, J = 11.0 Hz, 2H), 1.78 - 1.66 (m, 5H), 1.54 - 1.49 (m, 2H), 1.47 - 1.41 (m, 3H). Example 71 N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)methanesulfonamide

The titled compound was synthesized according to the following scheme: CuI, MNPMO K₃PO₄, DMSO 7_{0.2 Example 71} N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)methanesulfonamide (Example 71, 13 mg) was prepared in analogy to _{Example 70}, by replacing ethanesulfonamide with methanesulfonamide in the step (c). MS obsd. (ESI⁺) [(M+H)⁺]: 507.4.¹H NMR (500 MHz, CD₃OD) δ = 8.87 - 8.62 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.66 (td, J = 1.3, 7.9 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.10 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 2.1, 8.4 Hz, 1H), 3.28 (br d, J = 10.8 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H), 3.06 (s, 3H), 2.78 (br t, J = 10.7 Hz, 2H), 1.83 - 1.67 (m, 3H), 1.60 - 1.44 (m, 4H), 1.39 - 1.21 (m, 4H). Example 72 N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptacosa- 2(7),3,5,10(27),11,13-hexaen-4-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: CMBP DIEA, MeCN toluene I_{nt-59 72.1 72.2} CuI, MNPMO K₃PO₄, DMSO E_{xample 72} N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptacosa- 2(7),3,5,10(27),11,13-hexaen-4-yl)ethanesulfonamide (_{Example 72}, 8.0 mg) was prepared in analogy to the Example 70, by replacing 4-(4-piperidyl -butanol with 5-(4-piperidyl)pentan-1-ol. MS obsd. (ESI⁺) [(M+H)⁺]: 535.2. 1H NMR (400 MHz,CDCl₃) δ = 8.80 - 8.74 (m, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.66 - 7.55 (m, 3H), 7.16 (s, 1H), 7.10 - 7.03 (m, 1H), 3.28 (br d, J = 11.1 Hz, 2H), 3.21 (br d, J = 7.3 Hz, 2H), 2.81 (br s, 2H), 2.72 (br d, J = 8.1 Hz, 2H), 1.87 - 1.82 (m, 2H), 1.80 - 1.73 (m, 2H), 1.59 (br s, 3H), 1.50 - 1.39 (m, 4H), 1.34 (t, J = 7.3 Hz, 3H), 1.31 (br s, 2H). Example 73 N-(17-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: CMBP DIEA, MeCN Toluene I_{nt-59 73.1 73.2} CuI, MNPMO K₃PO₄, DMSO E_{xample 73} N-(17-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide (Example 73, 11.2 mg) was prepared in analogy to Example 70, by replacing 4-(4-piperidyl)–butanol with 5-(4-piperidyl)pentan-2-ol. MS obsd. (ESI⁺) [(M+H)⁺]: 535.2. 1H NMR (400 MHz, CD3OD) δ = 8.83 - 8.58 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.67 (td, J = 1.2, 8.0 Hz, 1H), 7.59 - 7.54 (m, 3H), 7.53 (t, J = 1.8 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 2.1, 8.4 Hz, 1H), 3.23 (br d, J = 4.0 Hz, 1H), 3.18 (q, J = 7.4 Hz, 3H), 2.86 - 2.66 (m, 2H), 1.88 - 1.65 (m, 2H), 1.63 - 1.51 (m, 3H), 1.46 - 1.36 (m, 4H), 1.32 (t, J = 7.4 Hz, 3H), 1.29 (d, J = 6.5, 2H), 1.27 - 1.20 (m, 2H). Example 74 N-(21-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: CMBP DIEA, MeCN Toluene I_{nt-59 74.1 74.2} CuI, MNPMO K₃PO₄, DMSO E_{xample 74} N-(21-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide (Example 74, 18.4 mg) was prepared in analogy to _{Example 70}, by replacing 4-(4-piperidyl)-butanol with 4-(4-methylpiperidin-4- yl)butan-1-ol hydrochloride. MS obsd. (ESI+) [(M+H)⁺]: 535.1.¹H NMR (400 MHz,CDCl₃) δ = 11.63 (s, 1H), 8.79 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.38 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.15 (d, J = 1.75 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H),4.53 -4.50 (m, 1H), 3.33 – 3.31 (m, 3H), 3.26 – 3.20 (m, 2H), 3.05 – 3.02 (m, 2H), 2.98 - 2.95 (m, 2H), 1.94 - 1.87 (m, 2H), 1.45 - 1.42 (m, 6H), 1.33 - 1.25 (m, 5H), 1.03 (s, 1H). Example 75 N-[16-(2,2-difluoroethyl)-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl]ethanesulfonamide The titled compound was synthesized according to the following scheme: CuI, MNPMO CMBP, toluene/THF K₃PO₄, DMSO 70.2 75.1 _{Example 75} Step (a): preparation of 4-bromo-16-(2,2-difluoroethyl)-15,15-dioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-8-one (compound 75.1) To a solution of 4-bromo-15,15-dioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-8-one (compound 70.2, 100 mg, 203.48 µmol) in THF (0.5 mL) toluene (1 mL) was added 2,2- difluoroethanol (16.69 mg, 203.48 µmol) and cyanomethylenetributylphosphorane (196.44 mg, 213.29 µL, 813.93 µmol) at rt. After being stirred for at 115°C for 1.5 hrs under microwave irradiation, the reaction mixture was concentrated. The crude material was purified by flash chromatography on silica gel to afford 4-bromo-16-(2,2-difluoroethyl)-15,15-dioxo-15λ⁶-thia- 1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-8-one (compound 75.1, 100 mg, 0.18 mmol). MS obsd. (ESI⁺) [(M+H)⁺]: 556.2. Step (b): preparation of N-[16-(2,2-difluoroethyl)-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7] hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl]ethanesulfonamide To a solution of 4-bromo-16-(2,2-difluoroethyl)-15,15-dioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-8-one (compound _75.1, 100 mg, 179.71 µmol) in DMSO (1.29 mL) was added ethanesulfonamide (58.85 mg, 539.12 µmol), MNPMO (57.2 mg, 179.2 µmol), copper (I) iodide (6.85 mg, 35.94 µmol), tripotassium phosphate (114.44 mg, 539.12 µmol). After bubbling with N2 for 2 min, the mixture was stirred for at 120°C for 2 hrs. The reaction mixture was diluted with sat. NH4Cl and extracted with EA twice. The organic layers were was washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by prep-HPLC to afford N-[16-(2,2-difluoroethyl)-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl]ethanesulfonamide (Example 75, 27.5 mg). MS obsd. (ESI⁺) [(M+H)⁺]: 585.2. 1H NMR (400 MHz, CDCl₃) δ = 11.97 (s, 1 H), 8.69 - 9.12 (m, 1 H), 8.18 (d, J = 8.51 Hz, 1 H), 7.51 - 7.79 (m, 1 H), 6.98 (dd, J = 8.50, 2.13 Hz, 1 H), 6.56 (s, 1 H), 5.88 - 6.24 (m, 1 H), 3.64 - 3.86 (m, 1 H), 3.35 (td, J = 13.20, 4.50 Hz, 1 H), 3.28 (brd, J = 11.51 Hz, 1 H), 2.83 (brt, J =10.57 Hz, 1 H), 1.66 - 1.82 (m, 1 H), 1.43 (t, J = 7.38 Hz, 1 H), 0.80 - 0.88 (m, 1 H). Example 76 N-(16-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: MeOH CuI, MNPMO CMBP, toluene/THF K₃PO₄, DMSO 7^0.2 76.1 _{Example 76} N-(16-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide (_{Example 76}, 15 mg) was prepared in analogy to Example 75 by replacing 2,2-difluoroethanol with methanol. MS obsd. (ESI⁺) [(M+H)⁺]: 535.2. 1H NMR (400 MHz, CD3OD) δ = 8.66 - 8.95 (m, 1 H), 7.88 - 8.00 (m, 1 H), 7.58 - 7.70 (m, 2 H), 7.55 (t, J = 1.81 Hz, 1 H), 7.15 (d, J = 2.13 Hz, 1 H), 7.06 (dd, J = 8.50, 2.13 Hz, 1 H), 3.48 (t, J = 6.13 Hz, 2 H), 3.27 (br d, J = 11.01 Hz, 2 H), 3.21 (q, J = 7.38 Hz, 2 H), 2.79 (br s, 2 H), 2.74 (s, 3H), 1.77 (br s, 3 H), 1.45 - 1.63 (m, 6 H), 1.31 - 1.37 (m, 5 H). Example 77 N-(16,21-dimethyl-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide The titled compound was synthesized according to the following scheme: MeOH CuI, MNPMO CMBP, toluene/THF K₃PO₄, DMSO 7^4.2 77.1 _{Example 77} N-(16,21-dimethyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7] hexacosa-2(7),3,5,10(26),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide (Example 77, 2 mg) was prepared in analogy to Example 76, by replacing 4-(4-piperidyl)–butanol and ethanesulfonamide with 4-(4-methylpiperidin-4-yl)butan-1-ol hydrochloride and 2- hydroxyethanesulfonamide. MS obsd. (ESI⁺) [(M+H)⁺]: 565.2. 1H NMR (500 MHz,CD3OD) δ = 8.78 - 8.61 (m, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.50 - 7.45 (m, 1H), 7.44 - 7.41 (m, 1H), 7.09 - 7.05 (m, 1H), 6.97 - 6.93 (m, 1H), 3.88 - 3.81 (m, 2H), 3.40 - 3.32 (m, 2H), 3.29 - 3.24 (m, 2H), 2.99 - 2.94 (m, 2H), 2.92 - 2.84 (m, 2H), 2.64 - 2.56 (m, 3H), 1.92 - 1.81 (m, 2H), 1.39 - 1.32 (m, 2H), 1.22 - 1.17 (m, 4H), 1.15 - 1.09 (m, 2H), 0.97 - 0.90 (m, 3H). Example 78 10,14 2,7 2-hydroxy-N-(8-oxo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- 2(7),3,5,10,12,14(27)-hexaen-4-yl)ethanesulfonamide The titled compound was synthesized according to the following scheme: 78.1 K₂CO₃ Grubbs-II HATU/DIEPA DMSO 7_{8.2 78.3} Pd/H₂ K3PO4, CuI DMF N,N'-Dimethyl-1,2 -cyclohexanediamine 7_{8.4 78.5 78} Step (a): preparation of 6-hex-5-enoxypyridin-2-amine (compound 78.1) To a solution of hex-5-en-1-ol (5.84 g, 58.34 mmol) in N, N-dimethylformamide was added NaH (6.22 g, 155.57 mmol) at rt. The mixture was stirred at rt for 30 min before being added dropwise to a solution of (6-chloro-2-pyridyl)-amine (5 g, 38.89 mmol) in N,N- dimethylformamide at 0 °C. The resulting mixture was then stirred at rt for 1 hr and NaH (6.22 g, 155.57 mmol) was added. After being stirred for 3 hrs at 90°C, the resulting mixture was quenched with water and the aqueous phase was extracted with EA. The combined organic solution was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to afford 6-hex-5-enoxypyridin-2-amine (compound 78.1, 2.5 g). MS obsd. (ESI⁺) [(M+H)⁺]: 193. Step (b): preparation of 4-bromo-2-fluoro-N-(6-hex-5-enoxy-2-pyridyl)benzamide (compound 78.2) To a solution of 4-bromo-2-fluoro-benzoic acid (219 mg, 999.95 µmol), HATU (569.73 mg, 1.5 mmol) in N, N-dimethylformamide (10 mL) were added 6-hex-5-enoxypyridin-2-amine (compound 78.1, 192.25 mg, 999.95 µmol) and DIPEA (323.09 mg, 436.6 µL, 2.5 mmol). After being stirred for 3 hrs at 90°C, the resulting mixture was quenched with water and the aqueous phase was extracted with EA. The combined organic solution was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford 4-bromo-2-fluoro-N-(6-hex-5-enoxy-2-pyridyl)benzamide (compound 78.2, 250 mg). MS obsd. (ESI⁺) [(M+H)⁺]: 394. S_{tep (c): preparation of} 4-bromo-N-(6-hex-5-enoxy-2-pyridyl)-2-(4-vinyl-1- piperidyl)benzamide (compound 78.3) To a solution of 4-bromo-2-fluoro-N-(6-hex-5-enoxy-2-pyridyl)benzamide (300 mg, _compound (_78.2, 762.87 µmol) in DMSO (15.68 mL) were added 4- vinylpiperidine;hydrochloride (135.17 mg, 915.45 µmol) and K₂CO₃ (316.31 mg, 2.29 mmol). After being stirred for 3 hrs at 90°C, the resulting mixture was quenched with water and the aqueous phase was extracted with EA. The combined organic solution was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford 4-bromo-N-(6-hex-5-enoxy-2-pyridyl)-2-(4-vinyl-1-piperidyl)benzamide (compound 78.3) (compound 78.3, 300 mg). MS obsd. (ESI⁺) [(M+H)⁺]: 485. Step (d): preparation of (20Z)-4-bromo-15-oxa-1,9,27- 10,14 2,7 triazatetracyclo[20.2.2.1 .0 ]heptacosa-2(7),3,5,10,12,14(27),20-heptaen-8-one (compound 78.4) 10,14 2,7 (20Z)-4-bromo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- 2(7),3,5,10,12,14(27),20-heptaen-8-one _{(compound 78.4)} was prepared in analogy to _Example ₆₀, by replacing N-[6-(4-allyl-3,3-difluoro-pyrrolidin-1-yl)-2-pyridyl]-4-nitro-2-(4-vinyl-1- piperidyl)benzamide _{(compound 60.2)} with 4-bromo-N-(6-hex-5-enoxy-2-pyridyl)-2-(4-vinyl-1- ^{piperidyl)benzamide} _{(300 mg, compound 78.3) in step (c).} ^{(20Z)-4-bromo-15-oxa-1,9,27-} 10,14 2,7 triazatetracyclo[20.2.2.1 .0 ]heptacosa-2(7),3,5,10,12,14(27),20-heptaen-8-one _(compound 78.4, 90 mg) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 457. Step (e): preparation of 2-hydroxy-N-[(20Z)-8-oxo-15-oxa-1,9,27- 10,14 2,7 triazatetracyclo[20.2.2.1 .0 ]heptacosa-2(7),3,5,10,12,14(27),20-heptaen-4- yl]ethanesulfonamide (compound 78.5) 10,14 2,7 To a solution of (20Z)-4-bromo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- ^{2(7),3,5,10,12,14(27),20-heptaen-8-one} _{(compound 78.4, 50 mg, 109.56 µmol), potassium} phosphate (69.77 mg, 328.67 µmol) in N,N-dimethylformamide (3 mL) were added copper (I) iodide (20.87 mg, 109.56 µmol) and trans-N¹,N²-dimethylcyclohexane-1,2-diamine (7.79 mg, 54.78 µmol ). After being stirred for 3 hrs at 90 °C, the resulting mixture was quenched with water and the aqueous phase was extracted with EA. The combined organic solution was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford 2-hydroxy-N-[(20Z)-8-oxo-15-oxa-1,9,27- 10,14 2,7 triazatetracyclo[20.2.2.1 .0 ]heptacosa-2(7),3,5,10,12,14(27),20-heptaen-4- yl]ethanesulfonamide (compound 78.5, 40 mg,). MS obsd. (ESI⁺) [(M+H)⁺]: 501. S_{tep (f): preparation of} ^{2-hydroxy-N-(8-oxo-15-oxa-1,9,27-} 10,14 2,7 triazatetracyclo[20.2.2.1 .0 ]heptacosa-2(7),3,5,10,12,14(27)-hexaen-4- yl)ethanesulfonamide (Example 78) 10,14 2,7 2-Hydroxy-N-(8-oxo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- 2(7),3,5,10,12,14(27)-hexaen-4-yl)ethanesulfonamide`(Example 78, 18.9 mg) was prepared in analogy to Example 60, by replacing (20Z)-17,17-difluoro-4-nitro-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28),20-heptaen-8-one (compound 60.3) with 2-hydroxy-N-[(20Z)-8-oxo-15-oxa-1,9,27- 10,14 2,7 triazatetracyclo[20.2.2.1 .0 ]heptacosa-2(7),3,5,10,12,14(27),20-heptaen-4- yl]ethanesulfonamide (compound 78.5) in step (d). MS obsd. (ESI⁺) [(M+H)⁺]: 503. ¹H NMR (400 MHz, CD3OD) δ 8.09 (d, 1H, J = 8.6 Hz), 7.91 (d, 1H, J = 7.8 Hz), 7.68 (t, 1H, J = 8.0 Hz), 7.27 (d, 1H, J = 2.1 Hz), 7.13 (dd, 1H, J = 2.1, 8.6 Hz), 6.51 (d, 1H, J = 8.1 Hz), 4.57 (t, 2H, J = 6.9 Hz), 3.96 (t, 2H, J = 6.3 Hz), 3.38 (t, 2H, J = 6.3 Hz), 3.27 (br d, 2H, J = 11.5 Hz), 2.83 (br t, 2H, J = 11.2 Hz), 2.07 (br dd, 2H, J = 2.7, 12.2 Hz), 1.8-1.9 (m, 2H), 1.7-1.8 (m, 3H), 1.6-1.7 (m, 2H), 1.5-1.6 (m, 6H). Example 79 N-(18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd₂ ₂(dba 3), Xantphos CsCO,₂ dioxane Int-46 _{79.1 79.2} PEPPSI-Pd B(OH) 4,4 ^'-₂bipyri₄dine Cs dio₂CO xane₃ DMF TEA, DCM 79.3 79.4 79.5 LAH, THF Example 79 N-(18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ^{ethanesulfonamide} (Example 79, 150.0 mg) was prepared in analogy to Example 40, by replacing tert-butyl 3-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (_Int-42) with tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4- piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int-46). MS obsd. (ESI⁺): 581.3 [(M+H)⁺]. Example 79A and Example 79B 2-hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-20-oxa- 10,14 15,19 2,7 1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide Example 79A ^and Example 79B Separation of Example 79 by SFC afforded Example 79A (faster eluting, 47.9 mg) and Example 79B (slower eluting, 50.32 mg) with Column: DAICEL CHIRALCEL OX (250mm*30mm, 10um), CO₂-EtOH (0.1% NH₃H₂O), 50%, 120 ml/min. Example 79A (faster eluting): MS obsd. (ESI⁺): 581.3 [(M+H)⁺].¹H NMR (400 MHz, DMSO-d6) δ = 11.80 (br. s, 1H), 10.18 (br. s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.14 (s, 1H), 7.05 (dd, J = 2.0, 8.8 Hz, 1H), 5.01 (br. s, 1H), 4.55 (m, 2H), 3.90 - 3.81 (m, 1H), 3.75 (t, J = 6.4 Hz, 2H), 3.71 - 3.61 (m, 2H), 3.48 - 3.38 (m, 1H), 3.37 - 3.33 (m, 2H), 3.28 - 3.23 (m, 1H), 3.06 - 2.97 (m, 1H), 2.85 - 2.75 (m, 1H), 2.63 - 2.51 (m, 2H), 2.30 (s, 3H), 2.05 - 1.93 (m, 3H), 1.86 - 1.61 (m, 5H), 1.48 - 1.39 (m, 1H). E_{xample 79B}: (slower eluting): MS obsd. (ESI⁺): 581.3 [(M+H)⁺].¹H NMR (400 MHz, DMSO-d6) δ = 11.80 (br. s, 1H), 10.23 (br. s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.16 (s, 1H), 7.11 - 7.00 (m, 1H), 5.01 (br. s, 1H), 4.63 - 4.37 (m, 2H), 3.96 - 3.82 (m, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.73 - 3.61 (m, 2H), 3.50 - 3.38 (m, 1H), 3.37 - 3.34 (m, 2H), 3.29 - 3.23 (m, 1H), 3.08 - 2.98 (m, 1H), 2.86 - 2.76 (m, 1H), 2.62 - 2.52 (m, 2H), 2.31 (s, 3H), 2.05 - 1.91 (m, 3H), 1.83 - 1.60 (m, 5H), 1.48 - 1.39 (m, 1H). Example 80 N-(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide

The titled compound was synthesized according to the following scheme: TFA, DCM P Cds₂ ₂(CdOba 3,)₂ d,i Xoxaanntpehos Int-47 _{80.1 80.2} PEPPSI-Pd 4,4 B ^'-₂b(iOpHyr)i₄dine C diso₂xCaOne₃ DMF TEA, DCM 8_0.3 80.4 _80.5 LAH, THF Example 80 N-(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (_{Example 80}, 57.9 mg) was prepared in analogy to _{Example 40}, by replacing tert-butyl 3-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (Int-42) with tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4- piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int-47). MS obsd. (ESI⁺) [(M+H)⁺]: 595.3.¹H NMR (400 MHz, DMSO-d₆) δ = 10.93 (br. s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.97 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 4.97 - 4.83 (m, 1H), 4.79 - 4.67 (m, 1H), 4.06 - 3.95 (m, 1H), 3.77 - 3.68 (m, 3H), 3.63 - 3.55 (m, 1H), 3.34 - 3.30 (m, 2H), 3.22 - 3.14 (m, 1H), 3.12 - 3.02 (m, 2H), 2.95- 2.74 (m, 3H), 2.29 (s, 3H), 2.06 - 1.87 (m, 4H), 1.73 - 1.64 (m, 1H), 1.44 - 1.30 (m, 2H), 1.09 - 1.01 (m, 1H), 0.96 (s, 3H). Example 80A and Example 80B 2-hydroxy-N-[(19S)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa- 10,14 15,19 2,7 1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide Example 80A and Example 80B Separation of Example 80 by SFC afforded Example 80A (faster eluting, 30.32 mg) and Example 80B (slower eluting, 30.86 mg) with Column: (s, s) DAICEL CHIRALPAK IG (250mm*30mm, 10um); Condition: CO2-EtOH (0.1%NH3H2O); B%: 45-45%; FlowRate (mL/min): 120. Example 80A (faster eluting): MS obsd. (ESI⁺) [(M+H)⁺]: 595.2.¹H NMR (400 MHz, DMSO-d6) δ = 10.95 (br. s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.07 (s, 1H), 6.97 (dd, J1 = 8.4 Hz, J₂ = 2.0 Hz, 1H), 4.94 - 4.83 (m, 1H), 4.77 - 4.65 (m, 1H), 4.08 - 3.94 (m, 1H), 3.77 - 3.67 (m, 3H), 3.66 - 3.56 (m, 1H), 3.40 - 3.32 (m, 2H), 3.24 - 3.16 (m, 1H), 3.13 - 3.03 (m, 2H), 2.95- 2.74 (m, 3H), 2.29 (s, 3H), 2.06 - 1.89 (m, 4H), 1.73 - 1.65 (m, 1H), 1.45 - 1.32 (m, 2H), 1.10 - 1.02 (m, 1H), 0.97 (s, 3H). E_{xample 80B}: (slower eluting): MS obsd. (ESI⁺) [(M+H)⁺]: 595.2.¹H NMR (400 MHz, DMSO-d6) δ = 10.95 (br. s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.07 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.94 - 4.81 (m, 1H), 4.78 - 4.63 (m, 1H), 4.06 - 3.93 (m, 1H), 3.78 - 3.67 (m, 3H), 3.66 - 3.55 (m, 1H), 3.36 - 3.33 (m, 2H), 3.24 - 3.16 (m, 1H), 3.14 - 3.03 (m, 2H), 2.95- 2.73 (m, 3H), 2.29 (s, 3H), 2.07 - 1.88 (m, 4H), 1.73 - 1.64 (m, 1H), 1.45 - 1.32 (m, 2H), 1.09 - 1.03 (m, 1H), 0.97 (s, 3H). Example 81 N-(23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd₂(dba)₂, Xantphos Cs₂CO₃, dioxane Int-48 _{81.1 81.2} PEPPSI-Pd B 4,4 ^'-₂(OH) bipyri₄dine Cs dio₂CO xane₃ DMF TEA, DCM 8_1.3 81.4 _81.5 LAH, THF Example 81 N-(23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (_{Example 81}, 10.6 mg) was prepared in analogy to _{Example 40}, by replacing tert-butyl 3-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (Int-42) with tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-ethyl- 4-piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int-48). MS obsd. (ESI⁺): 609.3 [(M+H)⁺].¹H NMR (400 MHz, DMSO-d₆) δ = 11.02 (br. s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.99 - 4.86 (m, 1H), 4.81 - 4.66 (m, 1H), 4.09 - 3.96 (m, 1H), 3.79 - 3.67 (m, 3H), 3.57 (d, J = 8.0 Hz, 1H), 3.30 - 3.25 (m, 2H), 3.22 - 3.15 (m, 1H), 3.10 - 2.99 (m, 2H), 2.93 - 2.73 (m, 3H), 2.29 (s, 3H), 2.02 - 1.86 (m, 4H), 1.74 - 1.61 (m, 1H), 1.55 - 1.45 (m, 2H), 1.42 - 1.34 (m, 1H), 1.31 - 1.20 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H). Example 81A and Example 81B 2-hydroxy-N-[(19S)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20- 10,14 15,19 2,7 oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)- hexaen-4-yl]ethanesulfonamide Example 81A and Example 81B Separation of Example 81 by SFC afforded Example 81A (faster eluting, 50.0 mg) and _{Example 81B} (slower eluting, 15.7 mg) with column: DAICEL CHIRALPAK IG (250mm×30mm×10µm. CO₂-EtOH(0.1% NH₃H₂O. Example 81A (faster eluting): MS obsd. (ESI⁺): 609.2 [(M+H)⁺].¹H NMR (400 MHz, Chloroform-d) δ = 10.96 (br. s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 2.0, 8.4 Hz, 1H), 5.07 - 4.76 (m, 2H), 4.14 (t, J = 5.2 Hz, 2H), 4.11 - 4.02 (m, 1H), 3.74 - 3.56 (m, 2H), 3.37 - 3.30 (m, 2H), 3.29 - 3.08 (m, 3H), 3.06 - 2.96 (m, 2H), 2.88 - 2.75 (m, 1H), 2.38 (s, 3H), 2.18 - 2.08 (m, 2H), 2.01 - 1.93 (m, 2H), 1.75 - 1.70 (m, 2H), 1.56 - 1.48 (m, 1H), 1.44 (d, J = 7.2 Hz, 1H), 1.36 - 1.28 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H). Example 81B: (slower eluting): MS obsd. (ESI⁺): 609.2 [(M+H)⁺]. H NMR (400 MHz, Chloroform-d) δ = 10.95 (br. s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 2.0, 8.4 Hz, 1H), 5.11 - 4.71 (m, 2H), 4.15 (t, J = 5.2 Hz, 2H), 4.11 - 4.03 (m, 1H), 3.73 - 3.64 (m, 1H), 3.64 - 3.58 (m, 1H), 3.37 - 3.30 (m, 2H), 3.30 - 3.08 (m, 3H), 3.07 - 2.96 (m, 2H), 2.86 - 2.76 (m, 1H), 2.38 (s, 3H), 2.21 - 2.09 (m, 2H), 2.01 - 1.92 (m, 2H), 1.74 - 1.69 (m, 1H), 1.55 - 1.52 (m, 1H), 1.47 - 1.39 (m, 2H), 1.31 (d, J = 14.4 Hz, 2H), 0.82 (t, J = 7.6 Hz, 3H). Example 82 N-(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide The titled compound was synthesized according to the following scheme: TFA, DCM Pd₂ ₂(dba 3), Xantphos CsCO,₂ dioxane Int-49 82.1 82.2 PEPPSI-Pd B(OH) 4,4 ^'-₂bipyri₄dine Cs dio₂CO xane₃ DMF TEA, DCM 82.3 82.4 82.5 LAH, THF Example 82 N-(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (_{Example 82}, 120.0 mg) was prepared in analogy to _{Example 40}, by replacing tert-butyl 3-[3-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]propyl]-4,4-difluoro- piperidine-1-carboxylate (Int-42) with tert-butyl 3-[2-[1-(2-carbamoyl-3-methyl-5-nitro- phenyl)-4 piperidyl]ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int-49). MS obsd. (ESI⁺) [(M+H)⁺]: 595.2 Example 82A and Example 82B 2-hydroxy-N-[(19S)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa- 10,14 15,19 2,7 1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide Example 82A and Example 82B Separation of _{Example 82} by SFC afforded _{Example 82A} (faster eluting, 58.21 mg) and Example 82B (slower eluting, 51.56 mg) with Column: (s, s) DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 um), CO2-ACN/i-PrOH (0.1% NH3H2O): 35%-35%. E_{xample 82A} (faster eluting): MS obsd. (ESI⁺): 595.2 [(M+H)⁺].¹H NMR (400 MHz, DMSO-d₆) δ = 10.04 (br. s, 1H), 7.34 (s, 1H), 6.86 (s, 1H), 6.78 (s, 1H), 5.06 - 4.98 (m, 1 H), 4.88 - 4.76 (m, 1 H), 3.87 - 3.52 (m, 6H), 3.35 - 3.25 (m, 4H), 3.20 - 3.13 (m, 2H), 2.37 (s, 3H) 2.31 (s, 3H), 2.04 - 1.44 (m, 10H), 1.35 - 1.15 (m, 2H). Example 82B: (slower eluting): MS obsd. (ESI⁺): 595.2 [(M+H)⁺].¹H NMR (400 MHz, DMSO-d6) δ = 10.04 (br. s ,1H), 7.34 (s, 1H), 6.86 (s, 1H), 6.78 (s, 1H), 5.06 - 4.98 (m, 1 H), 4.88 - 4.76 (m, 1 H), 3.82 - 3.55 (m, 6H), 3.35 - 3.25 (m, 4H), 3.20 - 3.13 (m, 2H), 2.37 (s, 3H) 2.31 (s, 3H), 2.04- 1.44 (m, 10H), 1.35 - 1.15 (m, 2H). BIOLOGICAL EXAMPLES Example B1 Kif18A motor assay The motor activity of KIF18A was studied using an ADP-Glo assay (promega). This assay determined the potency of compounds in inhibiting KIF18A ATPase in the presence of microtubules (MT). Recombinant human KIF18A (1-355) protein was expressed in E. coli with an N-terminal GST tag. The protein was purified sequentially on a GST Bestarose FF column, a Mono S 10/100 GL column and a Superdex200 gel filtration column. The entire assay was conducted at RT. KIF18A at a concentration of 8nM was pre- incubated with a three-fold dilution of the test compound or DMSO for 15 minutes in an assay buffer consisting of 15mM Tris pH 7.5, 10mM MgCl₂, 0.01% Pluronic F-68, 1μM Taxol, and 50μg/ml microtubules (MT).52μM ATP was added to initiate the enzymatic reaction. At 30 minutes, the ADP-Glo reagent was added to terminate the reaction. Following a 40-minute incubation, the detection reagent (Promega#V913A) was added, and luminescence was measured using a PHERAstar FSX reader (BMG). The percentage of inhibition was calculated using the following formula: % Inhibition = 100 - (Signal compound- Signal positive control) / (Signal vehicle control - Signal positive control) × 100. The positive control represented the group without KIF18A, while the vehicle control was the DMSO group. To determine the effect-dose curve and IC50, a 4-parameter nonlinear regression equation with a variable slope was used, and the analysis was performed using GraphPad Prism 9.0. Table 1: The activities of the compounds of the present invention in Kif18A motor assay Example B2 The anti-proliferation activity of KIF18A was studied using a Cell Titer Glo assay (promega). This assay determined the potency of compounds in inhibiting cell growth. Cell lines were seeded as follows 24 hours before compound treatment: HT-29 (ATCC) 1800 cells/well, 90µl of McCoy’s 5A media supplemented with 10% FBS. Test compounds were added to cells in a 10x dilution scheme by adding 10 µl of serially diluted compound to the plate, and the treated cells were incubated in a 37°C, 5% CO₂ incubator. After 3 days incubation, the media and compounds were refreshed with 90 µl media and 10 µl 10x compounds accordingly, and the treated cells were incubated for additional 3 days in a 37°C, 5% CO2 incubator. The cells were treated for 6 days in total, and cell viability determined via the Promega Cell Titre-Glo® Assay kit. Luminescence units were used to calculate %Inhibition. %Inhibition was calculated for each well as: ([max - min] - [test - min]/[max – min]. EC50 values were calculated from concentration vs. %Inhibition data via a four-parameter variable slope model. Table 2: The activities of the compounds of the present invention in HT29 Cell Titer Glo assay

Claims

CLAIMS 1. A compound of formula (I), wherein each of A1, A2, and A3 is independently selected from N and CR^a, wherein R^a is H, halogen, or C_1-6alkyl; R¹ is selected from H, halogen, cyano, OH, NO₂, CON(R^b1)(R^b2), NR^b1SO₂R^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_1-6alkyl optionally substituted with one, two, or three substituents independently selected from halogen and OH, each of _R ^b1 and _R ^b2 is independently selected from H, C_3-10cycloalkyl, and C_1-6alkyl optionally substituted with one, two, or three substituents independently selected from halogen and OH; L_{1 is selected from CONH, NHCO,} each of B₁, B₂, and B₃ is independently selected from N and CR²; R² is selected from H, halogen, C_1-6aalkyl, and C_1-6aalkoxy; 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 occurs once or twice and is independently selected from H, halogen, and haloC1- ₆alkyl, R^d is H, C_1-6aalkyl, or haloC_1-6aalkyl; L3 is (CH2)q1, (CH2)q2NH, or -(CH2)r-O-(CH2)s-, optionally substituted by R^e, q is 2, 3, 4, 5, or 6, r is 0, 1, or 2, s is 0, 1, or 2, R^e is halogen, C_3-10cycloalkyl or C_1-6alkyl; each of n₁ and n₂ is independently 0 or 1; R³ is absent or selected from halogen, C_1-6aalkyl, and haloC_1-6aalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein A1 is N or CH; A₂ is N or CH; A₃ is N or CR^a, wherein R^a is H, fluoro, or methyl.

3. The compound according to claim 1 or claim 2, wherein each of A₁ and A₂ is CH, A3 is CR^a, wherein R^a is H or methyl.

4. The compound according to any one of claims 1 - 3, wherein R¹ is NR^b1SO₂R^b2 or , R^b1 is H, R^b2 is C_1-6alkyl optionally substituted with OH.

5. The compound according to any one of claims 1 - 4, wherein R¹ is NR^b1SO₂R^b2, R^b1 is H, R^b2 is selected from methyl, ethyl, and hydroxyethyl.

6. The compound according to any one of claims 1 - 5, wherein L_{1 is selected from CONH, NHCO, and a .}

7. The compound according to any one of claims 1 - 6, wherein R² is selected from H, fluoro, methyl, and methoxy.

8. The compound according to any one of claims 1 - 5, wherein B₁ is N or CH, B₂ is N, B3 is N or CR², R² is H or C_1-6aalkyl.

9. The compound according to any one of claims 1 - 8, wherein R² is H or methyl.

10. The compound according to any one of claims 1 - 9, wherein m1 is 1 or 2, m₂ is 0 or 1, R^c occurs once or twice and each R^c is independently selected from H, fluoro, and difluoromethyl, R^d is H, methyl, or difluoroethyl.

11. The compound according to any one of claims 1 - 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 is independently selected from H and halogen.

12. The compound according to any one of claims 1 - 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 is H or fluoro.

13. The compound according to any one of claims 1 - 12, wherein L₃ is (CH2)q1, (CH2)q2NH, or -(CH2)r-O-(CH2)s-, optionally substituted by R^e, q1 is 3, 4, 5, or 6, q₂ is 2, r is 0, s is 2, R^e is fluoro or methyl.

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

16. The compound according to any one of claims 1 - 15, wherein R³ is absent or selected from fluoro, methyl, ethyl, difluoromethyl, and trifluoromethyl.

17. A compound according to claim 1, wherein, each of A₁ and A₂ is CH, A₃ is CR^a, wherein R^a is H or C_1-6aalkyl; R¹ is NR^b1SO2R^b2, R^b1 is H, R^b2 is hydroxyC_1-6aalkyl; L₁ is NHCO, B1 is N or CH; B2 is N; _B3 is N or CR²; R² is H or C_1-6alkyl; L₂ is ^c , ( )_m2 R^c ( )_m1 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 is independently selected from H and halogen; _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; R³ is absent or selected from halogen, C_1-6aalkyl, and haloC_1-6aalkyl. 18. The compound according to claim 17, wherein each of A₁ and A₂ is CH, A3 is CR^a, wherein R^a is H or methyl, _R ¹ is NR^b1SO₂R^b2, R^b1 is H, R^b2 is hydroxyethyl; L1 is NHCO^, B1 is N or CH; B₂ is N; B₃ is N or CR²; R² is H or methyl; L2 is ^c , ( )_m2 R^c ( )_m1 Y is N, Z1 is C(R^c)2, Z₂ is CH, m₁ is 1 or 2, m2 is 0 or 1, R^c is H or fluoro; 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; R³ is absent or selected from fluoro, methyl, ethyl, and difluoromethyl. 19. A compound selected from: 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-(20-fluoro-8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 2-hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide, 15,18 2,6 9,14 N-(10-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 17,20 2,6 7,10 11,16 N-(24-fluoro-1,8,9,10,17,32-hexazahexacyclo[22.2.2.2 .1 .1 .0 ]dotriaconta- 2(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-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 2-hydroxy-N-[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 12-(1,1-dioxo-1,2-thiazolidin-2-yl)-22-fluoro-1,7,15,29- tetrazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa-2(29),3,5,9,11,13-hexaen-8-one, 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 15,18 2,6 9,14 N-[22-(difluoromethyl)-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy-ethanesulfonamide, N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(18S)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(18R)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl]-2- hydroxy-ethanesulfonamide, 2-hydroxy-N-[(19S)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl]-2-hydroxy- ethanesulfonamide, N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,3,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 2-hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29- tetrazapentacyclo[21.2.2.1^10,14.1^15,19.0^2,7]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide, 10,14 15,19 2,7 17,19 N-(18,18-difluoro-8-oxo-1,9,15,29-tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, 10,14 15,19 2,7 2-hydroxy-N-(8-oxo-18-oxa-1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)ethanesulfonamide, N-(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, 15,18 2,6 9,14 N-(22-fluoro-3-methoxy-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)methanesulfonamide, N-(17,17-difluoro-8-oxo-1,9,15,28-tetrazapentacyclo[20.2.2.1^10,14.1^15,18.0^2,7]octacosa- 2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide, N-(18,22-difluoro-8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide, N-(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-(7-oxo-1,8,15,29-tetrazapentacyclo[20.2.2.2^15,18.1^2,6.0^9,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)methanesulfonamide, N-(8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptacosa- 2(7),3,5,10(27),11,13-hexaen-4-yl)ethanesulfonamide, N-(17-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-(21-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-[16-(2,2-difluoroethyl)-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl]ethanesulfonamide, N-(16-methyl-8,15,15-trioxo-15λ⁶-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide, N-(16,21-dimethyl-8,15,15-trioxo-15λ⁶-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 10,14 2,7 2-hydroxy-N-(8-oxo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- 2(7),3,5,10,12,14(27)-hexaen-4-yl)ethanesulfonamide, N-(18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-(23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-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- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, N-(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide, 2-hydroxy-N-[(19S)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, 2-hydroxy-N-[(19R)-18,

18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,

19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

20. A process for the preparation of a compound having the structure of formula (Ia), (Ib), (Ic), or (Id)

comprising one of the following steps: (a) substituent reaction of compound formula III with NH₂SO₂R_b2 in the presence of a base in a solvent provides compound of formula (Ia), wherein Q is fluoro, the base is preferably TEA, DIPEA, K2CO3, or Cs2CO3, the solvent is preferably DMF, DMSO, dioxane or CH3CN; (b) reduction reaction of compound of formula IIb in the presence of a reducing agent in a solvent provides compound of formula (Ib), wherein the reducing agent is preferably LiAlH₄ or LiBH₄, the solvent is preferably DCM or THF; (c) the reaction of compound of formula _IIc with NH2SO2R^b2 in the presence of CuI and MNPMO in organic solvent using inorganic base provides compound of formula (Ic), wherein the organic solvent is preferably DMF or DMSO, the inorganic base is preferably potassium triphosphate; (d) the reaction of compound of formula IId

with NH2SO2R^b2 in the presence of CuI and MNPMO in organic solvent using inorganic base, wherein the organic solvent is preferably DMF or DMSO, the inorganic base is preferably potassium triphosphate; wherein L3, R², R³, R^b2, R^c, R^d, A1, A2, A3, B1, B2, B3, Y, Z1, Z2, n1, n2, m1, m2 are as defined in any one of claims 1 to 18.

21. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, when manufactured according to the process of claim 20.

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

23. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 for use as therapeutically active substance.

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

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

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

27. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 for the preparation of a medicament for the treatment of cancer.

28. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 for the preparation of a medicament for the inhibition of KIF18A.

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

30. The use of according to any one of claim 25 to 28, or the method according to claim 29, 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.