PROTEIN SECRETION INHIBITORS BASED ON TRIAZACYCLODECANSULFONAMIDE ('TCD')

Abstract

Triazacyclododecansulfonamide (“TCD”)-based protein secretion inhibitors, such as Sec61 inhibitors, methods for their preparation, related pharmaceutical compositions, and methods for their use are provided. For example, compounds of formula (1), and pharmaceutically acceptable salts and compositions including them, are provided herein. The compounds described herein may be used, for example, in the treatment of diseases including inflammation and / or cancer.

Description

PROTEIN SECRETION INHIBITORS BASED ON TRIAZACYCLODODECANSULPHONAMIDE (TCD) FIELD OF INVENTION The present description relates to triazacyclododecanesulfonamide (TCD)-based protein secretion inhibitors, including methods for making and using the same. Incorporation by Reference of Electronically Submitted Material This application contains, as a separate part of the description, a sequence listing in machine-readable form (file name: 40056P2 Seqlisting.txt; 20,193 bytes; created February 11, 2019) which is incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Protein translocation into the endoplasmic reticulum (ER) constitutes the first step of protein secretion. The import of ER proteins is essential in all eukaryotic cells and is particularly important in tumor cells of IF-2019-36422718-APN-ANP#INPI Page 1 of 250 rapid growth. Therefore, the protein secretion process may serve as a target for both potential anticancer drugs and bacterial virulence factors. See Kalies and Romisch, Traffic, 16 (10): 1027-1038 (2015). Protein transport to the ER is initiated in the cytosol when N-terminal hydrophobic signal peptides protrude from the ribosome. The binding of the signal recognition particle (SRP) to the signal sequence allows directing the ribosome-nascent chain-SRP complex to the ER membrane where the contact of the SRP with its receptor activates the transfer of the signal peptide to Sec61. Sec61 is an ER membrane protein translocator (also known as translocon) that is donut-shaped with 3 major subunits (heterotrimeric). Includes a stopper, which blocks transport in or out of ER. The plug is displaced when the hydrophobic region of a nascent polypeptide interacts with the seam region of Sec61, allowing translocation of the polypeptide into the ER lumen. In mammals, only short proteins (<160 amino acids) can enter the ER after translation, and proteins shorter than 120 amino acids are required to use this pathway. Part of the translocation competence is maintained by the binding of calmodulin to the signal sequence. Upon reaching the canal IF-2Q19-36422718-APN-ANP#INPI Page 2 of 25Q Sec61, the signal peptide or signal anchor, is sandwiched between transmembrane domains (TMDs) 2 and 7 of Sec61", which form the lateral portion of the gate, allowing the channel to open for soluble secretory proteins. As the Sec61 channel consists of 10 TMDs (Sec61«) surrounded by a hydrophobic clamp formed by Sec61y, the opening of the channel depends on conformational changes involving almost all TMDs. Inhibiting protein transport across the ER membrane has the potential to treat or prevent diseases, such as cancer cell growth and inflammation. Known secretion inhibitors, ranging from broad-spectrum to highly substrate-specific, can interfere with virtually any stage of this multistep process, and even with the transport of endocytic antigens to the cytosol for cross-presentation. These inhibitors interact with the signal peptide, chaperones, or the Sec61 channel to block substrate binding or to prevent conformational changes necessary for protein import into the ER. Examples of protein secretion inhibitors include calmodulin inhibitors (e.g. E6 Berbamine and Ophiobolin A), Lanthanum, sterols, cyclodepsipeptides (e.g. HUN7293, CAM741, NFI028, Cotrainsin, Apratoxin A, Decatransine, Valinomycin), CADA, Micolactonin, IF-2019-36422718-APN-ANP#INPI Page 3 of 250 Eeyarestatin I (ESI), and exotoxin A. However, the above secretion inhibitors have one or more of the following: lack of selectivity for the Sec61 channel, challenging manufacturing due to structural complexity, and limited molecular weight delivery , bioavailability and distribution. Therefore, there is a need for new small molecule inhibitors of protein secretion. BRIEF DESCRIPTION OF THE INVENTION In one aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt of the (I) where: each of Ray Rbes independently H or C1-3 alkyl; R1 is H, OH, C13 alkyl, O-C1-3 alkyl, =CH2, or = NOR5; or R1 is C3-6 cycloalkyl or C3-6 heterocycloalkyl and forms a spiro group with the carbon ring to which it is attached; each of R1a and R1bes independently H or C1-3 alkyl; R2 * *is C1-6 alkyl, IF-2019-36422718-APN-ANI4 / INPI Page 4 of 250 N(R5)2, cycloalkyl C3-8, heterocycloalkyl C3-9, C3-9 heterocycloalkenyl or C6-10 aryl; R3 is H, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C37 heterocycloalkyl, C6-10 aryl or C2-6 heteroaryl; R4 is C3-8 cycloalkyl, C3-9 heterocycloalkyl, C6-10 aryl or C2-9 heteroaryl; each R5 is independently H, C1-3 alkyl or C0-2alkylene C6-10aryl; X is absent, C1-3 alkylene, C=O, or (C=O)O; And it is SO or SO2; each heterocycloalkyl, heterocycloalkenyl and heteroaryl group independently has 1, 2 or 3 ring heteroatoms selected from N, O and S. In some embodiments, each Y is SO. In various embodiments, each Y is SO2. In several cases, Raes H. In some cases, Raes C1-3 alkyl. In some embodiments, Raes CH3. In some embodiments, Rbes H. In various embodiments, Rbes C1-3 alkyl. In several cases, Rbes CH3. In several cases, each of Ray Rbes H. In some cases, R1 is H, OH or =NOR5. In various cases, R5 is each R5 is independently H, C1-3 alkyl or C0-2 alkylene-C6-10 aryl. In some cases, R5 is H or CH3. In some embodiments, R1 is C1-3 alkyl or O-C1-3 alkyl. In various embodiments, R1 is CH3 or OCH3. In some cases, R1 is CH3 and exhibits S stereochemistry. In various embodiments, R1 is C3-6 cycloalkyl or C36 heterocycloalkyl and forms a spiro group with the carbon ring to which it is attached. In some cases, R1 together with the atom of the IF-2019-36422718-APN-ANI5 / INPI Page 5 of 250 ring to which it is attached forms o-i o '—I In several cases, R1 is =CH2. In some cases, each of R1a and R1bes H. In some cases, at least one of R1a and R1bes C1-3 alkyl. In some cases, each of R1a and R1bes CH3. In some embodiments, R2 is C1-6 alkyl or N(R5)2. In various cases, each R5 independently comprises H, C1-3 alkyl or benzyl. In various embodiments, R2 is Et, iPr, N(CH3)2, In some cases, R2 comprises C3-8 cycloalkyl. In several cases, R2 comprises cyclopentyl or cyclohexyl. In some embodiments, R2 is C3-9 heterocycloalkyl or C3-9 heterocycloalkenyl. In various embodiments, R2 comprises oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, azepanyl, morpholinyl or tetrahydropyridinyl. In various embodiments, the C3-9 heterocycloalkyl or C3-9 heterocycloalkenyl comprises a bridge or a spiro group. In some cases, the C3-9 heterocycloalkyl comprising a bridge or a spiro group is selected from the group consisting of, and R6 is C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl. In IF-2019-36422718-APN-ANI6 / INPI Page 6 of 250 In some cases, R6 is phenyl optionally substituted with one to three groups independently selected from halo, C1-3 alkyl, C1-3 alkoxy and CN. In several cases, R2 is selected from the group consisting of, IF-2019-36422718-APN-ANP#INPI Page 7 of 250 IF-2019-36422718-APN-ANI8 / INPI Page 8 of 250 F of IF-2019-3 6422718-A PN-A N1¾ IN PI Page 9 of 250 In several cases, R2 is C6-10 aryl. In some embodiments, R2 is, ,—t__ __ In various embodiments, X is absent. In some embodiments, R3 comprises C1-6 alkyl or H. In some cases, R3 is 2-methylbutyl, isopropyl, isopentyl, CH2CH2OCH3, CH2C(CH3)2CN, CH2CF3 or CH2CH2CF3. In several cases, R3 is isobutyl. In some embodiments, X is C1-3 alkylene. In some cases, X is CH2, CH2CH2, or CH(CH3). In various cases, R3 comprises C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, C6-10 aryl or C2-6 heteroaryl. In some embodiments, R3 comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. In various embodiments, X-R3 is selected from the group consisting of IF-2019-36422718-APN-AT1E0#INPI Page 10 of 250 In some cases, X-R3es, In some cases, X-R3es, In some embodiments, X is C=O or (C=O)O. In various embodiments, R3 comprises C1-6 alkyl or C6-10 aryl. In some cases, X-R3es, In several cases R4 comprises C3-8 cycloalkyl or C3-9 heterocycloalkyl. In some modalities R4 is In various forms, R4 includes IF-2019-36422718-APN-ANP#INPI Page 11 of 250 C6-10 aryl or C2-9 heteroaryl, and R4 is optionally substituted with one to three groups independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C(O)N(Rn)2 and N( Rn)2, and each RN is independently H or C1-3 alkyl. In some embodiments, R4 is selected from the group consisting of In various embodiments, R4 is In some modalities Ra, Rb, R1a and R1b are each H; R1 is =CH2 or CH3; R2es IF-2G19-36422718-APN-ANp#INPI Page 12 of 25G ; R4es N\; and each Y is SO2. In some embodiments, R1 is in an (S) configuration. Also provided herein are compounds listed in Table A, Table B, and pharmaceutically acceptable salts thereof. In some embodiments, there is provided a compound that is selected from the group consisting of: IF-2019-36422718-APN-AT1P#INPI Page 13 of 250 AND IF-2019-36422718-APN-ANP#INPI Page 14 of 250 Herein further provided is a pharmaceutical composition comprising a compound of Formula (I), a compound listed in Table A, a compound listed in Table B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also provided herein is a method of inhibiting protein secretion in a cell comprising contacting the cell with the compound or salt of Formula (I), the compound listed in Table A or a pharmaceutically acceptable salt thereof, a compound listed in Table B or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein in an amount effective to inhibit secretion. In some cases, contacting comprises administering the compound or composition to a subject. Further provided herein is a method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of a compound or salt of Formula (I), a compound listed in Table A or a pharmaceutically acceptable salt thereof, a compound listed in Table B or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein. Also provided herein is a method of treating or preventing cancerous or precancerous conditions in a subject comprising administering to the subject an amount IF-2G19-36422718-APN-ANP#INPI Page 15 of 25G therapeutically effective compound or salt of Formula (I), a compound listed in Table A or a pharmaceutically acceptable drug. salt thereof, a compound listed in Table B or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein. Other aspects and advantages will be apparent to those skilled in the art from a review of the following detailed description, taken in conjunction with the drawings. The following description includes specific embodiments with the understanding that the description is illustrative, and is not intended to limit the invention to the specific embodiments described herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts B16F10 efficacy data for compound A87 compared to an anti-PD-1 therapy. Compound A87 showed superior efficacy with weekly dosing over anti-PD-1 therapy in the refractory model with respect to tumor growth inhibition and percent body weight. Other aspects and advantages will be apparent to those skilled in the art from a review of the following detailed description. Although the compounds and methods described herein are susceptible to embodiments in IF-2G19-36422718-APN-ANP#INPI Page 16 of 25G various forms, the description below includes specific embodiments with the understanding that the description is illustrative, and is not intended to limit the invention to the specific embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION Compounds that inhibit protein secretion are provided here. The compounds described here can be used to treat or prevent diseases associated with excessive protein secretion, such as inflammation and cancer, improving the quality of life of affected individuals. The compounds described here have a structure of Formula (I) (I) wherein the substituents are described in detail below. Without being limited by any particular theory, the compounds described herein inhibit protein secretion by binding and disabling components of the translocon, including but not limited to ΙΡ-2019-36422718-ΑΡΝ-ΑΤ1Ε7#ΙΝΡΙ Page 17 of 250 to Sec61, and in some cases, they disrupt interactions in a sequence-specific manner between the nascents. signaling sequence proteins translated with translocon components including, but not limited to, Sec61. The compounds described here can bind specifically to the signal sequence with little or no interaction with the translocon itself. The compounds described here can advantageously inhibit TNFα secretion with an IC50 of up to 5 μΜ, or up to 3 μΜ, or up to 1 μΜ. In various cases, the compounds described herein can inhibit IL-2 secretion with an IC50 of up to 5 μΜ, or up to 3 μΜ, or up to 1 μΜ. In some cases, the compounds described herein can inhibit PD-1 secretion with an IC50 of up to 5 μΜ, or up to 3 μΜ, or up to 1 μΜ. The compounds described here are effective in reducing tumor growth and body weight. For example, compound A87 showed superior efficacy in reducing tumor growth with weekly dosing in a refractory model compared to anti-PD-1 therapy. See the Examples section and Figure 1. Chemical definitions As used herein, the term alkyl refers to straight-chain and branched-chain saturated hydrocarbon groups containing from one to thirty atoms of IF-2019-36422718-APN-ANP#INPI Page 18 of 250 carbon, for example, one to twenty carbon atoms, or one to ten carbon atoms. The term Cn means that the alkyl group has n carbon atoms. For example, C4 alkyl refers to an alkyl group having 4 carbon atoms. C1-7 alkyl refers to an alkyl group having a number of carbon atoms spanning the entire range (i.e., 1 to 7 carbon atoms), as well as all subgroups (e.g., 1-6, 2-7, 1-5, 3-6, 1, 2, 3, 4, 5, 6 and 7 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2methylpropyl), t-butyl (1,1-dimethylethyl), 3,3dimethylpentyl and 2-ethylhexyl. Unless otherwise indicated, an alkyl group may be an unsubstituted alkyl group or a substituted alkyl group. As used herein, the term alkylene refers to a bivalent saturated aliphatic radical. The term Cn means that the alkylene group has n carbon atoms. For example, C1-6 alkylene refers to an alkylene group having a number of carbon atoms spanning the entire range, as well as all subgroups, as described above for alkyl groups. As used herein, the term alkenyl is defined identically to alkyl, except that it contains at least one carbon-carbon double bond, and that it has IF-2019-36422718-APN-ANP#INPI Page 19 of 250 two to thirty carbon atoms, for example, two to twenty carbon atoms, or two to ten carbon atoms. The term Cn means that the alkenyl group has n carbon atoms. For example, C4 alkenyl refers to an alkenyl group having 4 carbon atoms. C2-7 alkenyl refers to an alkenyl group having a number of carbon atoms spanning the entire range (i.e., 2 to 7 carbon atoms), as well as all subgroups (e.g., 2-6, 2-5, 3-6, 2, 3, 4, 5, 6 and 7 carbon atoms). Alkenyl groups specifically contemplated include ethenyl, 1-propenyl, 2-propenyl and butenyl. Unless otherwise indicated, an alkenyl group may be an unsubstituted alkenyl group or a substituted alkenyl group. As used herein, the term cycloalkyl refers to an aliphatic cyclic hydrocarbon. The term Cn means that the cycloalkyl group has n carbon atoms. For example, C5 cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring. C5-8 cycloalkyl refers to cycloalkyl groups having a number of carbon atoms spanning the entire range (i.e., 5 to 8 carbon atoms), as well as all subgroups (e.g., 5-6, 6-8, 7-8, 5-7, 5, 6, 7 and 8 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and IF-2G19-36422718-APN-ANP#INPI Page 2G of 25G cyclooctyl. Unless otherwise indicated, a cycloalkyl group may be an unsubstituted cycloalkyl group or a substituted cycloalkyl group. As used herein, the term cycloalkenyl is defined similarly to cycloalkyl, except that it contains at least one carbon-carbon double bond, but is not aromatic. The term Cn means that the cycloalkenyl group has n carbon atoms. For example, C5 cycloalkenyl refers to a cycloalkenyl group having 5 carbon atoms in the ring. C5-8 cycloalkenyl refers to cycloalkenyl groups having a number of carbon atoms spanning the entire range (i.e., 5 to 8 carbon atoms), as well as all subgroups (e.g., 5-6, 6-8, 7-8, 5-7, 5, 6, 7 and 8 carbon atoms). Non-limiting examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise indicated, a cycloalkenyl group may be an unsubstituted cycloalkenyl group or a substituted cycloalkenyl group. As used herein, the term heterocycloalkyl is defined similarly to cycloalkyl, except that the ring contains one to three heteroatoms independently selected from oxygen, nitrogen, or sulfur. Non-limiting examples of heterocycloalkyl groups include piperdine, tetrahydrofuran, tetrahydropyran, IF-2019-36422718-APN-AT2]1#INPI Page 21 of 250 dihydrofuran, morpholine, oxazepanil and the like. The cycloalkyl and heterocycloalkyl groups may be saturated or partially unsaturated ring systems optionally substituted with, for example, one to three groups, independently selected alkyl, alkyleneOH, C(O)NH2, NH2, oxo (=O), aryl, haloalkyl, halo , and OH. The heterocycloalkyl groups may optionally be additionally N-substituted as described herein. As used herein, the term aryl refers to monocyclic or polycyclic carbocyclic aromatic ring systems (e.g., fused bicyclic and fused tricyclic). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, indenyl, anthracenyl, fluorenyl, tetralinyl. Unless otherwise indicated, an aryl group may be an unsubstituted aryl group or a substituted aryl group. As used herein, the term heteroaryl refers to monocyclic or polycyclic aromatic ring systems (e.g., fused bicyclic and fused tricyclic), wherein one to four ring atoms are selected from oxygen, nitrogen or sulfur, and the atoms of the remaining ring are carbon, said ring system is linked to the rest of the molecule by any of the ring atoms. Non-limiting examples of groups IF-2019-36422718-APN-ANp#INPI Page 22 of 250 heteroaryl include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thienyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl , benzofuranyl, benzothiazolyl, triazinyl, triazolyl, purinyl, pyrazinyl, purinyl, indolinyl, phthalzinyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyridopyridinyl, indolyl, 3H-indolyl, pteridinyl, and quinooxalinyl. Unless otherwise indicated, a heteroaryl group may be an unsubstituted heteroaryl group or a substituted heteroaryl group. As used herein, the term hydroxy or hydroxyl as used herein refers to the -OH group. As used herein, the term alkoxy or alkoxyl refers to an -O-alkyl group. As used herein, the term halo is defined as fluorine, chlorine, bromine, and iodine. As used herein, the term carboxy or carboxyl refers to a -COOH group. As used herein, the term amino refers to a -NH2 or -NH- group, wherein any hydrogen can be replaced with an alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group. As used herein, the term sulfonyl is IF-2019-36422718-APN-AN2P#INPI Page 23 of 250 refers to a group O Hi o A substituted functional group (e.g., a substituted alkyl, alkylenyl, cycloalkyl, aryl, or heteroaryl) is a functional group that has at least one hydrogen radical that is substituted with a non-hydrogen radical (i.e., a substituent). Examples of non-hydrogen radicals (or substituents) include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, ether, aryl, heteroaryl, heterocycloalkyl, hydroxyl, oxy (or oxo), alkoxy, ester, thioester, acyl, carboxyl, cyano, nitro, amino, sulfhydryl and halo. When a substituted alkyl group includes more than one non-hydrogen radical, the substituents may be attached to the same carbon or two or more different carbon atoms. Protein secretion inhibitors In one aspect, the compounds of the disclosure have a structure of Formula (I), or a pharmaceutically acceptable salt thereof: where: IF-2019-36422718-APN-AN2P#INPI Page 24 of 250 each of Ray Rbes independently H or C1-3 alkyl; R1 is H, OH, C1-3 alkyl, O-C1-3 alkyl, =CH2, or =NOR5; or R1 is C3-6 cycloalkyl or C3-6 heterocycloalkyl and forms a spiro group with the carbon ring to which it is attached; each of R1a and R1bes independently H or C1-3 alkyl; R2 is C1-6 alkyl, N(R5)2, C3-8 cycloalkyl, C3-9 heterocycloalkyl, C3-9 heterocycloalkenyl or Cg10 aryl; R3 is H, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-7 heterocycloalkyl, C6-10 aryl or C2-6 heteroaryl; R4 is C3-8 cycloalkyl, C3-9 heterocycloalkyl, C6-10 aryl or C2-9 heteroaryl; each R5 is independently H, C1-3 alkyl or C0-2 alkylene-C6-10 aryl; X is absent, C1-3 alkylene, C=O, or (C=O)O; And it is SO or SO2; each heterocycloalkyl, heterocycloalkenyl and heteroaryl group independently has 1, 2 or 3 ring heteroatoms selected from N, O and S. In some embodiments, each Y is SO. In various embodiments, each Y is SO2. In several cases, Raes H. In some cases, Raes IF-2019-36422718-APN-ANp#INPI Page 25 of 250 C1-3 alkyl. In some embodiments, Raes CH3. In some embodiments, Rbes H. In various embodiments, Rbes C1-3 alkyl. In several cases, Rbes CH3. In some cases, both Racomo Rbson H. In some cases, R1 is H, OH or =NOR5. In several cases, R5 is H or CH3. Therefore, suitable R1 groups may include H, OH, =NOH and =NORCH3. In some embodiments, R1 is C1-3 alkyl or O-C1-3 alkyl. For example, R1 can be CH3 or OCH3. In some cases, R1 is CH3 and exhibits S stereochemistry. In various embodiments, R1 is C3-6 cycloalkyl or C3-6 heterocycloalkyl and forms a spiro group with the carbon ring to which it is attached. Suitable R1 spiro groups may include. In several cases, R1 is =CH2. In some embodiments, each of R1a and R1bes H. In some embodiments, at least one of R1a and R1bes C1-3 alkyl. In some embodiments, each of R1a and R1bes CH3. In some embodiments, Raes H, Rbes H, and R1 is CH3. In various embodiments, Raes CH3, Rbes H and R1es H. In some cases, Raes H, Rbes CH3 and R1es H. In several cases, Raes CH3, Rbes H and R1es CH3. In some embodiments, Raes H, Rbes CH3 and R1es CH3. In various embodiments, Raes CH3, Rbes CH3 and R1es H. In some embodiments, R2 is C1-6 alkyl or N(R5)2. In some cases, each R5 comprises IF-2019-36422718-APN-AN2P#INPI Page 26 of 250 independently H, C1-3 alkyl or benzyl. Suitable R2 groups may include Et, iPr, N(CH3)2 In some cases, R2 comprises C3-8 cycloalkyl. In several cases, R2 comprises cyclopentyl or cyclohexyl. In some embodiments, R2 is C3-9 heterocycloalkyl or C3-9 heterocycloalkenyl. In various embodiments, R2 comprises oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, azepanyl, morpholinyl or tetrahydropyridinyl. In various embodiments, the C3-9 heterocycloalkyl or C3-9 heterocycloalkenyl comprises a bridge or a spiro group. In some cases, the C3-9 heterocycloalkyl comprising a bridge or a spiro group is selected from the group consisting of, and R6 is C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl. In some cases, R6 is phenyl optionally substituted with one to three groups independently selected from halo, C1-3 alkyl, C1-3 alkoxy and CN. Examples of suitable R2 groups include IF-2019-36422718-APN-AN2P#INPI Page 27 of 250 OH IF-2019-36422718-APN-AN2P#INPI Page 28 of 250 IF-2019-36422718-APN-ANi%INPI Page 29 of 250 In some cases, R2 is selected from the group consisting of IF-2Q19-36422718-APN-ANfP#INPI Page 3Q of 25Q In several cases, R2 is C6-10 aryl. In some embodiments, R2 is i / =\ / =\ / =\ i ; ; or K ?-omb , , or . . In various embodiments, X is absent. In some embodiments, R3 comprises C1-6 alkyl or H. In some cases, R3 is C1-6 alkyl, such as methyl, ethyl, propyl, butyl, pentyl or hexyl. In some cases, R3 is 2methylbutyl, isopropyl, isopentyl, CH2CH2OCH3, CH2C(CH3)2CN, CH2CF3 or CH2CH2CF3. In several cases, R3 is isobutyl. In some embodiments, X is C1-3 alkylene. In some cases, X is CH2, CH2CH2, or CH(CH3). In various cases, R3 comprises C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, C6-10 aryl or C2-6 heteroaryl. In some embodiments, R3 comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. Examples of suitable X-R3 include IF-2019-36422718-APN-ANP#INPI Page 31 of 250 In some cases, X-R3es In some cases, X-R3es In some modalities, X is C=O or (C=O)O. In various modalities, R3 comprises C1-6 alkyl or C6-10 aryl. In some cases, X-R3es IF-2019-36422718-APN-AN3P#INPI Page 32 of 250 In various cases, R4 comprises C3-8 cycloalkyl or C3-9 heterocycloalkyl, such as In various embodiments, R4 comprises C6-10 aryl or C2-9 heteroaryl, and R4 is optionally substituted with one to three groups independently selected from halo, C13 alkyl, C1-3 alkoxy, C(O)N(RN)2 and N(RN). )2, and each RNis independently H or C1-3 alkyl. In some embodiments, R4 is selected from the group consisting of In some embodiments, Ra, Rb, R1 and R1b are each H, R1 is =CH2 or CH3; R2es IF-2G19-36422718-APN-ANp#INPI Page 33 of 25G in one or configuration (S) . In some cases, compounds comprising a structure and R3 is cyclobutyl, cyclopentyl or cyclohexyl. Examples of compounds of Formula (I) are shown in Table A, as compounds A1-A210 or a pharmaceutically acceptable salt thereof. In some cases, the compound is a compound of A1-A151, or a pharmaceutically acceptable salt thereof. IF-2Q19-36422718-APN-AN34 / INPI Page 34 of 25Q TABLE A IF-2Q19-36422718-APN-ANfP#INPI Page 35 of 25Q IF-2019-36422718-APN-ANfP#INPI Page 36 of 250 IF-2Q19-36422718-APN-ANfP#INPI Page 37 of 25Q IF-2019-36422718-APN-ANfP#INPI Page 38 of 250 IF-2O19-36422718-APN-ANP#INPI Page 39 of 250 IF-2019-36422718-APN-AT4I0 / INPI Page 40 of 250 A64 A65 IF-2019-36422718-APN-ANP#INPI Page 41 of 250 IF-2019-36422718-APN-ANp#INPI Page 42 of 250 A89 A90 A91 A92 A93 IF-2O19-36422718-APN-ANP#INPI Page 43 of 250 A94 a 0 o=s=o ,QjO 1I'° A95 g' Ó N O=S=O by-0 1 A96 F Φ 0 N o=s=o ,0X1 xv £ J θ 1 A97 Ιέ? o=s=o b2-° XjA Χ'Ν / χ / ' 1 A98 qr ci 1 o=s=o .001 ríJ 1 A99 ci N O=S=O rw Γ J 0 A100 / —z bv \ 0 P 0 / ζ^3ζ^ζνΧχΓ M b A101 2 N O=S=O ,QJ9 XX Γ J 0 A102 F 0 o=s=o bio r7V Γ J 0 A103 \ . > · r\ ,0 O X--- / AD' 0 IF-2O19-36422718-APN-ANP#INPI Page 44 of 250 IF-2Q19-36422718-APN-AT4I5#INPI Page 45 of 25Q IF-2Q19-36422718-APN-AT'4P#INPI Page 46 of 25Q A123 A124 IF-2019-36422718-APN-ANp#INPI Page 47 of 250 IF-2O19-36422718-APN-ANP#INPI Page 48 of 250 IF-2O19-36422718-APN-ANP#INPI Page 49 of 250 IF-2Q19-36422718-APN-AN5I0 / INPI Page 5Q of 25Q IF-2019-36422718-APN-AN5PÍ#INPI Page 51 of 250 IF-2019-36422718-APN-AN5I2 / INPI Page 52 of 250 IF-2019-36422718-APN-AT5l3 / INPI Page 53 of 250 A200 IF-2G19-36422718-APN-AblP#INPI Page 54 of 25G In some embodiments, the compounds of the description include IF-2G19-36422718-APN-AN5E5 / INPI Page 55 of 25G or a pharmaceutically acceptable salt thereof. Additional compounds of the disclosure are shown in Table B as compounds B1-B22, or a pharmaceutically acceptable salt thereof. In some cases, the compound is a B1-B20 compound, or a pharmaceutically acceptable salt thereof. IF-2019-36422718-APN-AN5P#INPI Page 56 of 250 TABLE B IF-2019-36422718-APN-AN5l7#INPI Page 57 of 250 IF-2019-36422718-APN-AT'5P#INPI Page 58 of 250 Chemical structures that have one or more stereocenters represented with dashed bonds and in bold (i.e., and — ) are intended to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure. Links symbolized by a single line do not indicate a stereo preference. Unless otherwise indicated, chemical structures that include one or more stereocenters that are illustrated here without indicating absolute or relative stereochemistry, encompass all possible stereoisomeric forms of the compound (e.g., diastereoisomers, enantiomers) and mixtures thereof. Structures with a single bold or dashed line, and at least one additional single line, encompass a single enantiomeric series of all possible diastereoisomers. Synthesis of protein secretion inhibitors The compounds provided herein can be synthesized using conventional techniques from readily available starting materials known to those skilled in the art. In general, the compounds provided here are conveniently obtained through standard organic chemistry synthesis methods. IF-2019-3 6422718-A PN-A NPfe IN PI Page 59 of 250 Synthesis of final compounds In some cases, the compounds described herein can be synthesized by reacting a sulfonyl chloride having a desired R2 group with propane-1,3diamine, and reacting the resulting product with an aldehyde having a desired R3 group to form N-substituted propyl amine compound. . A propyl amino group can be introduced into the N-substituted propylamine at the R4 position by reaction with 2-(3bromopropyl)isoindoline-1,3-dione followed by hydrazine, and a desired R4 group can be coupled to the compound by reacting the compound with a sulfonyl chloride functionalized with the desired R4 group. Finally, the compound can be cyclized through a cyclizing agent having a desired R1 group, such as 3-chloro-2chloromethyl-1-propene, 2-methylpropane-1,3-diyl diethanesulfonate, cyclopropane-1,1diylbis(methylene) diethanesulfonate, 1,3-dichloropropane or 1,4-dichlorobutane. In some embodiments, compounds having a methylene group in R1 can be synthesized by coupling a (3-aminopropyl)propane-1,3-diamine group derivatized with the desired R3 and R4 groups with a desired R2-sulfamoyl chloride or R2-sulfamoyl chloride group. sulfanyl, and then reacting the resulting compound with 3-chloro-2chloromethyl-1-propene to form the compound IF-2Q19-36422718-APN-ANP#INPI Page 6Q of 25Q dried triazacyclododecansulfonamide, as exemplified in Route 1 in the Examples section. In various embodiments, compounds having a methylene group in R1 can be synthesized by coupling protected butane-1,3-diamine with an aldehyde having a desired R3 group to form a 3-(azaneyl)-Nbutan-1-amine, reacting the group amino at the R2 position with a chloro group functionalized with a desired R2 group, introducing a propylamino group into 3(azaneyl)-N-butan-1-amine at the R4 position through reaction with 2-(3-bromopropyl)isoindoline- 1,3-dione followed by hydrazine, reacting the resulting amino group at the R4 position with a chloro group functionalized with a desired R4 group, and then reacting the resulting compound with 3-chloro-2-chloromethyl-1-propene to form the compound of desired triazacyclododecansulfonamide, as exemplified in Route 2 in the Examples section. In some cases, compounds having a spiro group on R1 can be synthesized by reacting an N-(3-(azaneyl)propyl)propane-1,3-diamino derivative group with the desired R2, R3, and R4 groups with 1,1diylbis(methylene). )diethanesulfonate derived with the desired spiro group, as exemplified in Routes 3, 8 and 9 in the Examples section. In several cases, the compounds provided here can be synthesized by reducing a benzyl group at R2 IF-2019-36422718-APN-AF6PÍ#INPI Page 61 of 250 in N-(3-(azaneyl)propyl)propane-1,3-diamino functionalized with the desired R3 and R4 groups, and then reacting the resulting product with a desired aldehyde derived with a desired R2 group (e.g., dimethylcyclohexyl) , as exemplified in Route 4 in the Examples section. In some embodiments, compounds having a carboxylate group at R2 can be prepared by reacting a triazacyclododensulfonyl group derived with the desired R1, R3 and R4 groups with a desired alkyl group and triphosgene under basic conditions, as illustrated in Route 5 in Section Examples. In various embodiments, compounds having a piperidinyl group at R2 can be prepared by reacting with DBU / mercaptoethanol, a triazacyclododenesulfonyl compound having the desired R1, R3, and R4 groups and functionalized at R2 with a nitrophenyl group, and then joining the resulting product with chloride. piperidinyl sulfonyl, as exemplified in Route 6 in the Examples section. In some embodiments, compounds having a hydrogen group on R1 can be synthesized by coupling N(3-(azaneyl)propyl)propane-1,3-diamino functionalized with the desired R2, R3, and R4 groups with 1,3-dichloropropane or 1,4 -dichlorobutane, as exemplified in routes 7 and 17 in the examples section. In some cases, compounds that have a IF-2O19-36422718-APN-ANP#INPI Page 62 of 250 chlorophenylmethanone group in R2 can be synthesized by reacting triazacyclododenesulfonyl functionalized with the desired R1, R3, and R4 groups with 4-chlorobenzoyl chloride under basic conditions, as exemplified in Route 10 in the Examples Section. In several cases, compounds having a 4-(dimethylamino)-2-methylbenzyl group on R4 and a spiro group on R1 can be prepared by reacting a functionalized N-(3-(azaneyl)propyl)propane-1,3-diamino compound. with the desired R2 and R3 groups with 4-(dimethylamino)-2-methylbenzenesulfonyl chloride, and then cyclizing the compound by coupling with 1,1diylbis(methylene)diethanesulfonate derivative with the desired spiro group using methods described above herein, as exemplified in the Route 11 in the Examples section. In some embodiments, the compounds described herein can be prepared by reacting a sulfonyl chloride having a desired R2 group with propane-1,3diamine, and reacting the resulting product with an aldehyde having a desired R3 group to form a 3-( azaneyl)-N-butan-1-amine. A propyl amino group can be introduced into 3-(azaneyl)-N-butan1-amine at the R4 position through reaction with 2-(3bromopropyl)isoindoline-1,3-dione followed by hydrazine, and the R4 group can be attach to the compound by making IF-2O19-36422718-APN-ANP#INPI Page 63 of 250 react the compound with the desired sulfonyl chloride (for example, 4-(dimethylamino)-2methylbenzenesulfonyl chloride). Finally, the compound can be cyclized through an appropriate cyclizing agent, such as 3-chloro-2-chloromethyl-1-propene, 2-methylpropane-1,3diyl diethanesulfonate, cyclopropane-1,1diylbis(methylene)diethanesulfonate, 1 ,3-dichloropropane or 1,4-dichlorobutane, as previously described herein, as exemplified in Route 12 in the Examples section. In various embodiments, compounds having a 4-phenylpiperidinyl-1-yl-sulfonyl group at R2 can be synthesized by reacting a triazacyclododenesulfonyl group functionalized with the desired R1, R3, and R4 groups with 3-methyl-1-((4-phenylpiperidin-1yl )sulfonyl)-1H-imidazole-3-ium trifluoromethanesulfonate, as exemplified in Route 14 in the Examples section. In some cases, compounds having a 4-phenylpiperidinyl-1-ylsulfonyl group on R2 can be synthesized by reacting functionalized N-(3(azaneyl)propyl)propane-1,3-diamino with the desired 3-methyl groups R3 and R4. -1-((4-phenylpiperidin-1yl)sulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate, and then cyclizing the compound with an appropriate cyclizing agent, such as 2-methylpropane-1,3-diyl IF-2Q19-36422718-APN-ANP4#INPI Page 64 of 25Q diethanesulfonate, 3-chloro-2-chloromethyl-1-propene, cyclopropane-1,1-diylbis(methylene)diethanesulfonate, 1,3-dichloropropane or 1,4-dichlorobutane, as previously described herein, as exemplified by Route 15 in the examples. Analogous compounds having a methyl group adjacent to the R4 nitrogen can be similarly synthesized using 3-chloro-2-(chloromethyl)prop-1ene, as exemplified in Route 18 in the Examples section. In some cases, compounds having an alcohol group for R1 can be synthesized by cyclization of a protected N-(3-(azaneyl)propyl)propane-1,3diamino compound with 1,3-dichloropropan-2-ol under basic conditions. , as exemplified by Route 19 in the Examples section. The alcohol group in R1 can be methylated by reaction with MeI and NaH in toluene, as exemplified in Route 21 in the examples section. The alcohol group in R1 can be oxidized to a carbonyl by reaction with Dess-Martin periodinane, as exemplified in Route 22 in the examples section. The carbonyl group in R1 can be reacted with hydroxylamine hydrochloride to form the oxime compound, as exemplified in Route 25 in the Examples section. In several cases, compounds that have an S-methyl group at R1 can be synthesized by reacting a functionalized amino group with an R2 group. IF-2019-36422718-APN-AF6f5 / INPI Page 65 of 250 desired with 2,3-dimethyl-1-((2-methyl-1H-imidazol-1yl)sulfonyl)-1H-imidazol-3-io trifluoromethanesulfonate, followed by CF3SO3Me, to form 2,3-dimethyl-1H-imidazol-3-io trifluoromethanesulfonate functionalized with a desired R2 group. The product can be reacted with (R)-N(3-amino-2-methylpropyl) functionalized with a desired R4 group to form (S)-N,N'-(2-methylpropane-1,3-diamino functionalized with the desired R2 and R4 groups. The resulting product can then be reacted with (azanediyl)bis(propane-3,1-diyl)dimethanesulfonate functionalized with a desired R3 group to result in the desired compound, as illustrated in Route 27 in the Examples section. . Synthesis of the intermediates The intermediates used to prepare the compounds described herein may also be prepared by standard methods known to those skilled in the art, as described in the Examples section below (e.g., Route 13, Route 16, Route 20, Route 24, Route 26, Route 28, Route 30, Route 31, Route 32, Route 33). Methods of use The compounds described herein (for example, the compounds of Formula (I), the compounds listed in Tables A and B, and the pharmaceutically acceptable salts of IF-2G19-36422718-APN-ANP#INPI Page 66 of 25G the above) can inhibit protein secretion of a protein of interest. The compounds described here may interfere with a cell's Sec61 protein secretion machinery. In some cases, a compound as described herein inhibits the secretion of one or more of TNFw, VCAM, PRL, IL-2, INFg, CD4, insulin and PD-1 (mouse and / or human), or each of TNFw , VCAM, PRL, IL-2, INFg, CD4, insulin and PD-1 (mouse and / or human). In some cases, a compound as described herein may inhibit the secretion of a checkpoint protein, or inhibit the secretion of a cell surface protein, an endoplasmic reticulum-associated protein, or a secreted protein involved in the regulation of antitumor immune responses. In various cases, a compound described herein can inhibit the secretion of one or more of PD-1, PD-L1, TIM-1, LAG-3, CTLA4, BTLA, OX-40, B7H1, B7H4, CD137, CD47, CD96 , CD73, CD40, VISTA, TIGIT, LAIR1, CD160, 2B4, TGFRp and combinations thereof. Protein secretion activity can be evaluated in the manner described in the examples section below. As used herein, the term inhibitor is intended to describe a compound that blocks or reduces the activity of a drug target (for example, a compound that inhibits Sec61 function in the protein secretion pathway). An inhibitor can act with competitive, decompetitive or non-competitive inhibition. an inhibitor IF-2019-36422718-APN-ANP#INPI Page 67 of 250 can bind reversibly or irreversibly, and therefore the term includes compounds that are suicidal substrates of a protein or enzyme. An inhibitor may modify one or more sites in or near the active site of the protein, or may cause a conformational change in another part of the enzyme. The term inhibitor is used more broadly here than in the scientific literature to also encompass other classes of pharmacologically or therapeutically useful agents, such as agonists, antagonists, stimulants, cofactors and the like. Therefore, methods are provided here to inhibit protein secretion in a cell. In these methods, a cell is contacted with a compound described herein (for example, a compound of Formula (I) or a compound listed in Table A or B, and pharmaceutically acceptable salts of the above), or a formulation pharmaceutical thereof, in an amount effective to inhibit the secretion of the protein of interest. In some embodiments, the cell is contacted in vitro. In various embodiments, the cell is contacted in vivo. In various embodiments, contacting includes administering the compound or pharmaceutical formulation to a subject. The biological consequences of Sec61 inhibition are numerous. For example, inhibition of Sec61 has been suggested for the treatment or prevention of IF-2019-36422718-APN-ANP#INPI Page 68 of 250 inflammation and / or cancer in a subject. Therefore, pharmaceutical formulations for specific Sec61 compounds provide a means of administering a drug to a subject and treating these conditions. As used herein, the terms treat, treating, treatment and similar terms refer to eliminating, reducing or improving a disease or condition, and / or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require that the disease, condition or symptoms associated with it be completely eliminated. As used herein, the terms treat, treating, treatment and the like may include prophylactic treatment, which refers to reducing the likelihood of developing a disease or condition, or of a recurrence of a previously controlled disease. or condition, in a subject who does not have, but is at risk or susceptible to developing a disease or condition or a recurrence thereof. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound of the invention to an individual in need of such treatment. In the sense of the invention, treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and / or dysfunctions. Treatment may be symptomatically oriented, for example to suppress symptoms. IF-2Q19-36422718-APN-AF6I%INPI Page 69 of 25Q It can be carried out for a short period, oriented towards the medium term or it can be a long-term treatment, for example, in the context of maintenance therapy. As used herein, the terms prevent, preventing, prevention are recognized in the art, and when used in relation to a condition, such as a local recurrence (for example, pain), a disease such as cancer, the complex of syndrome, such as heart failure or any other medical condition, is well understood in the art and includes the administration of a composition that reduces the frequency or delays the appearance of symptoms of a medical condition in a subject relative to a subject who does not receives the composition. Therefore, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths. in a treated population versus an untreated control population, for example, by a statistically and / or clinically significant amount. Prevention of an infection includes, for example, reducing the number of diagnoses of infection in a treated population versus an untreated control population, and / or delaying the onset of symptoms of infection in a treated population versus a control population. IF-2Q19-36422718-APN-AT7I0 / INPI Page 7Q of 25Q untreated control. Pain prevention includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population compared to an untreated control population. As used here, the terms patient and subject can be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals), and humans. The particular patients are mammals (eg, humans). The term patient includes men and women. Inhibition of Sec61-mediated secretion of inflammatory proteins (e.g., TNFw) can disrupt inflammatory signaling. Therefore, provided herein is a method of treating inflammation in a subject by administering to the subject a therapeutically effective amount of a compound described herein (i.e., a compound of Formula (I) or a compound listed in Table A or B, or a pharmaceutically acceptable salt of the above). Furthermore, the viability of cancer cells relies on increased secretion of proteins in the ER for survival. Therefore, nonselective or partially selective inhibition of Sec61-mediated protein secretion may inhibit tumor growth. Alternatively, in the context of IF-2019-36422718-APN-AT7]1#INPI Page 71 of 250 immunological oncology, inhibitors of the selective secretion of known secreted or transmembrane immune checkpoint proteins (e.g., PD-1, TIM-3, LAG3, etc.) can cause activation of the immune system against several cancers. Accordingly, also provided herein is a method of treating cancer in a subject by administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I), a compound listed in Table A or B, or a pharmaceutically acceptable salt of the above). Specifically contemplated cancers that can be treated using the compounds and compositions described herein include, but are not limited to, melanoma, multiple myeloma, prostate, lung, non-small cell lung carcinoma, squamous cell carcinoma, leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, lymphoma, NPM / ALK-transformed anaplastic large cell lymphoma, diffuse large B-cell lymphoma, neuroendocrine tumors, breast, mantle cell lymphoma, renal cell carcinoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer , small cell carcinoma, adenocarcinoma, gastric carcinoma, hepatocellular carcinoma, pancreatic cancer, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, head and neck cancer, bladder cancer IF-2019-36422718-APN-AT7]2 / INPI Page 72 of 250 colorectal. In some cases, the cancer is a solid tumor. In several cases, the cancer is head and neck cancer, squamous cell carcinoma, gastric carcinoma, or pancreatic cancer. The compounds described herein are also contemplated for use in the prevention and / or treatment of a multitude of diseases including, but not limited to, proliferative diseases, neurotoxic / degenerative diseases, ischemic conditions, autoimmune and autoinflammatory disorders, inflammation, diseases related to the immune system, HIV, cancers, organ graft rejection, septic shock, viral and parasitic infections, conditions associated with acidosis, macular degeneration, lung conditions, muscle wasting diseases, fibrotic diseases, bone growth diseases and the hair. Examples of proliferative diseases or conditions include diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart, scleroderma, radiation-induced fibrosis, and pulmonary fibrosis (idiopathic pulmonary fibrosis, collagen vascular disorder, sarcoidosis). , interstitial lung diseases and extrinsic lung disorders). IF-2Q19-36422718-APN-AT7]3#INPI Page 73 of 25Q Inflammatory diseases include acute (e.g., Bronchitis, conjunctivitis, myocarditis, pancreatitis) and chronic (e.g., chronic cholecstitis, bronchiectasis, aortic valve stenosis, restenosis, psoriasis, and arthritis) diseases, along with conditions associated with inflammation such as fibrosis, infection and ischemia. Immunodeficiency disorders occur when a part of the immune system does not work properly or is not present. They may affect B cells, T cells, or phagocytes and be inherited (e.g., IgA deficiency, severe combined immunodeficiency (SCID), thymic dysplasia, and chronic granulomatous) or acquired (e.g., acquired immunodeficiency syndrome (AIDS), human immunodeficiency (HIV) and drug-induced immunodeficiencies). Conditions related to the immune system include allergic disorders, such as allergies, asthma, and atopic dermatitis such as eczema. Other examples of such immune-related conditions include lupus, rheumatoid arthritis, scleroderma, ankylosing spondylitis, dermatomyositis, psoriasis, multiple sclerosis, and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease). . Tissue / organ graft rejection occurs when the immune system mistakenly attacks the IF-2019-36422718-APN-AT7I4 / INPI Page 74 of 250 cells that are introduced into the host's body. Graft versus host disease (GVHD), as a result of allogeneic transplantation, arises when T cells from the donor tissue go on the offensive and attack the host tissues. In all three circumstances, autoimmune disease, transplant rejection and GVHD, modulation of the immune system by treating the subject with a compound or composition of the disclosure could be beneficial. Also provided herein is a method of treating an autoimmune disease in a patient comprising administering a therapeutically effective amount of the compound described herein. An autoimmune disease as used herein is a disease or disorder that arises from and is directed against the tissues of an individual. Examples of autoimmune diseases include, but are not limited to, inflammatory responses such as inflammatory skin diseases including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); respiratory distress syndrome (including adult respiratory distress syndrome (ARDS)); dermatitis; meningitis; encephalitis; uveitis colitis; glomerulonephritis; allergic conditions such as eczema and asthma and others IF-2019-36422718-APN-ANp#INPI Page 75 of 250 conditions involving T cell infiltration and chronic inflammatory responses; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythematosus (SLE); diabetes mellitus (for example, type I diabetes mellitus or insulin-dependent diabetes mellitus); multiple sclerosis; Reynaud syndrome; autoimmune thyroiditis; allergic encephalomyelitis; Sjorgen syndrome; juvenile onset diabetes; and immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T cells typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia (Addison's disease); diseases involving leukocyte diapedesis; inflammatory disorder of the central nervous system (CNS); multiple organ injury syndrome; hemolytic anemia (including, but not limited to, cryoglobinemia or positive Coombs anemia); Myasthenia gravis; diseases mediated by the antigen-antibody complex; antiglomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; Graves' disease; Lambert-Eaton myasthenic syndrome; bullous pemphigoid pemphigus; Autoimmune polyendocrinopathies; Reiter's disease; stiff man syndrome; Behcet's disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathies; Purple IF-2019-36422718-APN-AT7I6 / INPI Page 76 of 250 immune thrombocytopenia (ITP) or autoimmune thrombocytopenia. The compounds provided herein may be useful for the treatment of conditions associated with inflammation, including, but not limited to, COPD, psoriasis, asthma, bronchitis, emphysema and cystic fibrosis. Also provided herein is the use of a compound as described herein for the treatment of neurodegenerative diseases. Neurodegenerative diseases and conditions include, but are not limited to, stroke, ischemic damage to the nervous system, neural trauma (e.g., percussive brain injury, spinal cord injury, and traumatic damage to the nervous system), multiple sclerosis, and other neuropathies. immunological. (e.g., Guillain-Barré syndrome and its variants, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, and Fisher syndrome), HIV / AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson's disease, Huntington's disease, multiple sclerosis , bacterial, parasitic, fungal and viral meningitis, encephalitis, vascular dementia, multiple infarct dementia, Lewy body dementia, frontal lobe dementia such as Pick's disease, subcortical dementias (such as Huntington's or progressive supranuclear palsy), atrophy syndromes focal cortical (such as primary aphasia), metabolic-toxic dementias (such as chronic hypothyroidism or B12 deficiency), and IF-2Q19-36422718-APN-AT7]7#INPI Page 77 of 25Q dementias caused by infections (such as syphilis or chronic meningitis). Additional guidance can be found for the use of compounds and compositions described herein (for example, a compound of Formula (I), a compound listed in Table A or B, or a pharmaceutically acceptable salt of the above) to inhibit the secretion of proteins in the Examples Section, below. Pharmaceutical formulations and administration The methods provided herein include the manufacture and use of pharmaceutical compositions, which include one or more of the compounds provided herein. The pharmaceutical compositions themselves are also included. Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. Therefore, provided herein are pharmaceutical formulations that include a compound described herein (e.g., a compound of Formula (I), a compound listed in Table A or B, or a pharmaceutically acceptable salt of the above), as described previously here, and one or more pharmaceutically acceptable carriers. The phrase pharmaceutically acceptable is used herein to refer to those ligands, materials, compositions and / or dosage forms that, within the scope of good medical judgment, are suitable for use. IF-2019-36422718-APN-AT7I8 / INPI Page 78 of 250 in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problem or complication, in proportion to a reasonable risk / benefit ratio. The phrase pharmaceutically acceptable carrier as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulation material. As used herein, pharmaceutically acceptable carrier language includes buffer, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, and the like, compatible with pharmaceutical administration. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not being harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and unsubstituted β-cyclodextrin; (3) cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as oil IF-2019-36422718-APN-AN7I%INPI Page 79 of 250 peanut, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other compatible non-toxic substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions provided herein are non-pyrogenic, that is, they do not induce significant temperature elevations when administered to a patient. The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic and organic acid addition salts of a compound provided herein. These salts can be prepared in situ during the final isolation and purification of a compound provided herein, or by separately reacting the compound in its free base form with a suitable organic or inorganic acid, and isolating the salt so formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, IF-2Q19-36422718-APN-ANfP#INPI Page 8Q of 25Q nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, nilate, mesylate glucoheptonate, lactobionate, laurylsulfonate salts and amino acids , and the like. (See, for example, Berge et al., (1977) Pharmaceutical Salts, J. Pharm. Sci. 66: 1-19). In some embodiments, a compound provided herein may contain one or more acidic functional groups and, therefore, is capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term pharmaceutically acceptable salts in these cases refers to the relatively non-toxic organic and inorganic base addition salts of a compound provided herein. These salts can also be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic, secondary or tertiary organic amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like. Representative organic amines useful for salt formation IF-2019-36422718-APN-ANfP#INPI Addition bases include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., Supra). Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and perfumes, preservatives and antioxidants may also be present in the compositions. The compositions prepared as described herein can be administered in various forms, depending on the disorder to be treated and the age, condition and body weight of the patient, as is well known in the art. For example, when the compositions are administered orally, they may be formulated as tablets, capsules, granules, powders or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), infusion drop preparations or suppositories. For application via the ophthalmic mucous membrane route, they may be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means in conjunction with the methods described herein and, if desired, the active ingredient can be mixed with any conventional additive or excipient, such as a binder, a disintegrating agent, a lubricant, a corrector, a solubilizing agent. , a IF-2019-36422718-APN-ANp#INPI Page 82 of 250 suspension aid, an emulsifying agent or a coating agent. The actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein may be varied to obtain a therapeutically effective amount, which is an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. administration, without being toxic to the patient. The concentration of a compound provided herein in a pharmaceutically acceptable mixture will vary depending on several factors, including the dose of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. In some embodiments, the compositions provided herein may be provided in an aqueous solution containing approximately 0.1-10% w / v of a compound described herein, among other substances, for parenteral administration. Typical dosage ranges may include from about 0.01 to about 50 mg / kg body weight per day, administered in 1-4 divided doses. Each divided dose may contain the same or different compounds. The dose will be a therapeutically effective amount that depends on several factors, including a patient's general health, IF-2019-36422718-APN-ANfP#INPI Page 83 of 250 and the formulation and route of administration of the selected compound or compounds. Dosage forms or compositions containing a compound as described herein may be prepared in the range of 0.005% to 100% with the balance made of the non-toxic carrier. Methods for preparing these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001%-100% of active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%. Although the dose will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, in general, a daily dose of 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this can be administered in a single dose or in divided doses. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect. In jurisdictions that prohibit the patenting of methods practiced on the human body, the meaning of administration of a composition to a human subject will be limited to prescribing a controlled substance that a human subject will self-administer. IF-2019-36422718-APN-ANÍP#INPI Page 84 of 250 any technique (for example, orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with the laws or regulations defining patentable subject matter is intended. In jurisdictions that do not prohibit the patenting of methods practiced on the human body, the administration of compositions includes both methods practiced on the human body and also the above activities. 10 Other modalities It should be understood that although the description is read in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the description, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims. IF-2019-36422718-APN-ANp#INPI Page 85 of 250 EXAMPLES The following examples are provided for illustration and are not intended to limit the scope of the invention. Route 1 HCl, 1,4-dioxane The starting material was synthesized using the method described in J. Med. Chem. 2016, 59, 2633-2647. To N (3-((3-aminopropyl)(cyclohexylmethyl)amino)propyl)-4methylbenzenesulfonamide (0.200 g, 0.523 mmol) in DCM (2.0 mL) was added DIEA (2 eq, 1.05 mmol, 179 uL) followed by sodium chloride. piperidine-1-sulfonyl (0.096 g, 0.523 mmol). After 16 h, the reaction was quenched with sodium bicarbonate (sat.), extracted with DCM, dried with sodium sulfate, filtered, and concentrated. A N-(3-((cyclohexylmethyl)(3-((4methylphenyl)sulfonamido)propyl)amino)propyl)piperidine-1 IF-2Q19-36422718-APN-ANP#INPI Page 86 of 25Q sulfonamide in DMF (10 ml) NaH (2.5 eq, 1.31 mmol, 0.052 g of a 60% dispersion in mineral oil) was added. The mixture was stirred for 1 h, then heated to 85°C and 3-chloro-2-chloromethyl-1-propene (0.9 eq, 0.471 mmol, 55 uL dissolved in 0.5 ml DMF) was added for 4 h. After heating for 16 h, the mixture was cooled to room temperature, diluted with brine and water, extracted with ethyl acetate (3X), washed with brine, dried over sodium sulfate, filtered and concentrated. Flash column chromatography (0-60% hexanes / ethyl acetate + 1% DEA) provided the free base product. Diethyl ether (1.0 mL) was added to the free base to dissolve and HCl (4 N in dioxane, 1.046 mmol, 262 uL). The HCl salt was filtered and dried under high vacuum to provide compound A5. MS (EI) for C29H48N4O4S2, found 581 [M+H]+. The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ A6 9-(cyclohexylmethyl)-1-(ethanesulfonyl)-5-(4methylbenzenesulfonyl)-3-methylidene-l,5,9triazacyclododecane 526 A7 9-(cyclohexylmethyl)-1-(4- methylbenzenesulfonyl)-3-methylidene-5(propane-2-sulfonyl)-1,5,9-triazacyclododecane 540 A8 1-(cyclohexanesulfonyl)-9-(cyclohexylmethyl)- 5-(4-methylbenzenesulfonyl)-3-methylidene- 1 ,5,9-triazacyclododecane 580 IF-2Q19-36422718-APN-Ab87#INPI Page 87 of 25Q Route 2 TsCI N32CO3, NaCl NHTS HCl (4N in dioxane NHBoc 4A MS, toluene, NaBH4; HCl (4N in Dioxane), diethyl ether TsCI N32CO3, NaCI DCM; HCl (4N in dioxane), diethyl ether NaH, DMF; HCl (4N in dioxane), diethyl ether For tert-butyl (3-aminobutyl)carbamate (2.5 g, 13.3 mmol) in DCM (12.5 mL), Na2CO3 sat. (12.5 mL), and sat. NaCl. (12.5 ml), TsCl (13.3 mmol, 2.54 g) was added. After 1 h, the organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated to provide tert-butyl (3-((4-methylphenyl)sulfonamido)butyl)carbamate which was carried out. without additional purification. TFA (66.5 mmol, 5.09 ml) and DCM (5.09 ml) were added to the tosylate (13.3 mmol). After 2 h, the reaction IF-2019-36422718-APN-ANfP#INPI Page 88 of 250 was concentrated, diluted with NaOH (1N, 30 ml), extracted with DCM (3 x 30 ml), dried over sodium sulfate, filtered and concentrated to give the amine. Toluene (49 ml) and cyclohexanecarboxaldehyde (1.34 g, 12.0 mmol) were added to the amine (10.94 mmol). The mixture was refluxed with a Dean Stark apparatus overnight (external temperature 185°C), then concentrated, diluted with ethanol (absolute, 19 mL), and NaBH4 (0.827 g, 21.8 mmol) was added in portions while maintaining the internal temperature at <20°C. After stirring for 2 h, the mixture was diluted with water (10 mL), stirred for 20 min, extracted with DCM (3X), washed with brine, dried over sodium sulfate, filtered and concentrated to provide the amine. The amine was diluted with diethyl ether (20 ml) and HCl (conc., ~0.3 ml) was added dropwise. The HCl salt was removed within 5 minutes and filtered with diethyl ether to wash. The product was dried under vacuum overnight to provide N(4-((cyclohexylmethyl)amino)butan-2-yl)-4methylbenzenesulfonamide hydrochloride. Acetonitrile (9 mL), sodium carbonate (0.99 g, 9.2 mmol), Lil (0.114 g) and 3-bromopropylphthalimide (2.30 g) were added to the HCl salt (3.5 mmol). The mixture was heated at 70°C for 5 h, at which time it was filtered and concentrated. The crude phthalimide was continued without further purification. IF-2O19-36422718-APN-ANP#INPI Page 89 of 250 Hydrazine monohydrate (4.2 ml) and ethanol (15 ml) were added to the phthalimide (3.5 mmol). After heating at 80°C for 30 min, the reaction was completed and the precipitate was filtered by washing with ethanol. The filtrate was concentrated and diluted with HCl (2 N, 30 mL) and then allowed to stand for 1 h. NaOH (1 N) was added to the aqueous mixture to basify at pH 10. The mixture was then extracted with DCM (3X), dried over sodium sulfate, filtered and concentrated to provide N-(4-(( 3aminopropyl)(cyclohexylmethyl)amino)butan-2-yl)-4methylbenzenesulfonamide. To the amine (695 mg, 1.7 6 mmol) was added DCM (9 mL), sat. Na2CO3. (9 ml), NaCl sat. (9 ml), TsCl (1.76 mmol, 336 mg). After stirring for 1 h, the mixture was extracted with DCM (3X), dried with sodium sulfate, filtered, and concentrated to give the free base. The HCl salt was prepared by diluting the free base in diethyl ether (50 mL) and adding HCl (conc., 300 uL). After placing under high vacuum for 2 h, the HCl salt (1.02 g) was collected. To the HCl salt (0.400 g, 0.683 mmol) in DMF (14 mL) was added NaH (3.5 eq, 2.39 mmol, 60% dispersion in mineral oil, 80.3 mg). After stirring for 1 h, 3-chloro-2-chloromethyl-1-propene (0.9 eq, 0.615 mmol, 71 uL in 7 mL DMF) was added dropwise over 3 h. After heating for an additional 2 h, the mixture was cooled to IF-2019-36422718-APN-ANP#INPI Page 90 of 250 room temperature, it was diluted with brine, water and ethyl acetate. The mixture was extracted with ethyl acetate (2X), washed with brine, dried with sodium sulfate, filtered and concentrated. Flash column chromatography (0-90% hexanes / ethyl acetate + 1% DEA) provided the product. The HCl salt was formed by diluting the free base in diethyl ether (20 vol) and adding HCl (4N in dioxane, 4 eq.) to provide 5(cyclohexylmethyl)-2-methyl-11-methylene-1,9-hydrochloride. ditosyl-1,5,9triazacyclododecane, compound B1. MS (EI) for C32H47N3O4S2, found 602 [M+H]+. The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ B2 1-(cyclohexylmethyl)-3-methyl-5,9-bis(4methylbenzenesulfonyl)-7-methylidene-l,5,9triazacyclododecane 602 A9 N,N-dimethyl-4-{[ 5-(4-methylbenzenesulfonyl)3-methylidene-9-[(oxan-4-yl)methyl]-1,5,9triazacyclododecan-1-yl]sulfonyl}aniline 619 Route 3 IF-2019-36422718-APN-AN9P#INPI Page 91 of 250 N-(3-((cyclohexylmethyl)(3-((4methylphenyl)sulfonamido)butyl)amino)propyl)-4methylbenzenesulfonamide (0.099 mmol) in DMF (10.0 mL) sodium hydride (0.350 mmol of a 60% dispersion) was added. % in mineral oil). The mixture was stirred at room temperature for 30 min and then heated to 80°C before cyclopropane-1,1diylbis(methylene)diethanesulfonate (0.099 mmol was dissolved in 1.0 mL DMF) over the course of 2 h. After stirring for a further 4 h at 80°C, the mixture was cooled to room temperature, quenched with brine, extracted with ethyl acetate (3X). The combined organic extracts were washed with brine (2X), dried with sodium sulfate, filtered and concentrated. Flash column chromatography (0-60% hexanes (1% DEA) / ethyl acetate) gave the free base product which was dissolved in diethyl ether (2 mL) and HCl (0.1 mL of a 4 N solution in 1 ,4-dioxane) was added. The mixture was concentrated to give 4-{[9(cyclohexylmethyl)-13-(4-methylbenzenesulfonyl)-5,9,13triazaspiro[2,11]tetradecan-5-yl]sulfonyl}-N,Ndimethylaniline hydrochloride, compound A11 . MS (EI) for C33H50N4O4S2, found 631 [M+H]+. IF-2019-36422718-APN-AN92 / INPI Page 92 of 250 Route 4 / The starting material was synthesized using the method described in J. Med. Chem. 2016, 59, 2633-2647. To the starting material (0.327 mmol) in methanol (2.0 ml) under argon was added Pd / C (20 mg). A hydrogen atmosphere was established and the mixture was stirred at room temperature. After 3 h, the reaction was filtered and purified by flash column chromatography (0-80% hexanes (1% DEA) / ethyl acetate) to give the product. Toluene (5 ml) was added to the starting material (0.028 mmol) followed by the aldehyde (0.028 mmol). The mixture was stirred for 3 h at reflux and then concentrated. Ethanol was added to the imine followed by sodium borohydride. The mixture was stirred at room temperature for 30 IF-2O19-36422718-APN-ANP#INPI Page 93 of 250 minutes, then diluted with water (1 ml), extracted with DCM (3 x 1 ml), dried with sodium sulfate, filtered and concentrated. The product was purified by flash column chromatography (0-60% hexanes (1% DEA) / ethyl acetate). The free base was diluted with ethyl ether (1 ml) and HCl (7 pl, 4 N in dioxane) was added. The mixture was filtered to give 4-((9-((4,4dimethylcyclohexyl)methyl)-3-methylene-5-tosyl-1,5,9triazacyclododecan-1-yl)sulfonyl)-N,N-dimethylaniline hydrochloride ( compound A10). MS (EI) for C34H52N4O4S2, found 645 [M+H]+. Route 5 THF 1-propanol, Triphosgene, DIEA To triphosgene (0.0316 mmol, 9.4 mg) in DCM (100 uL) was added 1-propanol, stirring for 45 minutes, amine (0.0158 mmol, 8.2 mg), (0.190 mmol 14 uL). After this solution was added to DIEA (0.126 mmol, 22 uL) and DCM (100 uL). The mixture was stirred at room temperature for h, then purified directly by chromatography IF-2019-36422718-APN-AN94 / INPI Page 94 of 250 column flash (0-70% hexanes / ethyl acetate) to provide propyl 5-((4(dimethylamino)phenyl)sulfonyl)-7-methylene-9-tosyl-1,5,9triazacyclododecane-1 -carboxylate (compound A12). MS (EI) for C29H42N4O6S2, found 607 [M+H]+. Route 6 The starting material, 4-((9-(cyclohexylmethyl)3-methylene-5-((2-nitrophenyl)sulfonyl)-1,5,9triazacyclododecan-1-yl)sulfonyl)-N,N-dimethylaniline was synthesized using a similar method described in Route 2 substituting with the appropriate sulfonyl chlorides. To the starting material (1.09 g, 1.68 mmol) in ACN (12.3 ml) was added DBU (0.780 ml, 5.22 mmol) followed by IF-2O19-36422718-APN-ANP#INPI Page 95 of 250 2-mercaptoethanol (0.135 ml, 1.92 mmol). The mixture was stirred at room temperature for 2 h, then an additional aliquot of 2-mercaptoethanol (1.14 eq) was added. After stirring for an additional 2 h, the mixture was concentrated and purified directly by FCC (0-100% hexanes (1% DEA) / ethyl acetate). 4-((9-(Cyclohexylmethyl)-3-methylene1,5,9-triazacyclododecan-1-yl)sulfonyl)-N,N-dimethylaniline. To the amine (70 mg, 0.152 mmol) in DCM (2 mL) was added DIEA (0.303 mmol, 52 uL) followed by piperidine-1-sulfonyl chloride (0.152 mmol, 28 mg). After standing overnight, the reaction was purified directly by flash column chromatography (hexanes (1% DEA) / 0-60% ethyl acetate). The HCl salt of the product was prepared by dissolving the free base in diethyl ether (1 mL) and adding HCl (4 N in dioxane, 38 uL). The filtrate was collected to give 4-((9(cyclohexylmethyl)-3-methylene-5-(piperidin-1-ylsulfonyl)1,5,9-triazacyclododecan-1-yl)sulfonyl)-N,N-dimethylaniline hydrochloride. (compound A15) . MS (EI) for C30H51N5O4S2,, found 610 [M+H]+. The following compounds were synthesized in a similar manner: IF-2O19-36422718-APN-ANP#INPI Page 96 of 250 IUPAC No. [M+H] + Al 6 9-(cyclohexylmethyl)-5-[4- (dimethylamino)benzenesulfonyl]-N,N-dimethyl3-methylidene-l,5,9-triazacyclododecane-lsulfonamide 570 A13 4-{[9-(cyclohexylmethyl)-3-methylidene-5(piperidine-1-sulfonyl)-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 610 Route 7 The starting material, N-(3((cyclohexylmethyl)(3-((4(dimethylamino)phenyl)sulfonamido)propyl)amino)propyl)-4methylbenzenesulfonamide, was synthesized using the same method described in Route 1 substituting with the chloride of appropriate sulfonyl. To the diamine (49 mg, 0.087 mmol) in DMF (2.5 ml) was added NaH (0.22 mmol, 9 mg). After stirring for 30 min at room temperature, 1,3-dichloropropane (0.087 mmol, 8.3 uL in 0.5 mL DMF) was added slowly over 1 h while heating to 80 °C. After 3 h, the mixture was cooled to room temperature, diluted with IF-2019-36422718-APN-AN97#INPI Page 97 of 250 brine (10 ml), water (5 ml) and ethyl acetate (10 ml). The aqueous layer was extracted with ethyl acetate (3 x 5 ml), the organic extracts were combined and washed with brine (1 x 5 ml), dried with sodium sulfate and concentrated. Flash column chromatography (050% hexanes (1% DEA / ethyl acetate) provided the free base product which was converted to the HCl salt with the addition of ether (1 mL) and then HCl (20 uL, 4 N in dioxane). MS (EI) for C31H48N4O4S2, found 605 [M+H]+. The following compound was synthesized in a similar manner: IUPAC No. [M+H]+ A17 4-{[10-(cyclohexylmethyl)-14-(piperidine- 1-sulfonyl)-2-oxa-6,10,14-triazaspiro[3.11]pentadecan-6yl]sulfonyl} -N,N-dimethylaniline 640 IF-2019-36422718-APN-ANfP#INPI Page 98 of 250 Route 8 The starting material was synthesized using the method described in J. Med. Chem. 2006, 49, 1291-1312. To N1(3-aminopropyl)-N1-benzylpropane-1,3-diamine (363 mg, 1.64 mmol) in DCM (2 ml) was added DIEA (1.14 ml, 6.56 ml) and then the sulfonyl chloride (345 pL , 2.46 mmol). The solution was allowed to sit overnight at room temperature. Concentration and purification by flash column chromatography (0-80% hexanes (1% DEA) / ethyl acetate) provided the product. To the starting material (260 mg, 504 pL) in DMF (20 ml) was added NaH (50 mg of a 60% dispersion in mineral oil, 1.26 mmol). The mixture was stirred at 80°C IF-2O19-36422718-APN-ANP#INPI Page 99 of 250 for 20 minutes and then bis-sulfonate (144 mg, 504 pl) was added over the course of 1 hour. After heating for 4 h, the reaction was completed and diluted with ethyl acetate (40 ml) and brine (40 ml), extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. Flash column chromatography (hexanes (1% DEA) / 0-50% ethyl acetate) gave the product which was diluted with ethyl ether (5 mL) and HCl (4 N in dioxane, 100 uL) was added. The mixture was concentrated, washed with diethyl ether and dried to give 9benzyl-5,13-bis(piperidin-1-ylsulfonyl)-5,9,13triazaspiro[2,11]tetradecane hydrochloride (compound A18). MS (EI) for C28H47N5O4S2, found 581 [M+H]+. IF-2019-36422718-APN-ANP#INPI Page 100 of 250 Route 9 The starting material, N-(3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)-4(dimethylamino)benzenesulfonamide, was synthesized using a method similar to that described in Route 2. To N-(3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)-4(dimethylamino)benzenesulfonamide (559 mg, 1.36 mmol) in DCM (2 ml) was added DIEA (0.71 ml, 4.08 mmol) then the chloride sulfonyl (250 mg, 1.36 mmol). The solution was allowed to sit overnight at room temperature. Concentration and purification by flash chromatography IF-2Q19-36422718-APN-ANP#INPI Page 1Q1 of 25Q on column (0-80% hexanes (1% DEA) / ethyl acetate) provided the product. The cyclization of N-(3-((cyclohexylmethyl) (3-((4(dimethylamino)phenyl)sulfonamido)propyl)amino)propyl)piperid ina-1-sulfonamide and salt formation was carried out similarly to Route 8 to provide 4-((9-(cyclohexylmethyl)-13-(piperidin-1-ylsulfonyl)-5,9,13triazaspiro[2.11]tetradecan-5-yl)sulfonyl)-N,Ndimethylaniline hydrochloride (compound A19 ). MS(EI) for C31H53N5O4S2, 10 found 624 [M+H]+. The following compounds were synthesized in a similar manner. The cyclization of compounds A25, A26, A27, A28 and A29 was carried out using NMP as a solvent. IF-2G19-36422718-APN-ANP#INPI Page 1G2 of 25G IUPAC No. [M+H]+ A20 4 -{[9-(cyclohexylmethyl)-13-[ (2methylpiperidin-l-yl)sulfonyl]-5,9,13triazaspiro[2.11]tetradecan-5-yl]sulfonyl}- N,N-dimethylaniline 638 A21 4-{[9-(cyclohexylmethyl)-13-[ (3methylpiperidin-l-yl)sulfonyl]-5,9,13triazaspiro[2.11]tetradecan-5-yl]sulfonyl}-N,N -dimethylaniline 638 A22 4 -{[9-(cyclohexylmethyl)-13-[ (4methylpiperidin-l-yl)sulfonyl]-5,9,13triazaspiro[2.11]tetradecan-5-yl]sulfonyl}-N,N-dimethylaniline 638 A23 4-{[9-(cyclohexylmethyl)-13-(pyrrolidine-1-sulfonyl)-5,9,13-triazaspiro[2.11]tetradecan-5yl]sulfonyl}-N,N-dimethylaniline 610 B3 4-{[8 -(cyclohexylmethyl)-4-(piperidine-1sulfonyl)-1,4,8-triazacycloundecan-lyl]sulfonyl}-N,N-dimethylaniline 584 B4 4-{[7-(cyclohexylmethyl)-3-(piperidine-1sulfonyl) -1,3,7-triazecan-l-yl]sulfonyl]N,N-dimethylaniline 570 A25 4-{[13-(azepane-l-sulfonyl)-9-(cyclohexylmethyl)-5,9,13triazaspiro[2.11] tetradecan-5yl]sulfonyl}-N,N-dimethylaniline 638 A26 4 -{[9-(cyclohexylmethyl)-13-[ (4,4dimethylpiperidin-l-yl)sulfonyl]-5,9, 13triazaspiro[2.11]tetradecan-5 -yl]sulfonyl}-N,N-dimethylaniline 652 A27 4 -{[9-(cyclohexylmethyl)-13-[ (4methoxypiperidin-l-yl)sulfonyl]-5,9,13-triazaspiro[2.11]tetradecan-5yl] sulfonyl]-N,N-dimethylaniline 654 A28 1-{[9-(cyclohexylmethyl)-13-[4-(dimethylamino)benzenesulfonyl]-5,9,13triazaspiro[2.11]tetradecan-5-yl]sulfonyl}piperidin-4 -ol 640 A29 4-{[9-(cyclohexylmethyl)-13-[(4-phenylpiperidin-1-yl)sulfonyl]-5,9,13triazaspiro[2.11]tetradecan-5-yl]sulfonyl}-N,N- dimethylaniline 700 IF-2019-36422718-APN-ANP#INPI Page 103 of 250 Route 10 CL To the amine (67 mg, 0.14 mmol) in DCM (12 mL) was added DIEA (35 mg, 0.27 mmol) followed by 410-chlorobenzoyl chloride (24 mg, 0.14 mmol). After standing at room temperature for 30 minutes, the reaction was stopped with sodium bicarbonate (sat.), extracted with DCM (3X), dried with sodium sulfate, and filtered. Flash column chromatography (0-60% hexanes (1% DEA) / ethyl acetate) provided (5,13-bis(piperidin-1ylsulfonyl)-5,9,13-triazaspiro[2.11]tetradecan-9-yl)(4chlorophenyl)methanone (compound A24). MS (EI) for C28H44CM5O5S2, found 630 [M+H]+. IF-2G19-36422718-APN-ANP#INPI Page 1G4 of 25G Route 11 To a solution of N,N-3-trimethylaniline (1.35 g, 10.0 mmol) in CHCl3 (4 ml) was added chlorosulfonic acid (4 ml). The reaction mixture was heated to 80°C for 18 h. The mixture was cooled to room temperature and diluted with DCM (20 ml). The resulting mixture was poured into ice water (30 mL) and then adjusted to pH = 7~8 with saturated aqueous Na2CO3. The organic layer was separated, washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated. The residue was recrystallized from petroleum ether / EtOAc (10:1, 10 mL) to give 4-(dimethylamino)-2-methylbenzenesulfonyl chloride.1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 9.6 Hz , 1H), 6.53 (m, 2H), 3.09 (s, 6H), 2.70 (s, 3H). 4-{[9-(cyclohexylmethyl)-13-(piperidine-1sulfonyl)-5,9,13-triazaspiro[2.11]tetradecane-5IF-2O19-36422718-APN-ANP#INPI Page 105 of 250 il]sulfonyl}-N,N,3-trimethylaniline was prepared following the procedure described in Route 12 to give the compound A30.1H NMR (400 MHz, DMSO-cfc): δ 9.57 (br s, 1H ), 7.50 (d, J = 8.8 Hz, 2H), 6.85 (m, 2H), 3.95 (br s, 5 1H), 2.89~3.55 (m, 24H), 1.45~1.90 (m, 15H), 1.28 ( m, 4H), 0.95 (m, 2H), 0.66 (br s, 4H). MS(EI) for C32H55N5O4S2, found 638 [M+H]+. The following compound was synthesized in a similar manner: No . IUPAC [M+H] + cfe) : δ 9.46 (br s, 1H), 3.372.95 (m, 15H), 2.01-1.01 (m, 33H), 0.95 (m, 2H), 0.73 (m, 4H). IF-2G19-36422718-APN-ANP#INPI Page 1G6 of 25G Route 12 To a solution of piperidine-1sulfonyl chloride (68.3 g, 0.37 mol) in toluene (350 mL) was added dropwise a solution of propane-1,3-diamine (83.4 g, 1.12 mol) in toluene (150). mL). The reaction mixture was stirred overnight at room temperature. The resulting suspension was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50:1 to 20:1) to provide N-(3-aminopropyl)piperidine-1-sulfonamide.1H IF-2O19-36422718-APN-ANP#INPI Page 107 of 250 NMR (400 MHz, CDCI3): δ 3.17 (m, 6H), 2.88 (t, J = 6.0 Hz, 2H), 1.65 (m, 6H), 1.54 (m, 2H). A mixture of N-(3-aminopropyl)piperidine-1sulfonamide (22.62 mmol) and cyclohexanecarbaldehyde (2.8 g, 24.89 mmol) in toluene (90.0 mL) was refluxed overnight with removal of water by Dean Apparatus. Stark. The mixture was cooled to room temperature and concentrated in vacuo. The resulting product was dissolved in ethanol (35 ml) and NaBH4 (1.66 g, 43.7 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was stopped with 2N aqueous HCl (30 mL) and then adjusted to pH = 10 with aqueous NaOH. The resulting mixture was extracted with ethyl acetate (50 ml) and the organic layer was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50:1 to 40:1) to provide N-(3(cyclohexylmethylamino)propyl)piperidine-1-sulfonamide.1H NMR (400 MHz, CDCl3): δ 3.17 (m, 6H), 2.78 (t, J = 6.0 Hz, 2H), 2.45 (d, J = 6.4 Hz, 2H), 1.75 (m, 12H), 1.44 (m , 1H), 1.23 (m, 3H), 0.96 (m, 2H). MS(EI) for C15H31N3O2S, found 318 [M+H]+. To a solution of N-(3(cyclohexylmethylamino)propyl)piperidine-1-sulfonamide (2.8 g, 8.83 mmol) in CH3CN (50 mL) was added Na2CO3 (0.97 g, 9.19 mmol), LiI (0.28 g, 2.12 mmol ) and 3bromopropylphthalimide (5.66 g, 21.19 mmol). The mixture of IF-2O19-36422718-APN-ANP#INPI Page 108 of 250 reaction was heated to reflux overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:3) to provide N-(3-((cyclohexylmethyl)(3-(1,3dioxoisoindolin-2-yl ))propyl)amino)propyl)piperidine-1sulfonamide.1H NMR (400 MHz, CDCl3): δ 7.85 (m, 2H), 7.73 (m, 2H), 5.82 (br s, 1 H), 3.68 (t, J = 7.2 Hz, 2H), 3.17 (m, 6H), 2.46 (m, 4H), 2.14 (m, 2H), 1.82 (m, 2H), 1.67 (m 12H), 1.45 (m, 3H), 1.18 ( m, 2H), 0.87 (m, 2H). To a solution of N-(3-((cyclohexylmethyl)(3-(1,3dioxoisoindolin-2-yl)propyl)amino)propyl)piperidine-1sulfonamide (500 mg, 0.10 mmol) in EtOH (5 mL) was added NH2NH2 (1.5 ml, 2.55 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (20 ml). The resulting mixture was washed with water (2 x 10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to provide N-(3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)piperidine-1sulfonamide (380 mg, quantitative). 1H NMR (400 MHz, CDCl3) : δ 3.17 (m, 6H), 2.78 (t, J = 6.8 Hz, 2H), 2.45 (m, 4H), 2.14 (d, J = 7.2 Hz, 2H), 1.82 ( m, 2H), 1.67 (m 12H), 1.45 (m, 3H), 1.18 (m, 2H), 0.87 (m, 2H). MS(EI) for C18H38N4O2S, found 375 [M+H]+. To a solution of N-(3-((3 IF-2Q19-36422718-APN-ANP#INPI Page 1Q9 of 25Q aminopropyl)(cyclohexylmethyl)amino)propyl)piperidine-1sulfonamide (2.42 g, 6.49 mmol) and DIEA (1.31 g, 10.3 mmol) in DCM (50 mL) sulfonyl chloride (1.69 g, 7.13 mmol) was added ). The reaction mixture was stirred at room temperature for 2 h. The mixture was washed with water (50 ml). The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM = 1:80 to 1:30) to provide N-(3-((cyclohexylmethyl)(3-(4-(dimethylamino)-2fluorophenylsulfonamido)propyl) amino)propyl)piperidine-1sulfonamide.1H NMR (400 MHz, CDCl3): δ 7.66 (m, 1H), 6.43 (m, 2H), 5.58 (br s, 2H), 3.15 (m, 6H), 3.03 (s , 6H), 2.99 (br s, 2H) 2.46 (br s, 4H), 2.12 (br s, 2H), 1.30~1.70 (m, 18H), 1.21 (m, 4H), 0.82 (m, 2H). MS(EI) for C26H46FN5O4S2, found 575 [M+H]+. To a solution of N-(3-((cyclohexylmethyl)(3-(4(dimethylamino)-2fluorophenylsulfonamido)propyl)amino)propyl)piperidine-1sulfonamide (2.28 g, 3.97 mmol) in DMF (20 ml) was added sodium (400 mg, 3.97 mmol). The mixture was stirred for 30 min at room temperature. Cyclopropane-1,1-diylbis(methylene)diethanesulfonate (1.3 g, 3.97 mmol) was added and the reaction mixture was stirred at 80°C for 2 h. The mixture was cooled to room temperature and poured into water (150 ml). The resulting mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with IF-2019-36422718-APN-ANP#INPI Page 110 of 250 water (50 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:15 to 1:8) to provide the free base which was dissolved in ether (5 ml). Hydrochloric acid (1.5 ml or a 3 N solution in 1,4-dioxane) was added and the mixture was stirred for 0.5 h. The solvent was removed in vacuo and the residue was triturated with ether three times to give the compound A40.1H NMR (400 MHz, DMSO-cfc): δ 9.89 (br s, 1H), 7.54 (m, 10 1H), 6.63 (m, 2H), 3.67 (br s, 1H), 3.55-2.89 (m, 23H), 1.90-1.45 (m, 15H), 1.28 (m, 4H), 0.95 (m, 2H), 0.69 (m, 4H). MS(EI) for C31H52FN5O4S2, found 643 [M+H]+. The following compounds were synthesized in a similar manner: IF-2019-36422718-APN-ANp#INPI Page 111 of 250 No . IUPAC [M+H] + : δ 9.75 (br s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.55-2.89 (m, 18H), 1.90-1.45 (m, 15H), 1.28 (m, 4H), 0.95 (m, 2H), 0.66 (m, 4H). A3 2 9-(cyclohexylmethyl)-5-(3methoxybenzenesulfonyl)-13- (piperidine-l-sulfonyl)-5,9,13triazaspiro[2.11]tetradecane 611 XH NMR (400 MHz, DMSOde): δ 9.89 (br s, 1H ), 7.57 (m, 1H), 7.32 (m, 2H), 7.23 (s, 1H), 3.85 (s, 3H), 3.55-2.89 (m, 18H), 2.04-1.45 (m, 15H), 1.28 ( m, 4H), 0.95 (m, 2H), 0.67 (m, 4H) . A3 3 9-(cyclohexylmethyl)-5-(2methoxybenzenesulfonyl)-13- (piperidine-l-sulfonyl)-5,9,13triazaspiro[2.11]tetradecane 611 XH NMR (400 MHz, DMSOde) : δ 9.35 (br s, 1H ), 7.80 (m, 1H), 7.68 (m, 1H), 7.28 (m, 1H), 7.13 (m, 1H), 3.89 (s, 3H), 3.55-2.89 (m, 18H), 1.90-1.45 ( m, 15H), 1.28 (m, 4H), 0.95 (m, 2H), 0.66 (br s, 2H), 0.51 (br s, 2H). A34 5-(benzenesulfonyl)-9(cyclohexylmethyl)-13(piperidine-1-sulfonyl)-5,9,13triazaspiro[2.11]tetradecane 581 1H NMR (400 MHz, DMSOd6) : δ 10.26 (br s, 1H), 7.76 (m, 4H), 3.41-2.89 (m, 18H), 1.90-1.45 (m, 15H), 1.28 (m, 4H), 0.95 (m, 2H), 0.73 (br s, 4H). Route 13 OTf IF-2019-36422718-APN-ANP#INPI Page 112 of 250 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1Himidazol-3-ium trifluorosulfonate (1.69 g, 4.65 mmol, reference: J. Org. Chem. 2002, 68, 115-119) and 4phenylpiperidine (750 mg, 4.65 mmol) ACN (16 mL) was added and the solution was allowed to stand for 2 h, then concentrated and purified directly by flash column chromatography (0-80% hexanes / ethyl acetate). to provide the product. To 1-((1H-imidazol-1-yl)sulfonyl)-4phenylpiperidine (600 mg, 2.06 mmol) in DCM at 0°C was added methyl triflate (0.23 ml, 2.06 mmol) over 5 min. After standing for 30 minutes, the mixture was concentrated to provide 3-methyl-1-((4phenylpiperidin-1-yl)sulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate which was carried out without further purification. MS (EI) for C15H2oN3O2S, found 307 [M] +. The following compounds were synthesized in a similar manner: 1- ((8-chloro-3,4-dihydroisoquinolin-2(1H)yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A51). 1-((7-chloro-3,4-dihydroisoquinolin-2(1H)yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A52). 1-((6-chloro-3,4-dihydroisoquinolin-2(1H)IF-2019-36422718-APN-ANp#INPI Page 113 of 250 il)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A53). 1-((5-chloro-3,4-dihydroisoquinolin-2(1H)yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A54). 1-((6-fluoro-3,4-dihydroisoquinolin-2(1H)yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A59). 1-((6-bromo-3,4-dihydroisoquinolin-2(1H)yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A60). 1-((4-isopropoxypiperidin-1yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate hydrochloride (Intermediate for compound A66). 1-((4-(cyclopent-1-en-1-yl)-3,6-dihydropyridin1(2H)-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A67) . 1-((4-(cyclohex-1-en-1-yl)-3,6-dihydropyridin1(2H)-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A68) . 1-((4-(3-chlorophenyl)-3,6-dihydropyridin-1(2H)yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A69). 1-((4-(2-chlorophenyl)-3,6-dihydropyridin-1(2H)yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A73). IF-2019-36422718-APN-ANP#INPI Page 114 of 250 1-((4-(4-chlorophenyl)-3,6-dihydropyridin-1 (2H)yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A74). 1-((4-(1H-pyrazol-1-yl)piperidin-1-yl)sulfonyl)5 3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A79). 1-((4-(benzo[d]oxazol-2-yl)piperidin-1yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A80). 3-methyl-1-((4-(pyrimidin-2-yl)piperidin-1yl)sulfonyl)-1H-imidazole-3-io trifluoromethanesulfonate (Intermediate for compound A81). 1-((2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A82). 1-((5-chloroisoindolin-2-yl)sulfonyl)-3-methyl-1Himidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A89). IF-2019-36422718-APN-ANp#INPI Page 115 of 250 Route 14 To 4-((9-(cyclohexylmethyl)-3-methylene-1,5,9triazacyclododecan-1-yl)sulfonyl)-N,N-dimethylaniline (97 mg, 0.21 mmol) in ACN (0.8 ml) was added 3- methyl-1-((4phenylpiperidin-1-yl)sulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate (95 mg, 0.21 mmol) and the mixture was heated to 80°C for 8 h. It was concentrated and purified directly by flash column chromatography (0-70% hexanes (1% DEA) / ethyl acetate) to provide the free base. To this was added diethyl ether (5 mL) and HCl (52 μL of a 4 N HCl in 1,4-dioxane) and the mixture was allowed to stand for 10 minutes and then concentrated to give 4-{[9-( cyclohexylmethyl)-3methylidene-5-[(4-phenylpiperidin-1-yl)sulfonyl]-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,N-dimethylaniline IF-2O19-36422718-APN-ANP#INPI Page 116 of 250 hydrochloride (compound A35). MS (EI) for C36H55N5O4S2, found 686 [M+H]+. The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ A3 6 4 -{[9-(cyclohexylmethyl)-3-methylidene-5[ (4-phenylpiperazin-l-yl)sulfonyl]- 1,5,9-triazacyclododecan-l-yl ]sulfonyl}-N,N-dimethylaniline 687 A3 7 4 -{[9-(cyclohexylmethyl)-3-methylidene-5[ (4-phenoxypiperidin-l-yl)sulfonyl] 1,5,9-triazacyclododecan-l-yl ]sulfonyl}-N,N-dimethylaniline 702 A3 8 4 -{[9-(cyclohexylmethyl)-3-methylidene-5[ (3-phenylpiperidin-l-yl)sulfonyl]- 1,5,9-triazacyclododecan-l- yl]sulfonyl}-N,N-dimethylaniline 686 A3 9 1-{[9-(cyclohexylmethyl)-5-[4 (dimethylamino)benzenesulfonyl]-3-methylidene-1,5,9-triazacyclododecan-lyl]sulfonyl]piperidine -4-carbonitrile 635 A42 4-{[5-(cyclohexylmethyl)-9-[(4phenylpiperidin-l-yl)sulfonyl]-1,5,9triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 674 A43 4 -{[9-(cyclohexylmethyl)-3-methylidene-5{[(3S)-3-phenylpiperidin-l-yl]sulfonyl}1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 686 A4 6 4-{[9-(cyclohexylmethyl)-5-{[(3R)-3methyl-4-phenylpiperazin-1-yl]sulfonyl}3-methylidene-1,5,9-triazacyclododecan1-yl]sulfonyl}-N, N-dimethylaniline 701 IF-2ü19-36422718-APN-AW#INPI Page 117 of 250 A47 4-{[9-(cyclohexylmethyl)-5-{[(3S)-3methyl-4-phenylpiperazin-l-yl]sulfonyl}3-methylidene-l,5,9-triazacyclododecan1-yl]sulfonyl}-N, N-dimethylanilino 701 A48 4 -{[9-(cyclohexylmethyl)-5-[4 (dimethylamino)benzenesulfonyl]-3-methylidene-1,5,9-triazacyclododecan-lyl]sulfonyl}-1-phenylpiperazin-2-one 701 A49 4-{[9-(cyclohexylmethyl)-3-methylidene-5{[(3R)-3-phenylpiperidin-l-yl]sulfonyl}1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N -dimethylaniline 686 A50 4-{[9—(cyclohexylmethyl)-3-methylidene-5(1,2,3,4-tetrahydroisoquinoline-2sulfonyl)-1,5,9-triazacyclododecan-1yl]sulfonyl}-N,N- dimethylaniline 658 Route 15 N- (3- ( (3IF-2O19-36422718-APN-ANP#INPI Page 118 of 250 aminopropyl)(cyclohexylmethyl)amino)propyl)-4(dimethylamino)benzenesulfonamide (838 mg, 1.84 mmol) in ACN (5 ml) 3-methyl-1-((4-phenylpiperidin-1yl)sulfonyl) was added -1H-imidazole-3-ium trifluoromethanesulfonate (838 mg, 1.84 mmol) and the mixture was heated to 80°C for 8 h, concentrated and purified directly by flash column chromatography (0-70% hexanes (1% DEA) / ethyl acetate) to provide the product. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.8 Hz, 2H), 7.33 (m, 5H), 6.68 (d, J = 8.8 Hz, 2H), 5.75 (br s, 2H), 3.84(m, 2H), 3.18 (m, 2H), 3.05 (s, 6H), 2.91 (m, 4H), 2.65(m, 1H), 2.43 (m, 4H), 2.08 (m, 2H), 1.73 (m, 12H), 1.40(m, 1H), 1.15 (m, 4H), 0.85 (m, 2H). A 4-((9-(cyclohexylmethyl)-3-methyl-5-((4phenylpiperidin-1-yl)sulfonyl)-1,5,9-triazacyclododecan-1yl)sulfonyl)-N,N-dimethylaniline (123 mg, 0.194 mmol) in NMP (10 ml) sodium hydride (19 mg of a 60% dispersion in mineral oil, 0.485 mmol) for 20 min. The mixture was stirred at room temperature for 30 min, then at 80°C for an additional 20 min. The bis-sulfonate was then added over the course of 1 h. After 8 h at 80°C, the mixture was cooled to room temperature, diluted with brine and ethyl acetate, extracted with ethyl acetate (3X), the combined organic extracts were washed with brine (3X), dried with sodium sulfate, filtered and concentrated. Flash chromatography in IF-2019-36422718-APN-ANP#INPI Page 119 of 250 column (0-50% hexanes (1% DEA) / ethyl acetate) provided the free base. The free base was converted to the HCl salt with the addition of ethyl ether (5 mL) and HCl (4N in dioxane, 50 uL). Concentration after 10 minutes gave 4-{[9-(cyclohexylmethyl)-3-methyl-5[(4-phenylpiperidin-1-yl)sulfonyl]-1,5,9-triazacyclododecan1-yl]sulfonyl}-N hydrochloride ,N-dimethylaniline (compound A44). MS (EI) for C36H57N5O4S2, found 688 [M+H]+. The following compound was synthesized in a similar manner: IUPAC No. [M+H]+ B7 N-{3-[(cyclohexylmethyl)(3-{[(4phenylpiperidin-1-yl)sulfonyl]amino}propyl)amino]propyl}-4(dimethylamino)benzene-1- sulfonamide 634 Route 16 EtSO2CI, TEA, DCM EtO2SO BEAR2Et To 1,1-bis(hydroxymethyl)cyclopropane (5.00, 49.0 mmol) in acetone (20 ml) was added TEA (2.2 eq, 108 mmol) and the mixture was cooled to 0-5°C. Ethanesulfonyl chloride was added at a rate to maintain the internal temperature below 10°C (~1 h). After stirring for a further 2 h at room temperature, the mixture was diluted with 150 mL of water, extracted with ethyl acetate (2 x 50 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated to provide the product.1H NMR IF-2019-36422718-APN-A12P#INPI Page 120 of 250 (400 MHz, CDCI3): δ 4.16 (s, 4H), 3.20 (m, 4H), 1.46 (t, J = 7.2 Hz, 6H), 0.83 (s, 4H). MS(EI) for C9H18O6S2, found 287 [M+H]+. The following compound was synthesized in a similar manner to 2-methylpropane-1,3-diyl diethanesulfonate (Intermediate for compound A44). Route 17 Λ°i HN-S-N EITHER ' NaH, N.M.P. HCl (4N in dioxane), diethyl ether N-(3-((cyclohexylmethyl)(3-((4(dimethylamino)phenyl)sulfonamido)propyl)amino)propyl)-4phenylpiperidine-1-sulfonamide (89 mg, 0.14 mmol) in NMP (7 mL) NaH was added (14 mg of a 60% dispersion in mineral oil, 0.35 mmol) in portions for 20 min. The mixture was stirred at room temperature for 30 min and then at 80°C for 20 min. Then the dichloride was added and the IF-2019-36422718-APN-ANp#INPI Page 121 of 250 mixture was heated to 80°C. After 8 h at 80°C, the mixture was cooled to room temperature, diluted with brine and ethyl acetate, extracted with ethyl acetate (3X), the combined organic extracts were washed with brine (3X), dried with sodium sulfate, filtered and concentrated. Flash column chromatography (050% hexanes (1% DEA) / ethyl acetate) provided the product. The product was converted to the HCl salt with the addition of diethyl ether (5 mL) and HCl (4N in dioxane, 35 ul). The mixture was concentrated to give 4{[5-(cyclohexylmethyl)-9-[(4-phenylpiperidin-1-yl)sulfonyl]1,5,9-triazacyclotridecan-1-yl]sulfonyl}-N-dimethylaniline hydrochloride ( compound B5). MS (EI) for C36H57N5O4S2, found 688 [M+H]+. The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ B8 4-{[ (llZ)-5-(cyclohexylmethyl)-9-[ (4phenylpiperidin-l-yl)sulfonyl]-1,5,9triazacyclotridec-ll-en-1-yl ]sulfonyl}-N,N-dimethylaniline 686 B9 4-{[ (11E)-5-(cyclohexylmethyl)-9-[(4phenylpiperidin-1-yl)sulfonyl]-1,5,9triazacyclotridec-11-en-1- yl]sulfonyl}-N,N-dimethylaniline 686 IF-2019-36422718-APN-ANP#INPI Page 122 of 250 Route 18 N-(4-((3aminopropyl)(cyclohexylmethyl)amino)butan-2-yl)-4(dimethylamino)benzenesulfonamide was synthesized following Route 2 with substitution of the appropriate sulfonyl chloride. 4-((5-(cyclohexylmethyl)-2-methyl-11-methylene-9-((4phenylpiperidin-1-yl)sulfonyl)-1,5,9-triazacyclododecan-1yl)sulfonyl)-N,N-dimethylaniline is synthesized following the procedure described in Route 15 substituting with 3chloro-2-(chloromethyl)prop-1-ene to provide 4-((5(cyclohexylmethyl)-2-methyl-11-methylene-9-((4-phenylpiperidin1- yl)sulfonyl)-1,5,9-triazacyclododecan-1-yl)sulfonyl)-N,Ndimethylaniline (compound B6). MS (EI) for C37H57N5O4S2, found 700 [M+H]+. IF-2Q19-36422718-APN-ANp#INPI Page 123 of 25Q The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ NMR B19 4-{[5- (cyclohexylmethyl)-2methyl-ll-methylidene9- [ (4-phenylpiperidin1-yl)sulfonyl]-1,5,9triazacyclododecan-1yl]sulfonyl}-N ,Ndimethylaniline 700 A51 4 -({5-[ (8-chloro- 1,2,3,4- tetrahydroisoquinolin -2-yl)sulfonyl]-9- (cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl}sulfonyl )-N,Ndimethylaniline 692 A52 4-({5-[ (7-chloro- 1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclohexylmethyl)-3-methylidene-1,5,9triazacyclododecane -1yl}sulfonyl)-N,Ndimethylaniline 692 JF-2019-36422718-APN-A12WINPI Page 124 of 250 A53 4- ({5-[ (6-chloro- 1,2,3,4- tetrahydroisoquinolin -2-yl)sulfonyl]-9(cyclohexylmethyl)-3-methylidene-1,5,9triazacyclododecan-1yl}sulfonyl)- N,Ndimethylaniline 692 4H NMR (400 MHz, CDC13) : δ 7.59 (d, J z 8.8 Hz, 2H), 7.15 (m, 2H), 7.04 (m, 1H), 6.70 (d, J = 8.8 Hz, 2H) ), 5.25 (s, 1H), 5.13 (s, 1H), 4.34 (s, 2H), 4.12 (s, 2H), 4.10 (s, 2H), 3.51 (m, 6H), 3.05 (s, 6H) , 2.88 (m, 4H), 2.41 (m, 2H), 2.25 (m, 2H), 1.95 (m, 2H), 1.85 (m, 2H), 1.67 (m, 6H), 1.23 (m, 4H), 0.85 (m, 1H). A54 4-({5-[(5-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9-(cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl}sulfonyl)-N ,Ndimethylaniline 692 A56 4 — ({5 —[ (6-chloro1,2,3,4- tetrahydroisoquinolin -2-yl)sulfonyl]-9- (cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl}sulfonyl)- 3fluoro-N,Ndimethylaniline 710 A57 4-[ (5-{[4- (2chlorophenyl)piperidin1-yl]sulfonyl}-9(cyclohexylmethyl)-3-methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 720 IF-2019-36422718-APN-ANp#INPI Page 125 of 250 A58 4-[(5-{[4-(3chlorophenyl)piperidin1-yl]sulfonyl}-9-(cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 720 A59 4-{[9 - (cyclohexylmethyl)-5- [ (6-fluoro-l,2,3,4tetrahydroisoquinolin -2-yl)sulfonyl]-3methylidene-1,5,9-triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 676 A60 4_ ( {5-[ (6-bromo1,2,3,4- tetrahydroisoquinolin -2-yl)sulfonyl]-9- (cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl]sulfonyl)-N,Ndimethylaniline 736 A64 4- {[9-(cyclohexylmethyl)-5-[(4-cyclopentylpiperidin1-yl)sulfonyl]-3methylidene-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 678 A65 4-{[9-(cyclohexylmethyl)-5 - [(4-cyclohexylpiperidin1-yl)sulfonyl]-3methylidene-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 692 IF-2Q19-36422718-APN-ANP#INPI Page 126 of 25Q A66 4-{[9-(cyclohexylmethyl)-3methylidene-5-{[4-(propan-2-yloxy)piperidin-1yl]sulfonyl}-l,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 668 A67 4 -{[9-(cyclohexylmethyl)-5{[4-(cyclopent-l-en1-yl)-1,2,3,6tetrahydropyridin-1yl]sulfonyl}-3methylidene-1,5,9triazacyclododecan-1yl]sulfonyl}- N,Ndimethylaniline 674 A68 4 -[(5-{[4-(cyclohex1-en-l-yl)-1,2,3,6tetrahydropyridin-1yl]sulfonyl}-9- (cyclohexylmethyl)-3methylidene-1,5, 9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 688 A69 4— [ (5-{[4- (3chlorophenyl)-1,2,3,6tetrahydropyridin-1yl]sulfonyl}-9- (cyclohexylmethyl)-3methylidene-1,5 ,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 718 IF-2ü19-36422718-APN-AW#INPI Page 127 of 250 A70 2-{[9-(cyclohexylmethyl)-5-[4-(dimethylamino)benzene sulfonyl]-3-methylidene-1,5,9triazacyclododecan-1yl]sulfonyl}-l,2,3,4tetrahydroisoquinoline a-6-carbonitrile 683 A71 4-{[9-(cyclohexylmethyl)-5[(6-methoxy-1,2,3,4tetrahydroisoquinolin -2-yl)sulfonyl]-3methylidene-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 688 A72 4-[(5-{[4-(4chlorophenyl)piperidin -1-yl]sulfonyl}-9-(cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 720 A73 4- [(5-{[4-(2-chlorophenyl)-1,2,3,6tetrahydropyridin-1yl]sulfonyl}-9(cyclohexylmethyl)-3-methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 718 IF-2G19-36422718-APN-ANP#INPI Page 128 of 25G A74 4-[(5-{[4-(4chlorophenyl)-1,2,3,6tetrahydropyridin-1yl]sulfonyl}-9-(cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N, Ndimethylaniline 718 A78 4-{[9-(cyclohexylmethyl)-3methylidene-5-{[4-(oxan-4-yl)piperidin1-yl]sulfonyl}-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 694 A79 4-{[9-(cyclohexylmethyl)-3methylidene-5-{[4-(1Hpyrazol-1yl)piperidin-l-yl]sulfonyl}-l,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 676 A80 4- [ (5-{[4- (1,3benzoxazol-2yl)piperidin-lyl]sulfonyl}-9- (cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 727 A81 4-{[ 9-(cyclohexylmethyl)-3methylidene-5-{[4-(pyrimidin-2-yl)piperidin-1-yl]sulfonyl}-1,5,9-triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 688 IF-2019-36422718-APN-ANP#INPI Page 129 of 250 A82 4-({5-[(2-chloro5,6,7,8-tetrahydro-1,6-naphthyridin-6yl)sulfonyl]-9(cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl}sulfonyl)- N,Ndimethylaniline 693 A88 (3Z)-9- (cyclohexylmethyl)-1- [ 4- (dimethylamino)benzene sulfonyl]-N-methoxy-5[(4-phenylpiperidin-lyl)sulfonyl]-1,5,9triazacyclododecan-3imine 717 A83 4-[(5-{[4-(2chlorophenyl)piperazin1-yl]sulfonyl}-9-(cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 721 4H NMR (400 MHz , CDC13) : δ 7.61 (d, z = 8.8 Hz, 2H), 7.39 (m, 2H), 7.05 (m, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.35 (m, 2H), 4.10 (m, 2H), 3.41 (m, 6H), 3.10 (m, 4H), 3.05 (s, 6H), 2.88 (m, 2H), 2.41 (m, 3H), 2.21 (m, 4H), 2.01 (m, 3H), 1.85 (m, 6H), 1.55 (m, 11H), 1.15 (m, 9H), 0.82 (m, 3H) . A84 4— [ (5-{[4- (3chlorophenyl)piperazin- 1-yl]sulfonyl}-9(cyclohexylmethyl)-3-methylidene-1,5,9-triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 721 1H NMR (400 MHz, CDCl3) : δ 7.59 (d, J = 8.8 Hz, 2H), 7.18 (m, 1H), 6.85 (m, 3H), 6.78 (d, J = 8.8 Hz, 2H), 5.25 (m , 2H), 4.10 (m, 2H), 3.51 (m, 2H), 3.20 (m, 10H), 3.05 (s, 6H), 2.88 (m, 2H), 2.41 (m, 2H), 2.01 (m, 2H), 1.85 (m, 4H), 1.65 (m, 6H), 1.25 (m, 5H), 0.82 (m, 1H). IF-2019-36422718-APN-ANP#INPI Page 130 of 250 A85 4-[(5-{[4-(4chlorophenyl)piperazin1-yl]sulfonyl}-9-(cyclohexylmethyl)-3methylidene-1,5,9triazacyclododecan-1yl)sulfonyl]-N,Ndimethylaniline 721 4H NMR (400 MHz, CDC13) : δ 7.59 (d, J z 8.8 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H ), 5.25 (m, 2H), 4.10 (m, 2H), 3.51 (m, 2H), 3.20 (m, 10H), 3.05 (s, 6H), 2.88 (m, 2H), 2.41 (m, 2H) , 2.01 (m,2H), 1.85 (m, 4H), 1.65 (m,6H), 1.27 (m, 5H), 0.85 (m, 1H). A89 4-({5-[(5-chloro-2,3dihydro-1H-isoindol2-yl)sulfonyl]-9(cyclohexylmethyl)-3-methylidene-1,5,9triazacyclododecan-1yl}sulfonyl)-N,Ndimethylaniline 678 1H NMR (400 MHz, CDCl3) : δ 7.59 (d, J = 8.8 Hz, 2H), 7.25 (m, 4H), 6.68 (d, J = 8.8 Hz, 2H), 5.28 (s, 1H), 5.12 ( s, 1H), 4.64 (m, 4H), 4.12 (s, 2H), 3.45 (m, 4H), 3.05 (s, 6H), 2.88 (m, 2H), 2.25 (m, 2H), 1.95 (m , 2H), 1.65 (m, 8H), 1.23 (m, 8H), 0.85 (m, 1H). Route 19 To N-(3-((cyclohexylmethyl) (3-((4(dimethylamino)phenyl)sulfonamido)propyl)amino)propyl)-4phenylpiperidine-1-sulfonamide (33 mg, 0.052 mmol) in NMP (3 ml) was added sodium hydride (4.6 mg of a dispersion at IF-2Q19-36422718-APN-AW#INPI Page 131 of 25Q 60% in mineral oil, 0.11 mmol). The mixture was stirred at room temperature for 30 min, then at 80°C for an additional 20 min. The dichloride (19 mg, 0.052 mmol) was then added. After 2h at 80°C, the mixture was cooled to room temperature, diluted with brine and ethyl acetate, extracted with ethyl acetate (3X), the combined organic extracts were washed with brine (3X), dried with sodium sulfate, filtered and concentrated. Flash column chromatography (0-50% hexanes (1% DEA) / ethyl acetate) gave 9(cyclohexylmethyl)-1-[4-(dimethylamino)benzenesulfonyl]-5[(4-phenylpiperidin-1-yl)sulfonyl ]-1,5,9triazacyclododecan-3-ol (compound A55). MS (EI) for C35H55N5O5S2, found 690 [M + H] +. Route 20 To a solution of 3-fluoro-4-iodoaniline (1.11 g, 4.68 mmol) in acetonitrile (15.00 ml) was added 37% aqueous formaldehyde (8.0 ml, 99.9 mmol) and sodium cyanoborohydride (1.88 g, 29.97 mmol) . Acetic acid (1 mL) was then added dropwise over 10 minutes and the reaction mixture was stirred at room temperature overnight. Aqueous NaOH (1 N, 30 ml) was added and the IF-2019-36422718-APN-ANP#INPI Page 132 of 250 resulting mixture was extracted with ethyl acetate (50 ml). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3-fluoro-4-iodo-N,N-dimethylaniline.1H NMR (400 MHz, CDCl3): δ 7.47 (m, 1H) , 6.43 (m, 1H), 6.28 (m, 1H), 2.94 (s, 6H). To a solution of 3-fluoro-4-iodo-N,Ndimethylaniline (500 mg, 1.89 mmol) in ether (5 ml) was added n-BuLi (0.8 ml, 1.89 mmol) at -78°C. The mixture was stirred for 0.5 h at this temperature. Sulfuryl dichloride (405 mg, 3 mmol) was added and the reaction mixture was stirred for 1 h. The reaction was stopped with water (10 mL) and then adjusted to pH = 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with ethyl acetate (10 ml). The organic phase was separated and concentrated. The residue was purified by silica gel column chromatography to provide 4-(dimethylamino)-2fluorobenzene-1-sulfonyl chloride.1H NMR (400 MHz, CDCl3): δ 7.73 (m, 1H), 6.43 (m, 2H ), 3.15 (s, 3H). Route 21 MeI, NaH, toluene IF-2019-36422718-APN-ANP#INPI Page 133 of 250 For 9-(cyclohexylmethyl)-1-((4(dimethylamino)phenyl)sulfonyl)-5-((4-phenylpiperidin-1yl)sulfonyl)-1,5,9-triazacyclododecan-3-ol (30 mg, 0.043 mmol) In toluene (0.5 ml) NaH (1.6 mg of a 60% dispersion in mineral oil, 0.065 mmol) was added followed by iodomethane (14 pL, 0.22 mmol). After stirring for 1 h, the mixture was quenched with water, extracted with DCM (2X), the organic extracts were combined and dried over sodium sulfate, filtered and concentrated. Flash column chromatography (0-50% hexanes / ethyl acetate + 1% DEA) provided 4-{[9-(cyclohexylmethyl)-3methoxy-5-[(4-phenylpiperidin-1-yl)sulfonyl]-1, 5,9triazacyclododecan-1-yl]sulfonyl}-N,N-dimethylaniline (compound A61). MS (EI) for C36H57N5O5S2, found 704 [M+H]+. Route 22 IF-2019-36422718-APN-ANP#INPI Page 134 of 250 For 9-(cyclohexylmethyl)-1-((4(dimethylamino)phenyl)sulfonyl)-5-((4-phenylpiperidin-1yl)sulfonyl)-1,5,9-triazacyclododecan-3-ol (171 mg, 0.248 mmol) DCM (10 ml) was added followed by DessMartin periodinan (126 mg, 0.297 mmol). The mixture was allowed to stand for 2 hours at room temperature, then concentrated and directly purified by FCC (0-60% hexanes (1% DEA) / ethyl acetate) to provide 9(cyclohexylmethyl)-1-((4 -(dimethylamino)phenyl)sulfonyl)-5((4-phenylpiperidin-1-yl)sulfonyl)-1,5,9-triazacyclododecan3-one (compound B20). MS (EI) for C35H53N5O5S2, found 688 [M+H]+. Route 23 A 4-( (5-( (6-bromo-3,4-dihydroisoquinolin-2 (1H)yl)sulfonyl)-9-(cyclohexylmethyl)-3-methylene-1,5,9triazacyclododecan1-yl)sulfonyl)-N ,N-dimethylaniline (70 mg, 0.095 mmol) in DMF (0.7 ml) was added water (0.1 ml), phenylboronic acid (13 mg, 0.10 mmol), Pd (dppf)CX-DCM (7.8 mg, 0.001 mmol ) and sodium carbonate (30 mg, 0.29 mmol). The IF-2Q19-36422718-APN-ANP#INPI Page 135 of 25Q mixture was heated at 80°C for 1 h, then diluted with brine, extracted with ethyl acetate (2X), dried with sodium sulfate, filtered and concentrated. Flash column chromatography (0-50% hexanes (1% DEA) / ethyl acetate) afforded 4-((9-(cyclohexylmethyl)3-methylene-5-((6-phenyl-3,4-dihydroisoquinolin- 2 (1H))yl)sulfonyl)-1,5,9-triazacyclododecan-1-yl)sulfonyl)-N,Ndimethylaniline (compound A63). MS (EI) for C40H53N5O4S2, found 734 [M+H]+. Route 24 To a mixture of cyclopentanone (5.50 g, 65.5 mmol) and Na2CO3 (10.4 g, 98.2 mmol) in DCM (130 ml) was added Tf2O (18.6 g, 72.0 mmol) at -20°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solid was separated by filtration and the IF-2O19-36422718-APN-ANP#INPI Page 136 of 250 filtrate was concentrated to give cyclopentenyl trifluoromethanesulfonate. A solution of cyclopentenyl trifluoromethanesulfonate (7.7 g, 35.6 mmol) in 1,4-dioxane (105 mL) and water (50 mL) was degassed and then filled with argon. tert-Butyl 4(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-5, 6-dihydropyridine1(2H)-carboxylate (6.0 g, 19.4 mmol), Pd(PPh3)4 (1.02 g, 0.88 mmol) and sodium carbonate (10.3 g, 97.1 mmol) were added. The reaction mixture was stirred overnight at 90°C and then cooled to room temperature. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (ethyl acetate / hexanes = 1:99 to 5:95) afforded tert-butyl 4cyclopentenyl-5,6-dihydropyridine-1(2H)-carboxylate. 1H NMR (400 MHz, CDCl3): δ 5.73 (br s, 1H), 5.56 (br s, 1H), 4.00 (br s, 2H), 3.45 (br s, 2H), 2.47 (m, 4H), 2.33 (br s, 2H), 1.94 (m, 2H), 1.48 (s, 9H). To a solution of tert-butyl 4-cyclopentenyl-5,6dihydropyridine-1(2H)-carboxylate (3.3 g, 15.3 mmol) in methanol (30 ml) was added Pd / C (0.6 g). The mixture was hydrogenated at a pressure of 15 psi for 5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 4-cyclopentylpiperidine-1IF-2O19-36422718-APN-ANP#INPI Page 137 of 250 tert-butyl carboxylate. To a solution of tert-butyl 4-cyclopentylpiperidine-1carboxylate (2.9 g, 11.5 mmol) in ethyl acetate (15 ml) was added EtOAc / HCl (4N, 20 ml). The mixture was stirred for 2 h and the solvent was removed. The resulting product was washed with ether to provide 4-cyclopentylpiperidine hydrochloride. 1H NMR (400 MHz, D2O): δ 3.25 (m, 2H), 2.75 (m, 2H), 1.84 (m, 2H), 1.61 (m, 2H), 1.45 (m, 8H), 0.96 (m, 2H ). 4cyclopentylpiperidine hydrochloride (1.4 g, 9.5 mmol) and 1-(1H-imidazol-1ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (3.45 g, 9.5 mmol) were mixed in CH3CN (20 mL). The mixture was stirred at room temperature overnight. The solvent was removed. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:9 to 1:3) to provide 1-(1H-Imidazol-1ylsulfonyl)-4-cyclopentylpiperidine. 1H NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 7.24 (s, 1H), 7.14 (s, 1H), 3.87 (m, 2H), 2.51 (m, 2H), 1.83 (m, 4H ), 1.54 (m, 5H), 1.33 (m, 2H), 1.08 (m, 3H). To a solution of 1-(1H-Imidazol-1-ylsulfonyl)-4cyclopentylpiperidine (500 mg, 1.8 mmol) in DCM (5 ml) was added MeOTf (0.3 g, 1.8 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the resulting product was washed with IF-2019-36422718-APN-ANP#INPI Page 138 of 250 ether to provide 1-((4-cyclopentylpiperidin-1yl)sulfonyl)-3-methyl-1H-imidazol-3-io trilfluoromethanesulfonate. 1H NMR (400 MHz, CD3OD) : δ 9.59 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 4.00 (s, 3H), 3.95 (m, 2H), 2.87 (m, 2H ), 1.81 (m, 4H), 1.54 (m, 6H), 1.23 (m, 4H). The following compounds were synthesized in a similar manner: 1- ((4-cyclohexylpiperidin-1-yl)sulfonyl)-3-methyl1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate for compound A65). 3-methyl-1-((4-(tetrahydro-2H-pyran-4yl)piperidin-1-yl)sulfonyl)-1H-imidazol-3-io trifluoromethanesulfonate (Intermediate for compound A78). Route 25 Para 9-(cyclohexylmethyl)-1-((4(dimethylamino)phenyl)sulfonyl)-5-((4-phenylpiperidin-1yl)sulfonyl)-1,5,9-triazacyclododecan-3-one (19 mg, 0.028 IF-2019-36422718-APN-ANP#INPI Page 139 of 250 mmol) in DCM (0.5 ml) and methanol (0.05 ml) hydroxylamine hydrochloride (5.8 mg, 0.083 mmol) and sodium acetate (6.8 mg, 0.083 mmol) were added. The mixture was stirred for 6 hours at room temperature, then concentrated and purified by flash column chromatography (060% hexanes (1% DEA) / ethyl acetate) to provide 9-(cyclohexylmethyl)-1-((4 -(dimethylamino)phenyl)sulfonyl)-5((4-phenylpiperidin-1-yl)sulfonyl)-1,5,9-triazacyclododecan3-one oxime (compound A75). MS (EI) for C35H54N6O5S2, found 703 [M+H]+. Route 26 A solution of 1-chloro-2iodobenzene (5.0 g, 21.1 mmol) in DMF (150 mL) was degassed and then filled with argon. 4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl) tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate (7.13 g, 23.0 mmol), Pd(dppf)Cl2 (1.7 g, 2.1 mmol) and carbonate IF-2Q19-36422718-APN-ANP#INPI Page 14Q of 25Q of potassium (8.69 g, 63.0 mmol) were added. The reaction mixture was stirred overnight at 110°C and then cooled to room temperature. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (ethyl acetate / hexanes = 1:9 to 1:4) afforded tert-butyl 4-(2-chlorophenyl)-5,6-dihydropyridin-1(2H)carboxylate. . 1H NMR (400 MHz, CDCl3) : δ 7.37 (m, 1H), 7.18 (m, 3H), 5.67 (m, 1H), 4.06 (m, 2H), 3.64 (m, 2H), 2.46 (br s, 2H), 1.51 (s, 9H). To a solution of tert-butyl 4-(2-chlorophenyl)-5,6dihydropyridine-1(2H)-carboxylate (2.0 g, 6.8 mmol) in MeOH (20 mL) was added HCl / MeOH (3 M, 20 ml). The mixture was stirred at room temperature for 2 h. The resulting solution of 4-(2-chlorophenyl)1,2,3,6-tetrahydropyridine hydrochloride was used directly in the next step. To the solution of 4-(2chlorophenyl)piperidine hydrochloride in MeOH / HCl, PtO2 (0.1 g) . The mixture was hydrogenated at room temperature under 15 psi for 3 h. The catalyst was removed by filtration and the filtrate was concentrated to give the product. 1H NMR (400 MHz, DMSO-d6): δ 9.19 (br s, 2H), 7.37 (m, 1H), 7.36 (m, 4H), 3.44 (m, 1H), 3.33 (m, 2H), 3.08 ( m, 2H), IF-2019-36422718-APN-ANP#INPI Page 141 of 250 1.95 (m, 4H) . The free base (0.95 g, 4.8 mmol) and 1-(1Himidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate were mixed in CH3CN (10 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel column chromatography to provide 1-(1H-imidazole-1-ylsulfonyl)-4-(2chlorophenyl)piperidine. 1H NMR (400 MHz, CDCl3) : □ 8.01 (s, 1H), 7.36 (m, 2H), 7.18 (m, 4H), 4.07 (m, 2H), 3.06 (m, 1H), 2.74 (m, 2H), 1.99 (m, 2H), 1.81 (m, 2H). To a solution of 1-(1H-imidazole-1-ylsulfonyl)-4(2-chlorophenyl)piperidine (501 mg, 1.5 mmol) in DCM (5 ml) was added MeOTf (0.27 g, 1.63 mmol). The mixture was stirred at room temperature overnight. The solvent was removed. The resulting product was washed with ether to provide 1-((4-(2-chlorophenyl)piperidin-1-yl)sulfonyl)3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (intermediate for compound A57). 1H NMR (400 MHz, CD3OD): δ 9.65 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.39 (m, 4H), 4.16 (m, 2H), 4.02 (s, 3H ), 3.31 (m, 3H), 2.03 (m, 2H), 1.85 (m, 2H). The following compounds were synthesized in a similar manner: 1-((4-(3-chlorophenyl)piperidin-1-yl)sulfonyl)-3methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate IF-2O19-36422718-APN-ANP#INPI Page 142 of 250 for compound A58). 1- ((4-(4-chlorophenyl)piperidin-1-yl)sulfonyl)-3methyl-1H-imidazole-3-ium trifluoromethanesulfonate (Intermediate for compound A72). Route 27 CICO2Et DCM NaH, N.M.P. To a solution of 2-(3-chlorophenyl)ethanamine (149 g, 0.95 mol) and TEA (144 g, 1.42 mol) in DCM (1.5 L) ethyl carbonchloridate (107 g, 1.14 mol) was added dropwise to 0°C. The reaction mixture was stirred for 3 h and then washed with 1N aqueous HCl (1 L) and aqueous NaHCO3. IF-2019-36422718-APN-ANP#INPI Page 143 of 250 saturated (600 ml) . The DCM layer was dried over anhydrous sodium sulfate and concentrated to give methyl 3-chlorophenethylcarbamate. 1H NMR (400 MHz, CDCla): δ 7.27 (m, 3H), 7.08 (m, 1H), 4.77 (m, 1H) , 3.78 (s, 3H), 3.44 (m, 2H), 2.80 (m, 2H). Methyl 3-chlorophenethylcarbamate (193 g, 0.9 mol) was dissolved in CF3SO3H (1.36 kg). The mixture was heated to 120°C overnight. The mixture was cooled to room temperature and then poured into ice water (4 L). The resulting product was collected by filtration and washed with ether to give 6-chloro-3,4-dihydroisoquinolin1(2H)-one.1H NMR (400 MHz, CDCl3): δ 8.01 (m, 1H), 7.35 (m, 1H), 7.25 (m, 2H), 6.21 (br s, 1H), 3.60 (m, 2H), 3.01 (m, 2H) . To a solution of 6-chloro-3,4-dihydroisoquinolin1(2H)-one (33 g, 182 mmol) in THF (330 ml) was added dropwise BH3—Me2S (73 ml, 729 mmol). The reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and then quenched with 6N aqueous HCl (300 mL). The THF was removed under reduced pressure and the remaining solution was refluxed overnight. The mixture was concentrated to a certain volume and then basified with 2N aqueous NaOH. The resulting mixture was extracted with DCM. The DCM layer was dried over anhydrous sodium sulfate and concentrated to provide 6-chloro1,2,3,4-tetrahydroisoquinoline. IF-2Q19-36422718-APN-ANP#INPI Page 144 of 25Q a solution 6-chloro-1,2,3,4tetrahydroisoquinoline (18.5 g, 0.11 mol) in CH3CN (180 ml) was added 2,3-dimethyl-1-((2-methyl-1H-imidazol1-yl)sulfonyl compound) -1H-imidazole-3-ium trifluoromethanesulfonate (43.5 g, 0.11 mol, Reference: J. Org. Chem. 2002, 68, 115119). The reaction mixture was stirred overnight at 30°C. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:1) to provide 6-chloro-2-(2-methyl-1Himidazol-1-ylsulfonyl)-1, 2,3,4-tetrahydroisoquinoline. 1 HOUR NMR (400 MHz, CDCl3): δ 7.21 (m, 1H), 7.18 (s, 1H), 7.02 (m, 1H), 6.94 (m, 1H), 4.45 (s, 2H), 3.62 (m, 2H) , 2.92 (m, 2H), 2.67 (s, 3H). To a solution of 6-chloro-2-(2-methyl-1H-imidazol1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (25.5 g, 82 mmol) in DCM (260 ml) CF3SO3Me (13.45 g) was added. , 82 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was washed with ether to give 1-(6-chloro-3,4dihydroisoquinolin-2(1H)-ylsulfonyl)-2,3-dimethyl-1Himidazol-3-ium trifluoromethanesulfonate. To a solution of 1-(6-chloro-3,4dihydroisoquinolin-2(1H)-ylsulfonyl)-2,3-dimethyl-1Himidazol-3-ium trifluoromethanesulfonate (8.7 g, 18.4 mmol) in CH3CN (100 ml) was added (R)-N-(3-amino-2-methylpropyl)4-(dimethylamino)benzenesulfonamide (5.0 g, 18.4 mmol). The IF-2O19-36422718-APN-ANP#INPI Page 145 of 250 reaction mixture was stirred overnight at 30°C. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:3 to 1:1) to provide (S)-6-chloro-N-(3((4- (dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (compound B10).1H NMR (400 MHz, CDCl3): δ 7.85 (m, 2H), 7.43 (m, 2H), 7.18 (m, 2H), 7.03 (m, 1H), 4.35 (s, 2H), 3.48 (m, 2H) , 3.18 (s, 6H), 3.15 (m, 1H), 2.95 (m, 6H), 2.85 (m, 1H), 1.89 (m, 1H), 0.89 (m, 3H). (S)-6-Chloro-N-(3-((4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (300 mg, 0.6 mmol) was dissolved in NMP (3 ml) and NaH (60%, 96 mg, 2.4 mmol) was added. The mixture was stirred for 30 min at room temperature and then heated to 80°C for 20 min. The mixture was cooled to room temperature. A solution of ((cyclohexylmethyl)azanediyl)bis(propane-3,1diyl)dimethanesulfonate (231 mg, 0.6 mmol) in NMP (1 ml) was added. The reaction mixture was heated to 80°C for 1 h, then cooled to room temperature and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (15 ml). The extract was washed with brine and concentrated. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:8 to 1:3) to provide compound A87. MS(EI) for C34H52ClN5O4S2, IF-2O19-36422718-APN-ANP#INPI Page 146 of 250 found 695 [M+H]+.1H NMR (400 MHz, CDCI3): δ 7.59 (d, J = 8.8 Hz, 2H), 7.15 (m, 2H), 7.00 (m, 1H), 6.68 (d, J = 8.8 Hz, 2H), 4.34 (m, 2H), 3.71 (m, 2H), 3.45 (m, 2H), 3.17 (m, 3H), 3.05 (s, 6H), 2.88 (m, 4H), 2.25 (m, 2H), 2.15 (m, 6H), 1.95 (m, 2H), 1.65 (m, 8H), 1.23 (m, 6H), 0.95 (m, 5H). The following compounds were synthesized in a similar manner: IUPAC No. [M+H] + NMR BU N-[ (2R)-3-{[ (6-chloro1,2,3,4-tetrahydroisoquinolin-2yl)sulfonyl]amino]-2methylpropyl]-4- (dimethylamino) benzene-1sulfonamide 501 A90 4-{[ (3S)-9- (cyclohexylmethyl)-3methyl-5-{[ (3S)-3phenylpyrrolidin-1yl]sulfonyl]-l,5,9triazacyclododecan-1yl]sulfonyl]-N,Ndimethylaniline 674 A91 4-{[(3S)-9-(cyclohexylmethyl)-3methyl-5-{[(3R)-3phenylpyrrolidin-1yl]sulfonyl}-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 674 IF-2O19-36422718-APN-ANP#INPI Page 147 of 250 A92 4-{[ (33)-9- (cyclohexylmethyl)-3methyl-5-[(4phenoxypiperidin-1yl)sulfonyl]-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 704 A93 4-{[ (33) )-9- (cyclohexylmethyl)-3methyl-5-{[4-(pyrimidin-2yl)piperazin-1yl]sulfonyl}-l,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 691 A94 4-{[ (33)-9- (cyclohexylmethyl)-5-{[4(2-fluorophenyl)piperazin-1yl]sulfonyl}-3-methyl-1,5,9-triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 707 A95 4 -{[(33)-9-(cyclohexylmethyl)-5-{[4(3-fluorophenyl)piperazin-lyl]sulfonyl}-3-methyl1,5,9-triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 707 A96 4-{[(3S)-9-(cyclohexylmethyl)-5-{[4(4-fluorophenyl)piperazin-1yl]sulfonyl}-3-methyl1,5,9-triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 707 IF-2O19-36422718-APN-ANP#INPI Page 148 of 250 A97 4-{[(33)-9-(cyclohexylmethyl)-3-methyl-5-{[4-(2-methylphenyl)piperazin-1yl]sulfonyl}-l,5,9triazacyclododecan-1yl]sulfonyl}-N, Ndimethylaniline 703 A98 4-{[(33)-9-(cyclohexylmethyl)-3methyl-5-{[4-(3-methylphenyl)piperazin-1yl]sulfonyl}-l,5,9triazacyclododecan-1yl]sulfonyl}-N, Ndimethylaniline 703 A99 4-{[(33)-9- (cyclohexylmethyl)-3methyl-5-{[4 - (4-methylphenyl)piperazin-1yl]sulfonyl}-l,5,9triazacyclododecan-1yl]sulfonyl}-N, Ndimethylaniline 703 A1OO 4-{[(33)-5-((4benzoylpiperazin-1yl)sulfonyl]-9-(cyclohexylmethyl)-3methyl-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 717 A101 4-{[ (3S)-9-(cyclohexylmethyl)-3methyl-5-[(3phenylazetidin-1yl)sulfonyl]-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 660 IF-2019-36422718-APN-ANP#INPI Page 149 of 250 A102 4-{[(33)-9-(cyclohexylmethyl)-5-{[4(4-fluoro-2-methylphenyl)piperazin-1yl]sulfonyl}-3-methyl1,5,9-triazacyclododecan-1yl]sulfonyl} -N, Ndimethylaniline 721 A76 4-{[(3R)-9- (cyclohexylmethyl)-3methyl-5- [(4phenylpiperidin-1yl)sulfonyl]-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 688 4H NMR (400 MHz, CDCla) : δ 7.60 (d, J = 8.8 Hz, 2H), 7.33 (m, 5H), 6.82 (d, J = 8.8 Hz, 2H), 3.77 (m, 4H), 3.28 (m, 1H), 3.18 (m, 3H), 3.05 (s, 6H), 2.88 (m, 4H), 2.61 (m, 1H), 2.41 (m, 1H), 2.21 (m, 4H), 2.01 (m, 3H) ), 1.85 (m, 8H), 1.25 (m, 6H), 0.93 (m, 3H), 0.82 (m, 4H). A77 4-{[(3S)-9-(cyclohexylmethyl)-3methyl-5-[(4phenylpiperidin-1yl)sulfonyl]-1,5,9triazacyclododecan-1yl]sulfonyl}-N,Ndimethylaniline 688 1H NMR (400 MHz, CDCl3 ): δ 7.60 (d, J = 8.8 Hz, 2H), 7.33 (m, 5H), 6.82 (d, J = 8.8 Hz, 2H), 3.77 (m, 4H), 3.28 (m, 1H), 3.18 ( m, 3H), 3.05 (s, 6H), 2.88 (m, 4H), 2.61 (m, 1H), 2.41 (m, 1H), 2.21 (m, 4H), 2.01 (m, 3H), 1.85 (m , 8H), 1.25 (m, 6H), 0.93 (m, 3H), 0.82 (m, 4H). IF-2019-36422718-APN-ANP#INPI Page 150 of 250 Route 28 ho Cl Na2CO3, ACN H2, Pd / C MeOH NaBH(OAc)3, DCM TEA, MsCI, DCM To a solution of benzylamine (37.7 g, 0.350 mol) in CH3CN (1 L) was added 3-chloropropan-1-ol (100 g, 1.06 mol) and Na2CO3 (131 g, 1.24 mol). The reaction mixture was refluxed for 50h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 1:99 to 3:97) to provide 3,3'(benzylazanediyl)dipropan-1-ol.1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 3.70 (m, 4H), 3.61 (s, 2H), 3.48 (s, 2H), 2.68 (m, 4H), 1.78 (m, 4H). To a solution of 3,3'-(benzylazidiyl)dipropan-1ol (55 g) in MeOH (500 ml) was added Pd / C (10 g). The mixture was hydrogenated at room temperature under a pressure of 15 kg for 6 h. The mixture was filtered and the filtrate was concentrated to give 3,3'-azanodiyldipropan-1-ol. 1H NMR (400 MHz, CDCl3): δ 3.78 (m, 4H), 3.46 (s, 2H), 2.84 (m, 4H), 1.75 (m, 4H). IF-2019-36422718-APN-ANP#INPI Page 151 of 250 To a solution of 3,3'-azanodiyldipropan-1-ol (15 g, 113 mmol) in DCM (300 mL) was added cyclohexanecarbaldehyde (18.8 g, 141 mmol) and NaBH(OAc)3 (72.5 g, 0.34 mol) . The mixture was stirred for 0.5 h and HOAc (20.4 g, 0.34 mol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with water (150 mL) and then adjusted to pH = 12 with NaOH. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM = 3:97 to 1:9) to provide 3,3'((cyclohexylmethyl)azanediyl)bis(propan-1-ol).1H NMR (400 MHz, CDCl3): δ 3.75 (m, 4H), 2.64 (m, 4H), 2.18 (m, 2H), 1.75 (m, 9H), 1.55 (m, 1H), 1.21 (m, 3H), 0.89 ( m, 1H). To a solution of the compound 3,3'((cyclohexylmethyl)azanediyl)bis(propan-1-ol) (1.2 g, 5.2 mmol) and TEA (1.0 g, 10.4 mmol) in DCM (15 ml) was added MsCl ( 1.18 g, 10.4 mmol) at 0°C. The reaction mixture was stirred for 4h and then quenched with water (15 ml). The DCM layer was separated, dried over anhydrous sodium sulfate, and concentrated to provide the compound ((cyclohexylmethyl)azanediyl)bis(propane-3,1diyl)dimethanesulfonate. The dimesylate was used immediately without further purification. IF-2Q19-36422718-APN-ANP#INPI Page 152 of 25Q Route 29 or _ d cbzHNBr Boc2O ,NHBoc NaBH(OAc)3 Η2Ν'Χχ- / ~χΝΗ2------- ί mu -------------- BocHN'^ / XN'^- / ^NHCbz--------- - THF2TEA, DMFHDCM Cld-X1 NaH NMP To a solution of propane-1,3-diamine (100 g, 1.35 mol) in THF (800 ml) was added to a solution of Boc2O (73.6 g, 0.34 mol) in THF (200 ml) at 0~10°C. The reaction mixture was stirred for 3h and water (1L) was added. The resulting mixture was extracted with ethyl acetate (500 ml x 2). The organic layers were combined and concentrated to a volume of 400 ml. Hexane (300 mL) was added and 15% aqueous oxalic acid (1 L) was added to the resulting solution. The mixture was stirred for 0.5 h. The organic layer was decanted and the aqueous layer was adjusted to pH = 10 with 3N aqueous NaOH. The resulting mixture was extracted IF-2O19-36422718-APN-ANP#INPI Page 153 of 250 with DCM (600 ml x 2) . The combined extracts were dried over anhydrous sodium sulfate and concentrated to give tert-butyl 3-aminopropylcarbamate.1H NMR (400 MHz, CDCl3): δ 5.03 (br s, 1H), 3.23 (br s, 2H), 2.69 (m, 2H), 1.71 (m, 2H), 1.44 (s, 9H). Triethylamine (4.70 g, 46.5 mmol) was added dropwise to a stirred mixture of benzyl 3-bromopropylcarbamate (4.2 g, 15.5 mmol) to give tert-butyl 3-aminopropylcarbamate (2.7 g, 15.5 mmol) in DMF (50 mL). at room temperature. The reaction mixture was heated to 70°C for 1 h. Most of the DMF was removed in vacuo and the remaining mixture was diluted with water (120 mL) and washed with ether (150 mL x 4) to remove most of the dialkylated byproduct. The aqueous layer was adjusted to pH=11 with 1N aqueous NaOH and extracted with ether (200 ml). The extract was washed with water (150 mL x 3) to remove unreacted tert-butyl 3-aminopropylcarbamate, dried over anhydrous sodium sulfate, and concentrated to give (3-((3(((benzyloxy)carbonyl)amino)). propyl)amino)propyl)carbamate tert-butyl.1H NMR (400 MHz, CDCl3): δ 7.36 (m, 5H), 5.60 (br s, 1H), 5.11 (m, 3H), 3.30 (m, 2H), 3.20 (m, 2H), 2.68 (m, 4H), 1.70 (m, 5H), 1.44 (s, 9H). To a solution of tert-butyl (3((((benzyloxy)carbonyl)amino)propyl)amino)propyl)carbamate (100 mg, 0.27 mmol) in DCM (5 ml) was IF-2019-36422718-APN-ANP#INPI Page 154 of 250 added cyclohexanecarbaldehyde (31 mg, 0.27 mmol) and HOAc (30 mg, 1.1 mmol). The mixture was stirred for 0.5 h and NaBH(OAc)3 (235 g, 1.1 mmol) was added in one portion. The reaction mixture was stirred for 4 h. TLC analysis showed a 50% conversion and another portion of cyclohexane carbaldehyde (15 mg, 0.13 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water (10 mL) was added to quench the reaction and the mixture was adjusted to pH = 2 by adding HOAc. The mixture was stirred for another 0.5 h and then adjusted to pH = 12 with aqueous NaOH (1 N). The organic layer was separated and concentrated to give tert-butyl (3((((benzyloxy)carbonyl)amino)propyl)(cyclohexylmethyl)amino)propyl)carbamate.1H NMR (400 MHz, CDCl3): δ 7.27 (m, 5H), 6.12 (br s, 1H), 5.55 (br s, 1H), 5.01(s, 3H), 3.34 (m, 2H), 3.18 (m, 2H), 3.08 (m, 2H), 2.80(m, 4H), 1.65 (m, 9H), 1.44 (s, 9H), 1.12 (m, 6H). To a solution of tert-butyl(3((((benzyloxy)carbonyl)amino)propyl)(cyclohexylmethyl)amino)propyl)carbamate (0.50 g, 1.1 mmol) in MeOH (5 mL) Pd / C (0.1) was added. g). The mixture was hydrogenated at a pressure of 15 psi for 3 h. The mixture was filtered and the filtrate was concentrated to give tert-butyl (3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)carbamate. 1H NMR (400 MHz, CDCl3) : δ 5.78 (br s,1H), 3.19 (br s, 2H), 2.78 (m, 2H), 2.40 (m, 4H), 2.13 (m,2H), IF-2O19-36422718-APN-ANP#INPI Page 155 of 250 1.98 (br s, 2H), 1.67 (m, 9H), 1.44 (s, 9 H), 1.12 (m, 4H), 0.89 (m, 2H). To a solution of tert-butyl (3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)carbamate (1.2 g, 3.7 mmol) in CH3CN (10 mL) was added 3-methyl-1-(4)-phenylpiperidine -1-ylsulfonyl)-1H-imidazole-3-ium (1.47 g, 3.7 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel column chromatography to provide tert-butyl 3((cyclohexylmethyl)(3-(4-phenylpiperidine-1sulfonamido)propyl)amino)propylcarbamate. To a solution of tert-butyl 3-((cyclohexylmethyl)(3-(4-phenylpiperidine-1-sulfonamido)propyl)amino)propylcarbamate (0.85 g, 1.5 mmol) in DCM (15 ml) was added TFA (10 ml). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed and the residue was dissolved in DCM (50 ml). The solution was basified with 1N aqueous NaOH. The DCM layer was dried over anhydrous Na2SO4 and concentrated to provide N-(3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)-4phenylpiperidine-1-sulfonamide. To a solution of N-(3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)-4phenylpiperidine-1-sulfonamide (90 mg, 0.20 mmol) in DCM (5 ml) was added TEA (40 mg, 0.4 mmol). The mixture was cooled to IF-2O19-36422718-APN-ANP#INPI Page 156 of 250 0°C and a solution of 4(dimethylamino)-2,6-difluorobenzene-1-sulfonyl chloride (60 mg, 0.24 mmol) in DCM (1 ml) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (30 ml) and then washed with water (20 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to provide N-(3-((cyclohexylmethyl)(3-(4(dimethylamino)phenylsulfonamido)propyl)amino)propyl)-4phenylpiperidine-1-sulfonamide. To a solution of N-(3-((cyclohexylmethyl) (3-(4(dimethylamino)phenylsulfonamido)propyl)amino)propyl)-4phenylpiperidine-1-sulfonamide (80 mg, 0.123 mmol) in NMP (2 ml) was added NaH (12 mg, 0.29 mmoL). The mixture was heated at 80°C for 0.5 h. The mixture was cooled to room temperature and a solution of 3-chloro-2(chloromethyl)prop-1-ene (15 mg, 0.12 mmol) in NMP (0.1 ml) was added. The reaction mixture was heated to 80°C for 2 h. The mixture was cooled to room temperature and water (20 ml) was added. The resulting mixture was extracted with ethyl acetate (15 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10:30 to 20:10) to provide compound A86. MS(EI) for C36H53F2N5O4S2, found 733 [M+H] + .1H NMR (400 MHz, CDCl3): δ 7.31 (m, 5H), 6.18 (m, IF-2O19-36422718-APN-ANP#INPI Page 157 of 250 2H), 5.25 (m, 2H), 4.05 (s, 2H), 3.87 (m, 4H), 3.20 (m, 4H), 3.05 (s, 6H), 2.88 (m, 2H), 2.41 (m, 4H), 2.05 (m, 5H), 1.75 (m, 9H), 1.27 (m, 6H), 0.85 (m, 2H). Route 30 BuLi, SO2CI2 Et2O To a solution of 3,5-difluoro-4-iodo-N, Ndimethylaniline (500 mg, 1.77 mmol) in ether (5 ml) was added dropwise n-BuLi (0.71 ml, 1.77 mmol) at 78°C. The mixture was stirred for 0.5 h at -78°C. Sulfuryl dichloride (358 mg, 1.5 mmol) was added. The reaction mixture was stirred for another 0.5 h. The mixture was quenched with water (10 ml) and then extracted with ethyl acetate (15 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give the crude product, which was further recrystallized from hexane / EtOAc (10:1) to give 4-(dimethylamino)-2,6-difluorobenzene-1-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) : δ 6.21 (s, 1H), 6.18 (s, 1H), 3.09 (s, 6H). Route 31 o'NH2 HCI IF-2019-36422718-APN-ANP#INPI Page 158 of 250 To a suspension of 1,3-dichloropropan-2-one (5.0 g, 39.5 mmol) in H2O (50 ml) was added Omethylhydroxylamine hydrochloride (3.5 g, 41.5 mmol) and the reaction mixture was stirred at room temperature. Temperature for 1 h. The organic layer was separated, diluted with ether and concentrated in vacuo (<30°C) to provide 1,3dichloropropan-2-one O-methyl oxime. 1H NMR (400 MHz, CDCl3) : δ 4.33 (s, 2H), 4.27 (s, 2H), 3.94 (s, 3H). Route 32 A (S)-6-chloro-N-(3-( (4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (100.0 mg, 0.200 mmol) in dry NMP (3 ml) at 0°C NaH (24.0 mg, 0.600 mmol) was added and the mixture was stirred at room temperature for 20 minutes and turned from a cloudy to almost clear mixture during this time. Iodomethane (27 pl, 0.440 mmol) was added and the mixture was allowed to stir at room temperature for 1 hour and did not progress beyond completing 50%, so the same amount of NaH and methyl iodide was added again and completed the reaction. after an additional hour at room temperature. HE IF-2019-36422718-APN-ANP#INPI Page 159 of 250 added brine (10 ml) and EA (10 ml). The aqueous layer was extracted with EA (1 x 5 ml) and the organic extracts were combined, washed with brine (3 x 10 ml), dried with sodium sulfate, filtered and concentrated. FCC (hexanes / EA 0-70%) provided compound B12. MS(EI) for C23H33ClN4O4S2, found 529 [M+H]+. Route 33 (S)NH2 ClO2S N BocHN NHBoc TEA, DCM H O N To a solution of methyl methacrylate (300 g, 3.0 mol) in MeOH (1.5 l) was added (S)-1-phenylethanamine (363 g, 3 mol). The reaction mixture was refluxed for 5 days. The mixture was concentrated and the residue was IF-2Q19-36422718-APN-ANP#INPI Page 16Q of 25Q purified by silica gel column chromatography (EtOAc / petroleum ether = 1:9 to 1:1) to provide methyl 2methyl-3-((S)-1-phenylethylamino)propanoate.1H NMR ( 400 MHz, CDCl3): δ 7.25 (m, 5H), 3.75 (m, 1H), 3.69 (s, 3H), 2.75 (m, 3H), 1.39 (m, 1H), 1.28 (m, 3H), 1.09 (m, 3H). To a solution of 2-methyl 3-((S)-1phenylethylamino)propanoate (440 g, 1.99 mol) in acetone (6 L) was added TsOH-H2O (378 g, 1.99 mol). The mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and dried to give a salt (300 g) which was suspended in acetone (2 L) and refluxed for 1 h. The mixture was cooled to room temperature and the resulting precipitate was collected by filtration to provide a salt which was suspended in DCM (2 L) and saturated aqueous K2CO3 (1.5 L). The mixture was stirred for 0.5 h and the solid dissolved. The DCM layer was separated, dried over anhydrous Na2SO4 and concentrated to provide (R)-methyl 2-methyl-3-((S)-1phenylethylamino)propanoate. To a solution of (R)-methyl 2-methyl-3-((S)-1phenylethylamino)propanoate (140 g, 0.630 mol) in MeOH (1.4 L), HOAc (30 mL) and Pd / C ( 15g). The mixture was hydrogenated at a pressure of 20 kg at 60°C for 6 h. The catalyst was removed by filtration and the filtrate was concentrated to give 3-amino-2 IF-2ü19-36422718-APN-AW#INPI Page 161 of 250 (R)-methyl methylpropanoate.1H NMR (400 MHz, CDCI3) : δ 5.09 (br, 3H), 3.72 (s, 3H), 3.05 (m, 1H), 2.93 (m, 1H), 2.75 (m, 1H), 1.23 (d, J = 7.2 Hz, 3H). To a solution of (R)-methyl 3-amino-2-methylpropanoate (112 g, 0.63 mol) in dichloromethane (1 L) was added TEA (160 g, 1.58 mol) and Boc2O (152 g, 0.69 mol) at 0~5°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was washed with water (1 L), 2N aqueous HCl (1 L) and saturated aqueous NaHCO3 (1 L), respectively. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to provide (R)-methyl 3-(tert-butoxycarbonylamino)-2-methylpropanoate.1H NMR (400 MHz, CDCl3): δ 4.94 (br s, 1H), 3.70 (s, 3H), 3.31 (m, 2H), 2.70 (m, 1H), 1.52 (s, 9H), 1.18 (d, J = 7.2 Hz, 3H). To a solution of (R)-methyl 3-(tert-butoxycarbonylamino)-2methylpropanoate (6 g, 51.3 mmol) in THF (60 mL) was added LiBH4 (1.12 g, 102 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was quenched with water (30 ml) followed by the addition of 1N aqueous HCl to adjust the pH = 2~3. The resulting mixture was extracted with ethyl acetate and the extract was washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated to give (R)-tert-butyl 3-hydroxy-2methylpropylcarbamate.1H NMR (400 MHz, IF-2( j¡9-36422718-AP\-AN'P#I\PI Page 162 of 250 CDCI3): δ 3.57 (m, 1H), 3.37 (m, 2H), 3.05 (m, 1H), 1.77 (m, 1H), 1.48 (s, 9H), 0.88 (d, J = 7.2 Hz, 3H) . To a solution of (R)-tert-butyl 3-hydroxy-2methylpropylcarbamate (2.5 g, 13.2 mmol) in toluene (25 mL) was added PPh3 (4.15 g, 15.8 mmol) and isoindoline-1,3-dione (2.72 g, 18.5 mmol). The mixture was cooled to 0~5°C and DIAD (3.2 g, 15.8 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. The precipitated solid was separated by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:9 to 1:1) to provide (R)tert 3(1,3-dioxoisoindolin-2-yl)-2-methylpropylcarbamate. -butyl. 1H NMR (400 MHz, CDCl3): δ 7.85 (m, 2H), 7.47 (m, 2H), 5.23 (br s, 1H), 3.64 (m, 2H), 3.03 (br s, 2H), 2.13 (m , 1H), 1.43 (s, 9H), 0.96 (d, J = 6.4 Hz, 3H). To a solution of (R)-tert-butyl 3-(1,3-dioxoisoindolin-2-yl)-2methylpropylcarbamate (40 g, 8.83 mmol) in MeOH (200 mL) was added methylamine solution (7.8 g, 30% in MeOH). The reaction mixture was heated at 60°C for 6 h. The solvent was removed under reduced pressure. The residue was suspended in ether (300 ml) and then stirred for 0.5 h. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give (S)-tert-butyl 3-amino-2-methylpropylcarbamate. To a solution of 3-amino-2-methylpropylcarbamate IF-2O19-36422718-APN-ANP#INPI Page 163 of 250 of (S)-tert-butyl (12.5 g, 66.5 mmol) in DCM (250 ml) TEA (10.3 g, 101.7 mmol) was added. The mixture was cooled to 0~5°C and 4-(dimethylamino)benzene-1sulfonyl chloride (16 g, 72 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was washed with water and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 1:9 to 3:7) to provide (R)-tert-butyl 3-(4-(dimethylamino)phenylsulfonamido)-2methylpropylcarbamate. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 5.45 (m, 1H), 4.72 (m, 1H), 3.18 (m, 1H), 3.04(s, 6H), 2.98 (m, 2H), 2.75 (m, 1H), 1.78 (m, 1H), 1.41(s, 9H), 0.87 (m, J = 6.8 Hz, 3H). To a solution of (R)-tert-butyl 3-(4(dimethylamino)phenylsulfonamido)-2-methylpropylcarbamate (21 g, 59.3 mmol) in MeOH (150 mL) was added 4N HCl / MeOH (150 mL). The mixture was stirred for 3 h at room temperature. The solvent was removed under reduced pressure. The resulting solid was suspended in DCM (200 ml) and saturated aqueous K2CO3 (150 ml) was added. The mixture was stirred for 5 minutes and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the compound (R)-N-(3-amino-2-methylpropyl)-4-(dimethylamino)benzenesulfonamide. 1H NMR (400 MHz, CDCl3) : δ 7.70 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 3.04 (s, 6H), 2.98 IF-2019-36422718-APN-A16P#INPI Page 164 of 250 (m, 1H), 2.75 (m, 2H), 2.58 (m, 1H), 1.78 (m, 2H), 0.87 (m, J = 7.2 Hz, 3H). Using a similar method, (S)-N-(3amino-2-methylpropyl)-4-(dimethylamino)benzenesulfonamide (Intermediate for compound A76) was synthesized. Route 34 (dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-1,2,3,4tetrahydronaphthalene-2-sulfonamide (100 mg, 200 μΜ) in dry NMP (4 ml) at 0°C NaH (24 mg, 600 μmol) and the mixture was stirred at room temperature for 20 minutes, during which time it went from a cloudy mixture to almost clear. Dichloride (21.3 μ^ 200 μmol) was added and the mixture was heated to 80°C. After 40 minutes, the reaction was stopped with brine and the aqueous layer was extracted with ethyl acetate (2X), the combined organic extracts were washed with brine (3X), dried with sodium sulfate, filtered and concentrated. Column chromatography (0-50% hexanes + 1% IF-2Q19-36422718-APN-ANP#INPI Page 165 of 25Q diethylamine) / ethyl acetate provided the product (compound B21). MS(EI) for C25H35CIN4O4S2, found 555 [M+H]+. Route 35 IF-2O19-36422718-APN-ANP#INPI Page 166 of 250 a solution of 1-(4-fluoro-2-methoxyphenyl) piperazine (1.4 g, 6.8 mmol) in CH3CN (15 ml) was added 1-(1H-imidazole-1-ylsulfonyl)-3-methyl -1H-imidazole-3-ium trifluoromethanesulfonate (2.7 g, 6.8 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography to give 1-((1H-imidazol1-yl)sulfonyl)-4-(4-fluoro-2-methoxyphenyl)piperazine. CF3SO3Me (0.45 g, 2.7 mmol) at 0°C. The reaction mixture was stirred at room temperature for 5 h, then concentrated and the resulting product was washed with ether to provide 1-((4-(4-fluoro-2methoxyphenyl)piperazin-1-yl)sulfonyl)-3- methyl.-1H-imidazol3-io trifluoromethanesulfonate. To a solution of (R)-N-(3-amino-2-methylpropyl)4-(dimethylamino)benzenesulfonamide (0.6 g, 2.2 mmol) in CH3CN (6 ml) was added 1-((4-(4-fluoro -2methoxyphenyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-imidazol-3ium trifluoromethanesulfonate (1.1 g, 2.2 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography to give (S)-N-(3-((4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-4-(4fluoro-2-methoxyphenyl)piperazine -1-sulfonamide. IF-2O19-36422718-APN-ANP#INPI Page 167 of 250 a solution of (S)-N-(3-((4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-4-(4fluoro-2-methoxyphenyl)piperazine-1-sulfonamide (771 mg, 1.42 mmol) in NMP (7 ml) NaH (140 mg, 3.48 mmol, 60%) was added. The mixture was stirred for 0.5 h at 80°C. The mixture was cooled to 70°C and ((cyclohexylmethyl)azanediyl)bis(propane-3,1-diyl)dimethanesulfonate (820 mg, 2.1 mmol) was added. The reaction mixture was stirred for 2 hours at 70°C, then cooled and poured into water. The resulting mixture was extracted with ethyl acetate. The extract was concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc = 10:1) to give compound A137. MS (EI) for C36H57FN6O5S2, found 737 [M+H]+. 1H NMR (400 MHz, CDCl3) : δ 7.62 (d, J = 8.8 Hz, 2H), 7.16 (m, 2H), 7.05 (m, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.35 ( m, 2H), 3.62 (m, 4H), 3.19 (m, 2H), 3.04 (s, 6H), 2.87 (m 4H), 2.46 (m, 5H), 1.92 (m, 1H), 1.79 (m, 2H), 1.66 (m, 4H). The following compounds were synthesized in a similar manner: IF-2O19-36422718-APN-ANP#INPI Page 168 of 250 IUPAC No. [M+H]+ A153 4-{[ (3S)-9-(cyclohexylmethyl)-5-[4(dimethylamino)benzenesulfonyl]-3-methyl1,5,9-triazacyclododecan-l-yl]sulfonyl} tere-butyl piperazine-l-carboxylate 714 A118 2-(4-{[(3S)-9-(cyclohexylmethyl)-5-[4(dimethylamino)benzenesulfonyl]-3-methyl1,5,9-triazacyclododecan-l- il]sulfonyl}piperazin-l-yl)benzonitrile 715 A154 4-{[ (3S)-9-(cyclohexylmethyl)-5-{[4- (2methoxyphenyl)piperazin-l-yl]sulfonyl}-3methyl-1,5 ,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 720 A155 4-{[(3S)-9-(cyclohexylmethyl)-3-methyl-5(piperazine-l-sulfonyl)-1,5, 9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 613 A119 4-{[ (3S)-9- (cyclohexylmethyl)-5-{[4- (2,6dimethylphenyl)piperazin-l-yl]sulfonyl}-3methyl- 1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 717 A136 4-{[ (3S)-9- (cyclohexylmethyl)-5-[ (6-ethyl- 1,2,3, 4-tetrahydroisoquinolin-2-yl)sulfonyl]-3-methyl-l, 5,9-triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 688 A161 4-{[(3S)-9-(cyclohexylmethyl)-5 -{[6-(4fluoro-2-methylphenyl)-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl}-3methyl-1,5,9-triazacyclododecan-lyl]sulfonyl}-N,N-dimethylaniline 733 Al 62 4-{[ (3S)-9-(cyclohexylmethyl)-5-{[ (2S)-4- (4fluoro-2-methylphenyl)-2-methylpiperazin-lyl]sulfonyl}-3-methyl-l, 5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 735 A163 4-{[ (3S)-9-(cyclohexylmethyl)-5-{[ (2R)-4-(4fluoro-2-methylphenyl)-2- methylpiperazin-1yl]sulfonyl}-3-methyl-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 735 IF-2Q19-36422718-APN-ANP#INPI Page 169 of 25Q A166 4-{[(3S)-9-(cyclohexylmethyl)-3-methyl-5-[(5methyl-1,2,3,4-tetrahydroisoquinolin-2yl)sulfonyl]-1,5,9-triazacyclododecan-l- yl]sulfonyl}-N,N-dimethylaniline 674 A138 4-{[(3S)-9-(cyclohexylmethyl)-5-[(5-methoxy1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]3- methyl-l,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 690 A151 2-{[(3S)-9-(cyclohexylmethyl)-5-[4-(dimethylamino)benzenesulfonyl]-3 -methyl-l,5,9triazacyclododecan-l-yl]sulfonyl}-l,2,3,4-tetrahydroisoquinoline-5-carbonitrile 685 A170 4-{[(3S)-9-(cyclohexylmethyl)-3-methyl-5 -[(1methyl-1,2,3,4-tetrahydroisoquinolin-2yl)sulfonyl]-1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 674 A172 4-{[(3S)- 9-(cyclohexylmethyl)-3-methyl-5-[(3methyl-1,2,3,4-tetrahydroisoquinolin-2yl)sulfonyl]-1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N- dimethylaniline 674 A173 4-{[(3S)-9-(cyclohexylmethyl)-3-methyl-5-({4[2-(trifluoromethoxy)phenyl]piperazin-1yl]sulfonyl)-1,5,9-triazacyclododecan-lyl ]sulfonyl}-N,N-dimethylaniline 773 A174 4-{[(33)-9-(cyclohexylmethyl)-5-{[4-(3,4difluoro-2-methoxyphenyl)piperazin-1-yl]sulfonyl]-3 -methyl-l,5,9-triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 755 A175 4-{[ (33)-9-(cyclohexylmethyl)-5-{[4- (3-fluoro2-methoxyphenyl) piperazin-l-yl]sulfonyl]-3methyl-1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 737 A17 6 4-{[(33)-9-(cyclohexylmethyl)-5- {[4-(5-fluoro2-methoxyphenyl)piperazin-l-yl]sulfonyl]-3methyl-1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 737 A177 4-{[(3S )-9-(cyclohexylmethyl)-5-{[(3R)-4-(4fluoro-2-methoxyphenyl)-3-methylpiperazin-1yl]sulfonyl}-3-methyl-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 751 IF-2O19-36422718-APN-ANP#INPI Page 170 of 250 A178 4-{[(33)-9-(cyclohexylmethyl)-5-{[3-(4-fluoro-2-methoxyphenyl)azetidin-1-yl]sulfonyl}-3-methyl-l,5,9-triazacyclododecan- l-yl]sulfonyl]-N,Ndimethylaniline 708 A181 4-{[ (33)-5- [ (5-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9- (cyclohexylmethyl) -3-methyl-l,5,9-triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 694 A187 (33)-N-benzyl-9-(cyclohexylmethyl)-5-[4(dimethylamino)benzenesulfonyl]-3 -methyl1,5,9-triazacyclododecane-l-sulfonamide 634 Al 98 4-{[(3S)-5-{[4-(2-chlorophenyl)piperazin-1yl]sulfonyl}-9-(cyclohexylmethyl)-3-methyl1 ,5,9-triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 723 A199 4-{[(33)-9-(cyclohexylmethyl)-5-{[4-(4-methoxyphenyl)piperazin-1-yl]sulfonyl}-3methyl-1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 719 A201 4-{[(33)-9-(cyclohexylmethyl)-5-{[4-(3methoxyphenyl)piperazin -l-yl]sulfonyl}-3methyl-1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 719 A202 4-{[ (33)-9-(cyclohexylmethyl)-5-{[ 4 - (3fluoro-4-methoxyphenyl)piperazin-l-yl]sulfonyl]-3-methyl-l,5,9-triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 737 A206 4-{[(3S)- 5-{[4-(2-chloro-4-fluorophenyl)piperazin-l-yl]sulfonyl]-9(cyclohexylmethyl)-3-methyl-l,5,9-triazacyclododecan-l-yl]sulfonyl}-N, Ndimethylaniline 741 A147 4-{[(4S)-5-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclohexylmethyl)-4-methyl-1,5,9triazacyclododecane -1-yl]sulfonyl}-N,Ndimethylaniline 694 IF-2019-36422718-APN-AN]1#INPI Page 171 of 250 A148 4-{[(4R)-5-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclohexylmethyl)-4-methyl-l,5,9triazacyclododecan-l-yl ]sulfonyl]-N,Ndimethylaniline 694 A150 4-{[ (2S)-5-[ (6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclohexylmethyl)-2-methyl -l, 5,9triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 694 A14 9 4-{[ (2R) -5- [ (6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl] -9(cyclohexylmethyl)-2-methyl-l, 5,9triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 694 Al 90 4-{[ (3S)-5- [ (6-chloro-l,2,3 ,4- tetrahydroisoquinolin-2-yl)sulfonyl] -9[ (1S)-1-cyclohexylethyl]-3-methyl-l, 5,9triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 708 Al 91 4-{[ (3S)-5-[(6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9[(IR)-1-cyclohexylethyl]-3-methyl-l,5,9triazacyclododecan- l-yl]sulfonyl]-N,Ndimethylaniline 708 A207 4-{[(3S)-9-[(IS)-1-cyclohexylethyl]-5-{[(3R)4-(4-fluoro-2-methoxyphenyl) -3-methylpiperazin1-yl]sulfonyl]-3-methyl-l,5,9triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 765 A205 N,N-dimethyl-4-{[(3S)-3-methyl- 9-[(1S)-1phenylethyl]-5-(1,2,3,4-tetrahydroisoquinoline—2—sulfonyl)-1,5,9triazacyclododecan-1-yl]sulfonyl}aniline 668 IF-2Q19-36422718-APN-ANp#INPI Page 172 of 25Q Route 36 nh2nh2 To a solution of (R)-methyl 2-((tert-butoxycarbonylamino)methyl)butanoate (4.8 g, 20.8 mmol) in THF (50 mL) was added LiBH4 (0.7 g, 33 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was quenched with water (30 ml), followed by the addition of 1 N aqueous HCl dropwise to adjust to pH = 2~3. The resulting mixture was extracted with ethyl acetate and the extract was washed with saturated aqueous NaHCO3, dried over anhydrous sodium sulfate and concentrated to give (R)-tert-butyl 2-(hydroxymethyl)butylcarbamate. To a solution of (R)-tert-butyl 2-(hydroxymethyl)butylcarbamate (3.4 g, 16.7 mmol) in toluene (40 mL) was added PPh3 (6.2 g, 17.4 mmol) and isoindoline-1,3-dione ( 3.7 g, 25 mmol). The mixture was cooled to 0~5°C and added dropwise JF-2019-36422718-APN-A17Í3#INPI Page 173 of 250 drop DIAD (4.3 g, 22 mmol) . The reaction mixture was stirred at room temperature for 3 h. The resulting precipitate was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 9:1 to 1:1) to provide 1-(4-fluoro2-methoxyphenyl)-4-(2-methyl-1H-imidazol-1ylsulfonyl)piperazine. To a solution of 1-(4-fluoro-2-methoxyphenyl)-4(2-methyl-1H-imidazol-1-ylsulfonyl)piperazine (3.8 g, 11.4 mmol) in EtOH (70 mL) was added hydrazine hydrate ( 1.1g, 80%). The reaction mixture was refluxed for 6 h. The resulting product was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1N aqueous NaOH (20 mL) and then extracted with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to provide (S)-tert-butyl 2-(aminomethyl)butylcarbamate. To a solution of (S)-tert-butyl 2-(aminomethyl)butylcarbamate (1.87 g, 9.2 mmol) in DCM (20 ml) was added TEA (1.01 g, 10.1 mol). The mixture was cooled to 0~5°C and 4-(dimethylamino)benzene-1-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was washed with water and then concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 9:1 to 7:3) to provide 2-((4IF-2019-36422718-APN-aNP#INPI Page 174 of 250 (R)tert-butyl (dimethylamino)phenylsulfonamido)methyl)butylcarbamate. To a solution of (R)tert-butyl 2-((4(dimethylamino)phenylsulfonamido)methyl)butylcarbamate (2.9 g, 7.5 mmol) in MeOH (10 ml) was added 4N HCl / MeOH (15 ml). The mixture was stirred for 3 h at room temperature. The solvent was removed under reduced pressure. The resulting product was suspended in DCM (100 ml) and saturated aqueous K2CO3 (450 ml) was added. The mixture was stirred for 5 min. The DCM layer was separated, dried over anhydrous sodium sulfate and concentrated to provide (R)-N-(2-(aminomethyl)butyl)-4-(dimethylamino)benzenesulfonamide. To a solution of (R)-N-(2-(aminomethyl)butyl)-4(dimethylamino)benzenesulfonamide (0.9 g, 3.2 mmol) in CH3CN (9 ml) was added 1-((6-chloro-3,4 -dihydroisoquinolin-2(1H)yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-io trifluoromethanesulfonate (0.59 g, 3.2 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc = 8:1 to 2:1) to provide (S)-6-chloro-N-(2-((4(dimethylamino)phenylsulfonamido )methyl)butyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide. To a solution of (S)-6-chloro-N-(2-((4(dimethylamino)phenylsulfonamido)methyl)butyl)-3,4IF-2019-36422718-APN-ANp#INPI Page 175 of 250 dihydroisoquinoline-2(1H)-sulfonamide (0.8 g, 1.5 mmol) in NMP (3 ml) NaH (159 mg, 3.9 mmol, 60%) was added. The mixture was stirred for 0.5 h at 80°C. The mixture was cooled to 70°C and cyclopropane-1,1-diylbis(methylene) dimethanesulfonate (510 mg, 2.0 mmol) was added. The reaction mixture was stirred for 2 h at 70°C. The solvent was removed and the residue was purified by column chromatography (petroleum ether / EtOAc = 15:1) to provide compound A182. LC-MS: m / z 708.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.59 (m, 2H), 7.15 (m, 2H), 7.05 (m, 1H), 6.68 (m, 2H), 4.34 (m, 2H), 3.55 (m, 4H ), 3.19 (m, 6H), 3.04 (s, 6H), 2.87 (m, 4H), 2.15 (m, 4H), 1.89 (m, 10H), 1.32 (m, 8H), 0.88 (m, 3H) . Route 37 Para (S)-5- ((6-chloro-3,4-dihydroisoquinolin2(1H)-yl)sulfonyl)-9-((4-(dimethylamino)phenyl)sulfonyl)-7methyl-1,5,9-triazacyclododecane Benzyl-1-carboxylate IF-2019-36422718-APN-ANP#INPI Page 176 of 250 (25 mg) HBr (33% in acetic acid, 0.5 ml) was added. After 30 minutes at room temperature, the mixture was diluted with diethyl ether and water (1:1 mixture, 10 ml) and the organic layer was removed. The aqueous layer was washed with diethyl ether (1 x 5 ml), basified with NaOH (4 N) to pH ~ 12 and then extracted with DCM (3 x 2 ml). The organic extracts were dried with sodium sulfate, filtered and concentrated. Addition of hexanes (∼2 mL) followed by concentration was used to facilitate product precipitation. Drying under vacuum provided compound A183. MS(EI) for C27H40ClN5O4S2, found 598 [M+H] + . Route 38 To a solution of isobutyraldehyde (1.0 g, 7.5 mmol) in DCM (1.22 g, 11.3 for 30 min at temperature (1.8 g, 30.1 mmol) and 3,3'-azanodiyldipropan-1-ol (20 ml) was added (mmol). The mixture was stirred ambient. Acid was added and the mixture was stirred for another 30 minutes. Triacetoxyborohydride was then added. IF-2019-36422718-APN-ANi7#INPI Page 177 of 250 sodium (6.40 g, 30.1 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was adjusted to pH = 1-2 with 3N aqueous HCl and then stirred for 1 h. 20% aqueous NaOH was added to the mixture (to adjust the pH to 10-11) and then extracted with DCM (50 ml). The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3,3'-(isobutylazilanediyl)bis(propan-1-ol). To a solution of 3,3'(isobutylazanediyl)bis(propan-1-ol) (780 mg, 4.1 mmol) in DCM (10 ml) was added NEt3 (820 mg, 8.2 mmol). MsCl (935 mg, 8.2 mmol) was then added slowly at 0°C. The reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with DCM (20 ml) and then washed with water (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to provide 3,3'(isobutylazilanediyl)bis(propane-3,1diyl)dimethanesulfonate. To a solution of (S)-6-chloro-N-(3-((4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (0.515 g, 1.03 mmol) NaH (0.25 g, 2.26 mmol) was added to dry N-methylpyrrolidone at room temperature. The mixture was heated to 80°C with stirring for 30 minutes and then cooled to room temperature. 3,3'(isobutylazanediyl)bis(propane-3,1-diyl)dimethanesulfonate was added JF-2019-36422718-APN-A17Í8#INPI Page 178 of 250 (0.5 g, 1.5 mmol) and the reaction mixture was heated to 80°C for 2 h. The reaction was quenched with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to provide compound A152. MS (EI) for C31H4sClN5O4S2, found 654.4 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.59 (d, 2H), 7.16 (m, 2H), 7.04 (m, 1H), 6.69 (d, 2H), 4.32 (m, 2H), 3.60 (m, 4H), 3.31 (m, 3H), 3.04 (s, 6H ), 2.90 (m, 4H), 2.27 (m, 4H), 1.93 (m, 2H), 1.79 (m, 1H), 0.87 (m, 9H). The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ A123 4-{[ (3S)-5- [ (6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-3methyl-9-(3-methylbutyl) -1,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 668 A156 4-{[(3S)-5-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl ]-3methyl-9-[(3-methylphenyl)methyl]-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 702 IF-2019-36422718-APN-ANP#INPI Page 179 of 250 A131 4-{[(3S)-5-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-3methyl-9-[(4-methylphenyl)methyl]-1,5,9triazacyclododecan -l-yl]sulfonyl}-N,Ndimethylaniline 702 A157 4-{[ (3S)-5- [ (6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclopentylmethyl) -3-methyl-l,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 680 A106 4-{[(3S)-5-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl )sulfonyl] -3methyl-9-(2-methylbutyl)-1,5,9- triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 668 A108 4-{[ (3S)-5- [ (6-chloro- l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclobutylmethyl)-3-methyl-l,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 666 A134 4-{[(3S)- 5-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-9-(2cyclohexylethyl)-3-methyl-l,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 708 A122 4-{[(3S)-5-[(6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9-(2cyclopropylethyl)-3-methyl-l,5,9triazacyclododecan- l-yl]sulfonyl}-N,Ndimethylaniline 666 A120 4-{[ (3S)-5- [ (6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9-(2cyclopentylethyl) -3-methyl-l,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 694 A165 4-{[(3S)-5-[(6-chloro-1,2,3,4-tetrahydroisoquinoline-2 -yl)sulfonyl]-3methyl-9-(3,3,3-trifluoropropyl)-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 694 IF-2019-36422718-APN-ANP#INPI Page 180 of 250 A141 4-{[(3S)-5-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-3methyl-9-(propan-2-yl)-1,5,9triazacyclododecan- l-yl]sulfonyl]-N,Ndimethylaniline 640 A176 4-{[ (3S)-5- [ (6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9[ (cyclopent- l-en-l-yl)methyl]-3-methyl1,5,9-triazacyclododecan-l-yl]sulfonyl]N,N-dimethylaniline 678 A135 4-{[ (3S)-5- [ (6-chloro- l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9-[(cyclohex-l-en-l-yl)methyl]-3-methi1-1,5,9triazacyclododecan-l-yl]sulfonyl] -N,Ndimethylaniline 692 Al 67 4-{[ (3S)-5- [ (6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-3methyl-9- (2,2,2-trifluoroethyl )-1,5,9triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 680 A169 4-{[ (3S)-5- [ (6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl) sulfonyl]-9[ (3,3-difluorocyclobutyl)methyl]-3-methyl1,5,9-triazacyclododecan-l-yl]sulfonyl]N,N-dimethylaniline 702 A133 4-{[ (3S)-5- [ ( 6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-3methyl-9-[(2-methylphenyl)methyl]-1,5,9triazacyclododecan-l-yl]sulfonyl]-N,Ndimethylaniline 702 A140 4-{[(3S)-5-[(6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9-(2methoxyethyl)-3-methyl-l,5,9-triazacyclododecane -l-yl]sulfonyl]-N,Ndimethylaniline 656 A125 4-{[(3S)-5-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-3methyl-9- [(1,3-oxazol-2-yl)methyl]-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 679 IF-2019-36422718-APN-AW#INPI Page 181 of 250 A124 4-{[ (33)-5- [ (6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl] -3methyl-9- [ (l,2-oxazol-3-yl)methyl] -1,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 679 A183 4-{[(33)-5-[(6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl ]-3methyl-1,5,9-triazacyclododecan-l-yl]sulfonyl}-N,N-dimethylaniline 598 A185 4-{[ (33)-5- [ (6-chloro-l,2,3,4- tetrahydroisoquinolin-2-yl)sulfonyl]-9-[(4,4-difluorocyclohexyl)methyl]-3-methyl1,5,9-triazacyclododecan-l-yl]sulfonyl}N,N-dimethylaniline 730 A107 4-{[ ( 33)-5-[(6-chloro-l,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9(2,2-dimethylpropyl)-3-methyl-l,5,9triazacyclododecan-l-yl ]sulfonyl}-N,Ndimethylaniline 668 A204 4-{[ (3S)-5- [ (6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9- [(4-fluorocyclohexyl) methyl]-3-methyl-1,5,9triazacyclododecan-1-yl]sulfonyl}-N,Ndimethylaniline 712 IF-2019-36422718-APN-ANp#INPI Page 182 of 250 Route 39 To a mixture of 4-fluoro-2-methoxyaniline (25.0 g, 177 mmol), K2CO3 (36.7 g, 266 mmol) and NaI (10.6 g, 0.07 mmol) in i-PrOH (250 mL) was added bis( 2chloroethyl)amine (47 g, 177 mmol). The reaction mixture was heated to reflux overnight. The solvent was removed and the residue was purified by column chromatography (petroleum ether / EtOAc = 10:1) to provide 1-(4-fluoro-2-methoxyphenyl)piperazine. MS: m / z 212.36 IF-2019-36422718-APN-ANP#INPI Page 183 of 250 [M+H]+. A solution of 1-(4-fluoro-2methoxyphenyl)piperazine (4.0 g, 19 mmol) in MeCN (40 mL) was added to 2,3-dimethyl-1-(2-methyl-1H-imidazol-1-ylsulfonyl) 1H-imidazole-3-ium (7.5 g, 19 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed and the residue was purified by column chromatography (petroleum ether / EtOAc = 20:1) to provide 1-(4-fluoro-2-methoxyphenyl)-4-(2-methyl-1Himidazol-1-ylsulfonyl). )piperazine. MS: m / z 355.36 [M+H]+. To a solution of 1-(4-fluoro-2-methoxyphenyl)-4(2-methyl-1H-imidazol-1-ylsulfonyl)piperazine (6.0 g, 17 mmol) in DCM (60 mL) CF3SO3Me (2.78 g, 17 mmol). The reaction mixture was stirred for 2 h at room temperature. The solvent was removed and the residue was washed with ether to give 1-(4-(4-fluoro-2-methoxyphenyl)piperazin-1ylsulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate. To a solution of 1-(4-(4-fluoro-2methoxyphenyl)piperazin-1-ylsulfonyl)-2,3-dimethyl-1Himidazol-3-ium trifluoromethanesulfonate (740 mg, 2.3 mmol) in CH3CN (8 ml) was added tert-butyl 3-((3aminopropyl)(cyclohexylmethyl)amino)propylcarbamate (1.17 g, 2.3 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by chromatography in IF-2Q19-36422718-APN-ANP#INPI Page 184 of 25Q column (petroleum ether / EtOAc 2:1) to = 8:1 provide tert-butyl-3-((cyclohexylmethyl) (3-(4-(4fluoro-2-methoxyphenyl)piperazine-1sulfonamido)propyl)amino)propylcarbamate. To a solution of tert-butyl-3((cyclohexylmethyl)(3-(4-(4-fluoro-2-methoxyphenyl)piperazine1-sulfonamido)propyl)amino)propylcarbamate (600 mg, 1 mmol) in DCM (30 mL) TFA (30 ml) was added. The mixture was stirred for 2 h at room temperature. The solvent was removed and the residue was dissolved in ethyl acetate, then washed with saturated aqueous NaHCO3. The organic phase was dried over anhydrous sodium sulfate and concentrated to give N-(3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)-4-(4-fluoro-2methoxyphenyl)piperazine-1-sulfonamide. To a solution of N-(3-((3aminopropyl)(cyclohexylmethyl)amino)propyl)-4-(4-fluoro-2methoxyphenyl)piperazine-1-sulfonamide (416 mg, 0.83 mmol) in DCM (5 ml) was added Et3N (170 mg, 1.66 mmol) and 4-(dimethylamino)benzenesulfonyl chloride (365 mg, 1.66 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated and purified by column chromatography (petroleum ether / EtOAc = 8:1 to 2:1) to provide N-(3-((cyclohexylmethyl)(3-(4(dimethylamino)phenylsulfonamido)propyl)amino )propyl)-4-(4fluoro-2-methoxyphenyl)piperazine-1-sulfonamide. IF-2O19-36422718-APN-ANP#INPI Page 185 of 250 To a solution of N-(3-((cyclohexylmethyl)(3-(4(dimethylamino)phenylsulfonamido)propyl)amino)propyl)-4-(4fluoro-2-methoxyphenyl)piperazine-1-sulfonamide (320 mg, 0.45 mmol ) in NMP (3 ml) NaH (53 mg, 1.32 mmol, 60% dispersion) was added. The mixture was stirred for 0.5 hours at 80°C, then cooled to 70°C and cyclopropane-1,1diylbis(methylene)dimethanesulfonate (170 mg, 0.66 mmol) was added. The reaction mixture was stirred for 2 h at 70°C. The solvent was removed and the residue was purified by column chromatography (petroleum ether / EtOAc = 15:1) to provide compound A193. MS (EI) for C37H57FN6O5S2, found 745.0 [M+H]+. 1H NMR (400MHz, CDCl3): d 7.57 (t, 2H), 6.64 (t, 1H), 6.63 (br s, 4H), 3.86 (s, 3H), 3.19 (m, 4H), 3.04 (m, 8H), 2.87 (m , 12H), 2.36 (m, 2H), 1.56 (m, 15H), 0.43 (m, 4H). IF-2O19-36422718-APN-ANP#INPI Page 186 of 250 Route 40 BocHN CbzOSu BocHN AND NHCbz TFA To a solution of (S)-tert-butyl 3-amino-2-methylpropylcarbamate (4.0 g, 21.3 mmol) in THF (20 mL) and water (20 mL) was added CbzOSu (5.83 g, 23.5 mmol). Aqueous NaOH (4N) was added to adjust to pH = 11. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (15 ml) and then extracted with ethyl acetate (50 ml). The organic phase was washed with 1N aqueous HCl, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give benzyl tert-butyl (2methylpropane-1,3-diyl) (S)-dicarbamate. To a solution of benzyl tert-butyl (2IF-2O19-36422718-APN-ANP#INPI Page 187 of 250 methylpropane-1,3-diyl) (S)-dicarbamate (4.5 g, 14.0 mmol) in DCM (25 ml) TFA (20 ml) was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was dissolved in DCM (50 ml). The resulting solution was washed with saturated aqueous K2CO3 and the DCM layer was dried over anhydrous sodium sulfate and concentrated to provide (R)-benzyl 3-amino-2methylpropylcarbamate. To a solution of (R)-benzyl 3-amino-2-methylpropylcarbamate (2.7 g, 12.2 mmol) in CH3CN (25 ml) was added 1-(6-chloro-3,4-dihydroisoquinolin-2(1H) -ylsulfonyl)2,3-dimethyl-1H-imidazole-3-ium (5.7 g, 12.2 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography to give (S)-benzyl 3-(6-chloro1,2,3,4-tetrahydroisoquinoline-2-sulfonamido)-2methylpropylcarbamate. (S)-Benzyl 3-(6-chloro-1,2,3,4tetrahydroisoquinolin-2-sulfonamido)-2-methylpropylcarbamate (2.7 g, 6.0 mmol) was dissolved in HBr (48%) / HOAc (20 mL). . The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (100 ml) and then washed with ether (50 ml). The aqueous layer was basified with NaOH to pH = 10. The resulting mixture was extracted with DCM (100 ml). The DCM layer was dried over anhydrous sodium sulfate and concentrated to provide (S)-N-(3-amino-2-methylpropyl)-6-chloroIF-2O19-36422718-APN-ANP#INPI Page 188 of 250 3,4-dihydroisoquinoline-2(1H)-sulfonamide. To a solution of (S)-N-(3-amino-2-methylpropyl)6-chloro-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.6 g, 1.9 mmol) and TEA (270 mg, 2.7 mmol ) in DCM (6 ml) benzo[d]isoxazole-5-sulfonyl chloride (420 mg, 1.9 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 h. The mixture was washed with water and then concentrated. The residue was purified by column chromatography to provide (S)-N-(3-(6-chloro-1,2,3,4tetrahydroisoquinoline-2-sulfonamido)-2methylpropyl)benzo[d]isoxazole-5-sulfonamide. To a solution of (S)-N-(3-(6-chloro-1,2,3,4tetrahydroisoquinoline-2-sulfonamido)-2methylpropyl)benzo[d]isoxazole-5-sulfonamide (0.61 g, 1.22 mmol) in NMP (6 ml) NaH (122 mg, 3.05 mmol, 60%) was added. The mixture was stirred for 0.5 h at 80°C. The mixture was cooled to 70°C and 3,3'(cyclohexylmethylazierodiyl)bis(propane-3,1diyl)dimethanesulfonate (0.74 g, 1.83 mmol) was added. The reaction mixture was stirred for 2 h at 70°C. The mixture was cooled and poured into water. The resulting mixture was extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc = 12:1) to give compound A180. LC-MS (ESI): m / z 692.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.84 (S, 1H), 7.61 (m, 1H), 7.13 (m, 3H), 6.69 (m, 2H), IF-2G19-36422718-APN-ANP#INPI Page 189 of 25G 4.32 (m, 2H), 3.66 (m, 5H), 3.21 (m, 5H), 2.91 (m, 4H), 2.77 (m, 4H), 1.91 (m, 4H), 1.57 (m, 6H), 1.13 (m, 6H), 0.89 (m, 3H). The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ Al 68 3-{[(3S)-5-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclohexylmethyl)-3-methyl -l,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 694 A171 6-chloro-2-{[(3S)-9-(cyclohexylmethyl)-3methyl-5-phenylmethanesulfonyl-1,5,9-triazacyclododecan -l-yl]sulfonyl}-1,2,3,4 tetrahydroisoquinoline 665 A179 4 -{[ (3S)-5-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl]-9 (cyclohexylmethyl)-3-methyl-l,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylbenzamide 722 A184 (3S)-N-benzyl-9-(cyclohexylmethyl)-5-[4(dimethylamino)benzenesulfonyl]- N, 3dimethyl-1,5,9-triazacyclododecan-lsulfonamide 648 A188 6-chloro-2-{[ (3S)-9- (cyclohexylmethyl)-3methyl-5-[(1-methyl-1H-indol-5-yl )sulfonyl]-1,5,9-triazacyclododecan-1-yl]sulfonyl}1,2,3,4-tetrahydroisoquinoline 704 IF-2019-36422718-APN-ANP#INPI Page 190 of 250 A189 (3S)-9-(cyclohexylmethyl)-5-[4(dimethylamino)benzenesulfonyl]-N-[(4ethylphenyl)methyl]-3-methi1-1,5,9triazacyclododecane-l-sulfonamide 662 A192 N-{4- [ ({[(3S)-9-(cyclohexylmethyl)-5-[4(dimethylamino)benzenesulfonyl]-3-methyl1,5,9-triazacyclododecan-1-yl]sulfonyl}amino)methyl]phenyl}-Nmethylacetamide 705 Route 41 To a suspension of Mg (4.4 g 181 mmol) in THF (200 mL) 1-bromo-2-methoxybenzene (40 g, 214 IF-2O19-36422718-APN-ANP#INPI Page 191 of 250 mmol). The mixture was stirred at 80°C for 0.5 h. The mixture was cooled to 0°C and a solution of tert-butyl 3oxopiperidine-1-carboxylate (35.5 g, 181 mmol) in THF was added. The reaction mixture was stirred at room temperature for 2 h. The residue was purified by column chromatography to give tert-butyl 3-hydroxy-3-(2methoxyphenyl)piperidine-1-carboxylate.1H NMR (400 MHz, CDCl3): δ 7.48 (m, 1H), 7.32 (m, 1H), 6.98 (m, 2H), 4.08 (m, 1H), 3.96 (s, 3H), 3.82 (m, 1H), 3.31 (s, 1H), 2.98 (m, 1H), 2.25 (m, 1H), 1.99 (m, 2H), 1.62 (m, 2H), 1.63 (m, 9H). A solution of tert-butyl 3-hydroxy-3-(2methoxyphenyl)piperidine-1-carboxylate (23.0 g, 75 mmol) and triethylsilane (44 ml) in DCM (230 ml) was cooled to -30°C and added TFA (27 ml). The reaction mixture was stirred at 30°C for 2.5 h, then allowed to warm to room temperature and stirred for another 3.5 h. The mixture was poured into ice water and the solution was adjusted to pH = 9 with saturated aqueous sodium hydroxide. The resulting mixture was extracted three times with DCM. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to provide 3-(2methoxyphenyl)piperidine. A solution of 3-(2-methoxyphenyl) piperidine (6.5 g, 34 mmol) and D-tartaric acid (5.1 g, 34 mmol) in MeOH IF-2Q19-36422718-APN-ANP#INPI Page 192 of 25Q (25 ml) was heated at reflux for 2 h. The mixture was cooled to room temperature and filtered to provide the tartrate salt. This tartrate salt was recrystallized twice from MeOH and then treated with aqueous NaOH. The resulting mixture was extracted with DCM. The DCM layer was dried over anhydrous sodium sulfate and concentrated to provide (S)-3-(2-methoxyphenyl)piperidine. A solution of (S)-3-(2-methoxyphenyl)piperidine (500 mg, 2.6 mmol) and 2,3-dimethyl-1-((2-methyl-1H-imidazol-1yl)sulfonyl)-1H-imidazole- 3-io trifluoromethanesulfonate (1.1 g, 2.7 mmol) in MeCN (15 mL) overnight at room temperature. The solvent was removed. The residue was purified by column chromatography (petroleum ether / EtOAc=20:1) to provide (S)-3-(2methoxyphenyl)-1-((2-methyl-1H-imidazol-1yl)sulfonyl)piperidine. LC-MS (ESI): m / z 336.06 [M+H]+. To a solution of (S)-3-(2-methoxyphenyl)-1-((2methyl-1H-imidazol-1-yl)sulfonyl)piperidine (800 g, 2.4 mmol) in DCM (10 ml) was added CF3SO3Me ( 398 mg, 2.4 mmol). The reaction mixture was stirred for 2 h at room temperature. The solvent was removed and the residue was washed with ether to give (S)-1-(3-(2-methoxyphenyl)piperidin-1yl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate. To a solution of (S)-1-(3-(2methoxyphenyl)piperidin-1-yl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (1 g, 2 mmol) in CH3CN (24 ml) HE IF-2O19-36422718-APN-ANP#INPI Page 193 of 250 added (R)-N-(3-amino—2-methylpropyl)-4-(dimethylamino)benzenesulfonamide (0.55 g, 2 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 8:1 to 2:1) to provide (S)-N-((S)-3-((4(dimethylamino)phenyl)sulfonamido)-2 -methylpropyl)-3-(2methoxyphenyl)piperidine-1-sulfonamide. To a solution of (S)-N-((S)-3-((4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-3-(2methoxyphenyl)piperidine-1-sulfonamide (454 mg, 0.86 mmol) in NMP (14 ml) of NaH (104 mg, 2.6 mmol, 60%). The mixture was stirred for 0.5 h at 80°C. The mixture was cooled to 70°C and ((cyclohexylmethyl)azanediyl)bis(propane-3,1diyl)dimethanesulfonate (500 mg, 1.3 mmol) was added. The reaction mixture was stirred for 2 h at 70°C. The mixture was cooled to 0-5°C and poured into water. The resulting mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative HPLC to provide compound A210. LC-MS (ESI): m / z 718.17 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.60 (m, 2H), 7.23 (m, 2H), 6.95 (m, 2H), 6.68 (m, 2H), 3.82 (s, 3H), 3.73 (m, 5H ), 3.26 (m, 4H), 3.12 (s, 6H), 2.76 (m, 5H), 2.36 (m, 4H), 1.76 (m, 9H), 1.33 (m, 10H), 0.86 (m, 6H). The following compound was synthesized in a way IF-2G19-36422718-APN-ANP4#INPI Page 194 of 25G similar: IUPAC No. [M+H]+ A208 4-{[ (3S)-9-(cyclohexylmethyl)-5-{[ (3S)-3- (4methoxyphenyl)piperidin-1-yl]sulfonyl}-3methyl-1, 5,9-triazacyclododecan-1-yl]sulfonyl}-N,N-dimethylaniline 718 Route 42 To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-carboxylate (10.92 g, 35 mmol ), 1-bromo-3-methoxybenzene (6.6 g, 35 mmol) and CS2CO3 (3.44 g, 106 mmol) in 1,4-dioxane IF-2O19-36422718-APN-ANP#INPI Page 195 of 250 (50 ml) and H2O (10 ml) Pd(dppf)Cl2 (1.32 g, 1.75 mmol) was added. The reaction mixture was stirred overnight at 80°C. The solvent was removed. The residue was purified by column chromatography (petroleum ether / EtOAc = 10:1) to provide tert-butyl 3-(3-methoxyphenyl)-5,6-dihydropyridin1(2H)-carboxylate. LC-MS (ESI): m / z 290.12 [M+H]+.1H NMR (400 MHz, CDCl3): δ 7.26 (m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.81 (m, 1H), 6.19 (s, 1H), 4.25 (s, 2H), 3.81 (s, 3H), 3.54 (m, 2H), 2.30 (s, 2H), 1.49 (s, 9H). To a solution of tert-butyl 3-(3-methoxyphenyl)-5,6dihydropyridine-1(2H)-carboxylate (9.46 g, 32 mmol) in MeOH (75 mL) and EtOAc (25 mL) was added Pd / C (2 g). The mixture was stirred at room temperature for 4 h under H2 atmosphere. The mixture was filtered and the filtrate was concentrated to give tert-butyl 3-(3-methoxyphenyl)piperidine-1carboxylate. 1H NMR (400 MHz, CDCl3) : δ 7.25 (m, 1H), 6.81 (m, 3H), 3.99 (m, 2H), 3.73 (s, 3H), 2.65 (m, 1H), 2.55 (m, 1H ), 2.50 (m, 2H), 1.98 (m,1H), 1.65 (m, 2H), 1.44 (s, 9H). A solution of tert-butyl 3-(3-methoxyphenyl)piperidine-1carboxylate (7.85 g, 27 mmol) in HCl / MeOH (80 mL) was stirred at room temperature for 4 h. The mixture was treated with water and then adjusted to pH = 12 with 3N aqueous NaOH. The resulting mixture was extracted with EtOAc (100 ml x 2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to IF-2O19-36422718-APN-ANP#INPI Page 196 of 250 provide 3-(3-methoxyphenyl). LC-MS (ESI): m / z 192.09 [M+H]+. To a solution of D-tartaric acid (2.5 g, 16.7 mmol) in MeOH (12.5 ml) was added 3-(3-methoxyphenyl)piperidine (3.2 g, 16.7 mmol). The mixture was stirred at 80°C for 24 h, then cooled to room temperature. The resulting precipitate was collected by filtration and then recrystallized three times from MeOH to provide (S)-3-(3methoxyphenyl)piperidine. To a solution of (S)-3-(3-methoxyphenyl)piperidine (1.28 g, 6.7 mmol) in CH3CN (10 ml) was added 1-(1Himidazol-1-ylsulfonyl)-3-methyl-1H-imidazole- 3-io trifluoromethanesulfonate (2.87 g, 7.3 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed. The residue was purified by column chromatography (petroleum ether / EtOAc = 9:1 to 8:2) to provide (S)-3-(3-methoxyphenyl)-1-(2-methyl-1Himidazol-1-ylsulfonyl) piperidine. 1H NMR (400 MHz, CDCl3) : δ 7.27 (m, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.79 (m, 2H), 6.72 (s, 1H), 3.93 (m, 2H ), 3.82 (s, 3H), 2.68 (m, 1H), 2.65 (m, 2H), 2.62 (s, 3H), 2.06 (m, 1H), 1.95 (m, 1H), 1.82 (m, 1H), 1.62 (m, 1H). To a solution of (S)-3-(3-methoxyphenyl)-1-(2methyl-1H-imidazol-1-ylsulfonyl)piperidine (1.6 mg, 4.7 mmol) in DCM (20 mL) CF3CO2Me (782 mg, 4.7 mmol ). The reaction mixture was stirred at room temperature for 2 h. HE IF-2O19-36422718-APN-ANP#INPI Page 197 of 250 removed the solvent. The resulting product was washed with ether to provide (S)-1-(3-(3-methoxyphenyl)piperidin-1ylsulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate. To a solution of (S)-1-(3-(3methoxyphenyl)piperidin-1-ylsulfonyl)-2,3-dimethyl-1Himidazol-3-ium trifluoromethanesulfonate (1.1 g, 2.2 mmol) in CH3CN (11 mL) was added (R)-N-(3-amino-2-methylpropyl)-4(dimethylamino)benzenesulfonamide (896 mg, 33 mmol). The mixture was stirred at room temperature overnight. The solvent was removed. The residue was purified by column chromatography to provide (S)-N-((S)-3-(4(dimethylamino)phenylsulfonamido)-2-methylpropyl)-3-(3methoxyphenyl)piperidine-1-sulfonamide. 1H NMR (400 MHz, CDCl3): δ 7.68 (m, 2H), 7.28 (m, 1H), 6.85 (m, 1H), 6.80 (m, 2H), 6.68 (m, 2H), 4.81 (m, 2H ), 3.82 (s, 3H), 3.76 (m, 2H), 3.12 (m, 1H), 3.07 (s, 6H), 2.82 (m, 4H), 2.11 (m, 1H), 1.93 (m, 2H) , 1.77 (m, 1H), 1.29 (m, 3H), 0.91 (m, 3H). To a solution of (S)-N-((S)-3-(4(dimethylamino)phenylsulfonamido)-2-methylpropyl)-3-(3methoxyphenyl)piperidine-1-sulfonamide (550 mg, 1.05 mmol) in NMP ( 6 ml) sodium hydride (75.6 mg, 3.15 mmol) was added. The mixture was stirred for 30 min at 80°C. The mixture was cooled to 70°C and a solution of ((cyclohexylmethyl)azanediyl)bis(propane-3,1diyl)dimethanesulfonate (606 mg, 1.57 mmol) in NMP (3 ml) was added. IF-2O19-36422718-APN-ANP#INPI Page 198 of 250 The reaction mixture was stirred at 70°C for 1 h. The mixture was cooled to room temperature and poured into water (10 ml). The resulting mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with water (15 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (EtOAc / petroleum ether = 1:15 to 1:5) to provide compound A209. LC-MS (ESI) : m / z 719.2 [M+H]+.1H NMR (400 MHz, CDCl3): δ 7.61 (m, 2H), 7.28 (m, 2H), 6.84 (m, 3H), 6.70 (m, 2H), 3.83 (s, 3H), 3.70 (m, 2H), 3.55 (m, 2H), 3.30 (m, 1H), 3.11(s, 9H), 2.79 (m, 5H), 2.41 (m, 1H), 2.33 (m, 3H), 2.05 (m, 8H), 1.67 (m, 4H), 1.27 (m, 7H), 0.94 (m, 3H), 0.85 (m, 2H). Route 43 To a solution of (S)-N-(3-((4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-4-(4fluoro-2-methoxyphenyl)piperazine-1-sulfonamide (900 mg, 1.65 mmol) in NMP (5 ml) NaH (198 mg, 4.92 mmol, 60%) was added. The mixture was stirred for 0.5 h at 80°C. The mixture was cooled to 70°C and (S)-3,3'-(1 IF-2O19-36422718-APN-ANP#INPI Page 199 of 250 cyclohexylethylazediyl)bis(propane-3,1diyl)dimethanesulfonate (844 mg, 2.49 mmol). The reaction mixture was stirred for 2 hours at 70°C, then cooled to 0-5°C and poured into water. The resulting mixture was extracted with ethyl acetate. The extract was concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 15:1) to provide compound A203. LC-MS (ESI): m / z 751.33 [M+H]+.1H NMR (400 MHz, CDCl3): δ 7.68 (m, 2H), 6.92 (m, 1H), 6.78 (m, 4H), 3.92 (s, 4H), 3.86 (m, 1H), 3.62 (m, 1H), 3.40 (m, 2H), 3.19 (m, 3H), 3.04 (s, 9H), 2.87 (m 2H), 2.26 (m, 3H), 1.92 (m, 3H), 1.79 (m, 4H), 1.66 (m, 2H), 1.54 (m, 2H), 1.38 ( m, 4H), 1.26 (m, 5H), 0.98 (m, 3H), 0.83 (m, 4H). The following compounds were synthesized in a similar manner: IUPAC No. [M+H]+ B22 4-{[(lS,12R)-10-[(6-chloro-l,2,3,4tetrahydroisoquinolin-2-yl)sulfonyl] -6(cyclohexylmethyl)-2, 6,10triazabicyclo[10.2.0]tetradecan-2yl]sulfonyl}-N,N-dimethylaniline 706 A160 4-{[ (3S, 7S, US) -5- [ (6-chloro-l,2,3,4tetrahydroisoquinolin- 2-yl)sulfonyl]-9(cyclohexylmethyl)-3,7,11-trimethi1-1,5,9triazacyclododecan-l-yl]sulfonyl}-N,Ndimethylaniline 722 B16 4-{[(3S,7R,11S)- 5-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl]-9(cyclohexylmethyl)-3,7,11-trimethyl-1,5,9triazacyclododecan-1-yl]sulfonyl} -N,Ndimethylaniline 722 IF-2Q19-36422718-APN-A2'0E0 / INPI Page 2QQ of 25Q Route 44 °\ °\ °\ To a solution of 1-bromo-4-fluoro-2methoxybenzene (910 mg, 4.4 mmol) and 1M KHMDS (18 ml, 18 mmol) in 1,4-dioxane (9 ml) was added (3R,5R)-3, tert-butyl 5dimethylpiperazine-1-carboxylate (950 mg, 4.4 mmol). The reaction mixture was stirred at 100°C for 3 h. The solvent was removed and the residue was purified by column chromatography (petroleum ether / EtOAc = 20:1) to provide (3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5dimethylpiperazine-1- tert-butyl carboxylate. LC-MS (ESI) : m / z 339.0 [M+H]+. To a solution of tert-butyl (3R,5R)-4-(3-fluoro-5methoxyphenyl)-3,5-dimethylpiperazine-1-carboxylate (800 mg, 2.4 mmol) in DCM (4 ml) was added TFA (4 IF-2Q19-36422718-APN-A20I1#INPI Page 2Q1 of 25Q mL). The mixture was stirred at room temperature for 1 h. The solvent was removed. The residue was dissolved in DCM (50 ml) and then washed with saturated aqueous K2CO3. The organic layer was dried over anhydrous sodium sulfate and concentrated to provide (2R,6R)-1-(3-methoxy-5methylphenyl)-2,6-dimethylpiperazine. To a solution of (2R,6R)-1-(3-methoxy-5methylphenyl)-2,6-dimethylpiperazine (500 mg, 2.1 mmol) in MeCN (5 ml) was added 2,3-dimethyl-1-( (2-methyl-1Himidazol-1-yl)sulfonyl)-1H-imidazole-3-ium trifluoromethanesulfonate (825 mg, 2.1 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed. The residue was purified by column chromatography (petroleum ether / EtOAc = 20:1) to provide (2R,6R)-1-(3-fluoro-5-methoxyphenyl)-2,6dimethyl-4-((2-methyl -1H-imidazol-1-yl)sulfonyl)piperazine. LC-MS (ESI): m / z 383.53 [M+H]+. To a solution of (2R,6R)-1-(3-methoxy-5methylphenyl)-2,6-dimethylpiperazine (450 mg, 1.2 mmol) in DCM (5 ml) was added CF3SO3Me (193 mg, 1.2 mmol). The reaction mixture was stirred for 2 h at room temperature. The solvent was removed and the residue was washed with ether to give 1-(((3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5dimethylpiperazin-1-yl)sulfonyl)-2,3- dimethyl-1H-imidazol-3ium trifluoromethanesulfonate. To a solution of 1-(((3R, 5R)-4-(3-fluoro-5IF-2Q19-36422718-APN-A20I2 / INPI Page 2Q2 of 25Q methoxyphenyl)-3,5-dimethylpiperazin-1-yl)sulfonyl)-2,3dimethyl-1H-imidazole-3-ium trifluoromethanesulfonate (500 mg, 0.91 mmol) in CH3CN (5 mL) (R)-N -(3-amino-2-methylpropyl)-4(dimethylamino)benzenesulfonamide (248 mg, 0.91 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 8:1 to 2:1) to provide (2S,6S)-N-((S)-3-((4(dimethylamino)phenyl)sulfonamido) 2-methylpropyl)-4-(3-fluoro5-methoxyphenyl)-2,6-dimethylpiperazine-1-sulfonamide. LC-MS (ESI): m / z 572.4 [M+H]+. To a solution of (2S,6S)-N-((S)-3-((4(dimethylamino)phenyl)sulfonamido)-2-methylpropyl)-4-(3fluoro-5-methoxyphenyl)-2,6-dimethylpiperazine -1-sulfonamide (430 mg, 0.75 mmol) in NMP (4 ml) was added NaH (91 mg, 2.3 mmol, 60%) a. The mixture was stirred for 0.5 h at 80°C. The mixture was cooled to 70°C and ((cyclohexylmethyl)azanediyl)bis(propane-3,1diyl)dimethanesulfonate (435 mg, 1.1 mmol) was added. The reaction mixture was stirred for 2 h at 70°C. The solvent was removed and the residue was purified by column chromatography (petroleum ether / EtOAc = 15:1) to provide compound A200. LC-MS (ESI): m / z 764.3 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, 2H), 6.69 (d, 2H), 6.32 (d, 3H), 3.78 (s, 3H), 3.06 (q, 2H), 3.04 (s, 8H), 3.00 (s, 2H), 2.87 (d, 2H), 2.76 (s, 2H), 2.34 (br s, 4H), 2.09 (br IF-2O19-36422718-APN-A2'0P#INPI Page 203 of 250 s, 2H), 1.33 (s, 17H), 1.04 (d, 7H), 0.93 (d, 3H). (S)-3,3'- (1-cyclohexylethylazidiyl)dipropan-1-ol (Intermediate for compounds A203, A190, A207) O O To a solution of (S)-1-cyclohexylethaneamine (4.0 g, 31.46 mmol) in methanol (50 ml) was added methyl acrylate (8.1 g, 94.38 mmol). The reaction mixture was stirred for 72 h at 45°C. The mixture was concentrated and the residue was purified by column chromatography (EtOAc / petroleum ether = 30:1) to give (S)-dimethyl 3,3'-(1cyclohexylethylazidiodi)dipropanoate. To a solution of (S)-dimethyl 3,3'-(1cyclohexylethylazilanediyl)dipropanoate (4.0 g, 13.37 mmol) in THF (50 mL) was added LiBH4 (1.45 g, 66.84 mmol). The reaction mixture was stirred at 60°C for 2 h. The mixture was cooled to 0-5°C and quenched with water (30 ml). The mixture was adjusted to pH=3 with 1N aqueous hydrochloric acid and stirred for 30 minutes. The resulting mixture was washed with dichloromethane. The aqueous layer was adjusted to pH = 9-10 with saturated aqueous sodium carbonate and then extracted with DCM (3X). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide (S)-3,3'-(1 IF-2019-36422718-APN-A20E4 / INPI Page 204 of 250 cyclohexylethylazilanodi)dipropan-1-ol. 1H NMR (400 MHz, CDCI3): δ 3.66 (s, 1H), 2.82 (m, 2H), 2.42 (m, 2H), 2.21 (m, 1H), 1.96 (m, 2H), 1.67 (m, 4H ), 1.22 (m, 4H), 0.91 (m, 3H), 0.81 (m, 1H), 0.72 (m, 1H). The following compounds were synthesized in a similar manner: (R)-3,3'-(1-cyclohexylethylazidiyl)dipropan1-ol (Intermediate for compound A191) and (S)-3,3'-((1phenylethyl)azanediyl) bis(propan-1-ol) (Intermediate for compound A205) 6-chloro-N-(((1R,2S)-2-(4(dimethylamino)phenylsulfonamido)cyclobutyl)methyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (Intermediate for compound B22) nh2nh2 Page 205 of 250 a suspension of cis-3oxabicyclo[3.2.0]heptane-2,4-dione (32.8 g, 200 mmol) and quinine (71.4 g, 220 mmol) in toluene (1 L) was added to benzyl alcohol. (64.9 g, 600 mmol) dropwise over a period of 0.5 h at -55°C. The reaction mixture was stirred at -55°C for 96 h. The resulting clear solution was concentrated to dryness and the residue was dissolved in diethyl ether (1.2 L). The solution was washed with 2N aqueous HCl (1 L), the organic layer was extracted with saturated aqueous sodium bicarbonate (500 x 5 mL) and the resulting combined aqueous phases were washed with diethyl ether (500 mL) to remove traces of benzyl alcohol. The aqueous phase was acidified with 8N aqueous HCl and then extracted with DCM (1.0 l x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide (1S,2R)-2-(benzyloxycarbonyl)cyclobutanecarboxylic acid. To a solution of (1S, 2R)-2(benzyloxycarbonyl)cyclobutanecarboxylic acid (40.1 g, 171.4 mmol) and triethylamine (26.0 g, 257 mmol) in dichloroethane (400 mL) was added DPPA (51.8 g (188.5 mmol) to 0 °C. The mixture was stirred for 2 h at room temperature, then washed with water and dried over anhydrous NaSO4. BnOH (18.5 g, 171 mmol) and triethylamine (34.6 g, 342 mmol) were added to the organic solution. The reaction mixture is IP-2019-36422718-AP\-ANP#I\PI Page 206 of 250 refluxed overnight and then diluted with DCM (500 ml). The mixture was washed with 1N aqueous HCl (1 L) and saturated aqueous NaHCO3. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to provide (1R,2S)-benzyl 2-(benzyloxycarbonylamino)cyclobutanecarboxylate. To a solution of (1R,2S)-benzyl 2(benzyloxycarbonylamino)cyclobutanecarboxylate (20 g, 59 mmol) in THF (100 mL) was added 4N aqueous NaOH (50 mL) at 0°C. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with water (30 ml) and then washed with ether (50 ml x 2). The aqueous layer was acidified with 3N aqueous HCl and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated to give (1R, 2S)2-(benzyloxycarbonylamino)cyclobutanecarboxylic acid. 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 5.12 (m, 2H), 4.62 (m, 1H), 3.58 (m, 1H), 2.28 (m, 2H), 1.89 (m, 2H) ). To a solution of (1R, 2S)-2(benzyloxycarbonylamino)cyclobutanecarboxylic acid (4.0 g, 16.1 mmol) and K2CO3 (4.4 g, 32 mmol) in DMF (40 mL) was added MeI (2.96 g, 20.8 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured into water (150 ml) and then extracted with ether (200 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography in IF-2ü19-36422718-APN-AW#INPI Page 207 of 250 column to provide (1R, 2S)-methyl 2(benzyloxycarbonylamino)cyclobutanecarboxylate. 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 5.69 (m, 1H), 5.08 (s, 2H), 4.62 (m, 1H), 3.66 (s, 3H), 3.38 (m, 1H), 2.32 (m, 2H), 1.99 (m, 2H). To a solution of (1R, 2S)-methyl 2(benzyloxycarbonylamino)cyclobutanecarboxylate (8.9 g, 33.8 mmol) in MeOH (250 ml) was added NaOMe (9.1 g, 169 mmol). The mixture was heated to 45°C for 4 h, then cooled to 0°C and HOAc (10.2 g, 169 mmol) was added dropwise. The mixture was then poured into water (500 ml) and extracted with ethyl acetate (300 ml). The extract was washed with saturated aqueous NaHCO3 and dried over anhydrous sodium sulfate. The organic solution was concentrated and the residue was purified by column chromatography to provide (1S,2S)-methyl 2(benzyloxycarbonylamino)cyclobutanecarboxylate. 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 5.08 (m, 3H), 4.38 (m, 1H), 3.72 (s, 3H), 3.38 (m, 1H), 2.32 (m, 2H), 1.89 ( m, 2H). To a solution of (1S, 2S)-methyl 2(benzyloxycarbonylamino)cyclobutanecarboxylate (1.3 g, 4.9 mmol) in THF (10 mL) was added LiBH4 (0.38 g, 9.8 mmol). The reaction mixture was stirred for 3h at room temperature, then poured into water (15 ml) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give benzyl (1S, IP-2019-36422718-AP\-ANP#-|\PI Page 208 of 250 2S)-2-(hydroxymethyl)cyclobutylcarbamate.1H NMR (400 MHz, CDCI3): δ 7.34 (m, 5H), 5.08 (m, 3H), 3.72 (m, 1H), 3.57 (m, 2H), 2.32 ( m, 2H), 1.89 (m, 2H), 1.45 (m, 1H). To a solution of benzyl (1S, 2S)-2(hydroxymethyl)cyclobutylcarbamate (1.1 g, 4.94 mmol), PPh3 (1.5 g, 5.9 mmol) and isoindoline-1,3-dione (1.0 g, 6.9 mmol) in toluene ( 10 ml) DIAD (1.2 g, 5.9 mmol) was added at 0°C. The reaction mixture was stirred for 3 h. The precipitate was removed by filtration and the filtrate was concentrated and purified by column chromatography to give benzyl (1S, 2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)cyclobutylcarbamate. To a solution of benzyl (1S, 2R)-2-((1,3dioxoisoindolin-2-yl)methyl)cyclobutylcarbamate (2.0 g, 5.5 mmol) in EtOH (40 mL) was added hydrazine hydrate (0.64 g). The reaction mixture was refluxed for 3 h. The mixture was cooled, filtered and the filtrate concentrated. The residue was dissolved in 1N aqueous HCl (30 ml) and then washed with ether (20 ml). The aqueous layer was adjusted to pH = 10. The resulting mixture was extracted with DCM (50 ml x 2). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to provide benzyl (1S, 2R)-2(aminomethyl)cyclobutylcarbamate. To a solution of benzyl (1S, 2R)-2(aminomethyl)cyclobutylcarbamate (0.8 g, 3.4 mmol) in CH3CN IF-2019-36422718-APN-A2'0E%INPI Page 209 of 250 (10 ml) 1-((6-chloro-3,4-dihydroisoquinolin-2(1H)yl)sulfonyl)-2,3-dimethyl-1H-imidazole-3—io trifluoromethanesulfonate (2.4 g) was added , 5.12 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography to give benzyl (1S, 2R)2-((6-chloro-1,2,3,4-tetrahydroisoquinoline-2sulfonamido)methyl)cyclobutylcarbamate. To the 40% HBr solution in HOAc (10 ml) was added benzyl (1S, 2R)-2-((6-chloro-1,2,3,4tetrahydroisoquinoline-2sulfonamido)methyl)cyclobutylcarbamate (1.2 g, 2.6 mmol). The mixture was stirred for 3 h, then poured into water (50 mL) and washed with ether. The aqueous layer was adjusted to pH = 10 with 8N aqueous NaOH. The mixture was extracted with DCM (50 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give N-(((1R,2S)-2aminocyclobutyl)methyl)-6-chloro-3,4-dihydroisoquinoline2(1H)-sulfonamide. To a solution of N-(((1R,2S)-2aminocyclobutyl)methyl)-6-chloro-3,4-dihydroisoquinoline2(1H)-sulfonamide (0.66 g, 2.0 mmol) and NEt3 (350 mg, 3.5 mmol) in DCM (5 ml) was added to 4(dimethylamino)benzenesulfonyl chloride (426 mg, 2.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h, then concentrated. The residue was dissolved in DCM and IF-2019-36422718-APN-A21I0 / INPI Page 210 of 250 washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 6-chloro-N(((1R,2S)-2-(4(dimethylamino)phenylsulfonamido)cyclobutyl)methyl)-3,4dihydroisoquinoline-2(1H) -sulfonamide. 1H NMR (400MHz, CDCl3): δ 7.77 (m, 2H), 7.18 (m, 2H), 7.05 (m, 1H), 6.75 (m, 2H), 5.28 (m, 1H), 5.05 (m, 1H), 4.36 (s, 2H), 3.50 (m, 2H), 3.35 (m, 1H), 3.15 (m, 1H), 3.09 (s, 6H), 2.92(m, 3H), 2.42 (m, 1H), 2.03 (m, 1H), 1.65 (m, 2H), 1.25(m, 1 HOUR). (S)-3- ((Cyclohexylmethyl) ( (R)-2-methyl-3(methylsulfonyloxy)propyl)amino)-2methylpropylmethanesulfonate (Intermediate for the compound A178) To a solution of (S)-methyl-3-hydroxy-2methylpropanoate (4.0 g, 25.42 50.84 mmol) in DCM (60 mL) were methanesulfonyl (5.6 g, 10.20 mmol) and triethylamine (5.3 g, slowly added mmol chloride) at 0 — 5°C. The mixture of IF-2Q19-36422718-APN-ANP#INPI Page 211 of 25Q reaction was stirred for 1 h at room temperature. The mixture was then diluted with DCM (100 ml) and washed with water (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to provide (S)-methyl-2-methyl3-(methylsulfonyloxy)propanoate. To a solution of (R)-methyl 2-aminopropanoate hydrochloride (1.60 g, 10.20 mmol) in acetonitrile (200 ml) was added (S)-methyl 2-methyl-3(methylsulfonyloxy)propanoate (4.2 g, 21.43 mmol) and potassium carbonate (4.20 g, 30.60 mmol). The reaction mixture was heated at reflux for 16 h, then filtered and the filtrate concentrated to give (2R, 2'S)dimethyl 2,2'-azanediylbis(methylene)dipropanoate. To a solution of (2R, 2'S)-dimethyl 2,2'azanediylbis(methylene)dipropanoate (650 mg, 3.0 mmol) in DCM (10 mL) was added cyclohexanecarbaldehyde (336 mg, 3.0 mmol) and sodium triacetoxyborohydride (954 mg, 4.50 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was quenched with water and adjusted to pH = 10. The resulting mixture was extracted with DCM. The extract was concentrated and the residue was purified by column chromatography to give (2R, 2'S)dimethyl 2,2'(cyclohexylmethylazilanediyl)bis(methylene)dipropanoate. To a solution of (2R, 2'S)-dimethyl 2,2'(cyclohexylmethylolazanediyl)bis(methylene)dipropanoate (350 IF-2Q19-36422718-APN-ANP#INPI Page 212 of 25Q mg, 1.28 mmol) in THF (10 ml) LIBH4 (486 mg, 12.80 mmol) was added. The reaction mixture was stirred at 80°C overnight. The mixture was cooled and quenched with water. The resulting mixture was adjusted to pH = 5 with 1N aqueous hydrochloric acid and stirred for 0.5 h, then adjusted to pH = 10 and extracted with ethyl acetate three times. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to provide (2R, 2'S)-2,2'-(cyclohexylmethylazidi)bis(methylene)dipropan-1-ol. To a solution of (2R, 2'S)-2,2'(cyclohexylmethylazilanodiyl)bis(methylene)dipropan-1-ol (153 mg, 0.59 mmol) and triethylamine (0.12 g, 1.2 mmol) in DCM (5 mL) was added MsCl (135 mg, 1.18 mmol) at 0°C. The reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with DCM (15 ml) and then washed with water (20 ml x 2). The organic extracts were dried over anhydrous sodium sulfate and concentrated to give (S)-3-((cyclohexylmethyl)((R)-2-methyl-3(methylsulfonyloxy)propyl)amino)-2methylpropylmethanesulfonate. MS (EI) C17H35NO6S2, found 414 [M+H]+. The following compound was synthesized in a similar manner: (2S, 2'S)-((cyclohexylmethyl)azanediyl)bis(2methylpropane-3,1-diyl)dimethanesulfonate (Intermediate for compound A160). IF-2019-36422718-APN-ANP#INPI Page 213 of 250 (R)-6-Chloro-N-(4-(4(dimethylamino)phenylsulfonamido)butan-2-yl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (Intermediate for compound A148). (R)-6-Chloro-N-(4-(4(dimethylamino)phenylsulfonamido)butan-2-yl)-3,4 dihydroisoquinoline-2(1H)-sulfonamide (Intermediate for compound A148) A solution of (R)-tert-butyl 1-cyanopropan-2-ylcarbamate (13.0 g, 71 mmol) in ethanol (250 mL) saturated with anhydrous ammonia was treated with Raney-Ni (24 g) at 55 psi H2 overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by column chromatography to provide (R)-tert-butyl 4-aminobutan-2-ylcarbamate. To a solution of 4-aminobutan-2-ylcarbamate IF-2019-36422718-APN-ANP4#INPI Page 214 of 250 (R)-tert-butyl (2.5 g, 13.3 mmol) and triethylamine (1.33 g, 13.3 mmol) in DCM (25 ml) a solution of 4-(dimethylamino)benzene-1-chloride was slowly added. sulfonyl (2.93 g, 13.3 mmol) in DCM (15 ml) at 0-5°C. The reaction mixture was stirred for 1 h at room temperature. The mixture was diluted with DCM (50 ml) and washed with water (30 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to provide (R)tert-butyl 4-(4(dimethylamino)phenylsulfonamido)butan-2-ylcarbamate. To a solution of (R)tert-butyl 4-(4(dimethylamino)phenylsulfonamido)butan-2-ylcarbamate (1.2 g, 3.2 mmol) in DCM (15 ml) was added TFA (7 ml). The mixture was stirred for 2 h and the solvent was removed. The residue was dissolved in DCM (30 ml) and then washed with saturated aqueous NaHCO3. The organic phase was dried over anhydrous sodium sulfate and concentrated to give (R)-N-(3-aminobutyl)-4(dimethylamino)benzenesulfonamide (0.88 g, quantitative). To a solution of (R)-N-(3-aminobutyl)-4(dimethylamino)benzenesulfonamide (0.88 g, 4.0 mmol) in CH3CN (10 ml) was added 6-chloro-1,2,3,4tetrahydroisoquinoline (1 .98 g, 4.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by IF-2019-36422718-APN-A21I5 / INPI Page 215 of 250 column chromatography to provide (R)-6-chloro-N(4-(4-(dimethylamino)phenylsulfonamido)butan-2-yl)-3,4dihydroisoquinoline-2(1H)-sulfonamide. The following compounds were synthesized in a similar manner: (S)-6-chloro-N-(4-((4(dimethylamino)phenyl)sulfonamido)butan-2-yl)-3,4dihydroisoquinoline2(1H)-sulfonamide (Intermediate for compound A147); (S)-6-chloro-N-(3-((4(dimethylamino)phenyl)sulfonamido)butyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (Intermediate for compound A150); and (R)-6-chloro-N-(3-((4(dimethylamino)phenyl)sulfonamido)butyl)-3,4dihydroisoquinoline-2(1H)-sulfonamide (Intermediate for compound A149) (R)-1- (4-fluoro-2-methoxyphenyl)-2-methylpiperazine (Intermediate for compound A177) NaOtBu Pd Catalyst For (R)-3-methylpiperazine-1-carboxylate tert-butyl (5.37 g, 26.8 mmol) and 1-bromo-4-fluoro-2methoxybenzene (5.00 g, 24.4 mmol) in toluene (50 ml) IF-2G19-36422718-APN-ANP#INPI Page 216 of 25G added sodium tert-butoxide (4.69 g, 48.8 mmol) followed by BrettPhos palladacycle G3 (66.4 mg, 0.0732 mmol). The mixture was sealed under nitrogen and stirred at 100°C and after 1 h, the mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (040%, ethyl acetate / hexanes) to give the product. MS(EI) for C17H25FN2O3, found 325 [M+H]+. To tert-butyl (R)-4-(4-fluoro-2-methoxyphenyl)-3methylpiperazine-1-carboxylate (0.51 g, 1.6 mmol) HCl (1.6 ml, 4 N in dioxane) was added and the mixture was allowed to stand at room temperature for 16 h, then diluted with water (5 ml) and ethyl acetate (5 ml). The organic layer was removed and washed with water (1 x 5 ml). The combined aqueous layers were washed with ethyl acetate (1 x 5 ml), basified with NaOH (5 N at pH ~ 12), extracted with DCM (3 x 5 ml), dried with sodium sulfate, filtered and concentrated to give (R)-1-(4-fluoro-2-methoxyphenyl)-2-methylpiperazine which was carried out without further purification. MS(EI) for C12H17FN2O, found 225 [M+H]+. The following compounds were synthesized in a similar manner: 1-(4-fluoro-2-methoxyphenyl)piperazine (Intermediate for A137) IF-2019-36422718-APN-AW#INPI Page 217 of 250 1-(2-methoxyphenyl)piperazine (Intermediate A154) 2-(piperazin-1-yl)benzonitrile (Intermediate for A118) 1-(2,6-dimethylphenyl)piperazine (Intermediate for A119) 2-(4-fluoro-2-methyl)-2,6-diazaspiro[3.3]heptane (Intermediate for A161) (S)-1-(4-fluoro-2-methylphenyl)-3-methylpiperazine (Intermediate for A162) (R)-1-(4-fluoro-2-methylphenyl)-3-methylpiperazine (Intermediate for A163) 1-(2-(trifluoromethoxy)phenyl)piperazine (Intermediate for A173) 1-(3,4-difluoro-2-methoxyphenyl)piperazine (Intermediate for A174) 1-(3-fluoro-2-methoxyphenyl)piperazine (Intermediate for A175) 1-(5-fluoro-2-methoxyphenyl)piperazine (Intermediate for A176) 1-(2-chlorophenyl)piperazine (Intermediate for A198) 1-(4-methoxyphenyl)piperazine (Intermediate for A199) 1-(3-methoxyphenyl)piperazine (Intermediate for A201) 1-(3-fluoro-4-methoxyphenyl)piperazine (Intermediate for A202) IF-2019-36422718-APN-A2'1I8#INPI Page 218 of 250 1-(2-chloro-4-fluorophenyl)piperazine (Intermediate for A206) ​​(S)-1- (3-fluoro-5-methoxyphenyl)-2-methylpiperazine (Intermediate for A194) (R)-1-(3- fluoro-5-methoxyphenyl)-2-methylpiperazine (Intermediate for A195) (2S,6R)-1-(3-fluoro-5-methoxyphenyl)-2,6dimethylpiperazine (Intermediate for A197) (2R,6R)-1-( 3-fluoro-5-methoxyphenyl)-2,6dimethylpiperazine (Intermediate for A200) essays Dox-induced PD1-ss-Gluc assay Flp-In 293 T-Rex™ cells were transfected with pcDNATM5 / FRT / TO plasmid inserted with cDNA encoding Gaussia luciferase fused to the 3' end of the cDNA encoding the PD1 signal sequence plus 10 amino acids (NMQIPQAPWPVVWAVLQLGWRPGWFLDSPDR-C) (SEQ ID NOT: 1). Transfected cells were selected for resistance to the selectable markers, Hygromycin and Blasticidin, to create a stable cell line containing the PD1-ss+10aa / Gaussia Luciferase cDNA insert whose expression was regulated under the T-Rex™ system. The day before the assay, the cells were trypsinized and IF-2Q19-36422718-APN-A21I%INPI Page 219 of 25Q were placed in 384-well tissue culture plates. The next day, dilutions of compounds in DMSO / doxycycline-containing media were added to the wells and incubated at 37°C, 5% CO2. 24 hours later, coelenterazine substrate was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro for potency determination. The results for the selected compounds provided here are shown in Table 1, below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. Dox-induced PD1-FL-Gluc assay Flp-In 293 T-Rex™ cells were transfected with pcDNATM5 / FRT / TO plasmid inserted with a cDNA encoding Firefly Luciferase fused to the 3' end of the cDNA encoding the full length of PD1 (amino acids 1-288). Transfected cells were selected for resistance to the selectable markers Hygromycin and Blasticidin to create a stable cell line containing the firefly PD1-FL / Luciferase cDNA insert whose expression was regulated under the T-Rex™ system. The day before the assay, cells were trypsinized and plated into 384-well tissue culture plates. To the IF-2G19-36422718-APN-A22P#INPI Page 22G of 25G Next day, dilutions of compounds in DMSO / doxycycline-containing media were added to the wells and incubated at 37°C, 5% CO2. 24 hours later, coelenterazine substrate was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro for potency determination. The results for the selected compounds provided here are shown in Table 1, below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. Dox-induced TNF«-FL-Gluc assay Flp-In 293 T-Rex™ cells were transfected with the pcDNATM5 / FRT / TO plasmid inserted with a cDNA encoding Gaussia luciferase fused to the 3' end of the cDNA encoding full-length TNFw (amino acids 1-233). Transfected cells were selected for resistance to the selectable markers Hygromycin and Blasticidin to create a stable cell line containing the TNFw-FL / Gaussia Luciferase cDNA insert whose expression was regulated under the T-Rex™ system. The day before the assay, cells were trypsinized and plated into 384-well tissue culture plates. The next day, dilutions of compounds were added in IF-2019-36422718-APN-A22I1#INPI Page 221 of 250 DMSO / doxycycline-containing media were added to the wells and incubated at 37°C, 5% CO2. 24 hours later, coelenterazine substrate was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro for potency determination. The results for the selected compounds provided here are shown in Table 1, below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. Dox-induced IL2-FL-Gluc assay Flp-In 293 T-Rex™ cells were transfected with the pcDNATM5 / FRT / TO plasmid inserted with a cDNA encoding Gaussian Luciferase fused to the 3' end of the cDNA encoding full-length IL-2 (amino acids 1153). Transfected cells were selected for resistance to the selectable markers, Hygromycin and Blasticidin, to create a stable cell line containing the IL-2-FL / Gaussia Luciferase cDNA insert whose expression was regulated under the T-Rex™ system. The day before the assay, cells were trypsinized and plated into 384-well tissue culture plates. The next day, dilutions of compounds in DMSO / doxycycline-containing media were added to the wells and IF-2Q19-36422718-APN-A2'2P#INPI Page 222 of 25Q incubated at 37°C, 5% CO2. 24 hours later, coelenterazine substrate was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro for potency determination. The results for the selected compounds provided here are shown in Table 1, below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. Dox-induced HER3-ss-Gluc assay Flp-In 293 T-Rex™ cells were transfected with plasmid pcDNATM5 / FRT / TO inserted with cDNA encoding Gaussia luciferase fused to the 3' end of the cDNA encoding the HER3 signal sequence plus 4 amino acids (NMRANDALQVLGLLFSLARGSEVG-C) (SEQ ID NOT: 2). Transfected cells were selected for resistance to the selectable markers Hygromycin and Blasticidin to create a stable cell line containing the HER3-ss+ 4aa / Gaussia luciferase cDNA insert whose expression was regulated under the T-Rex™ system. The day before the assay, cells were trypsinized and plated into 384-well tissue culture plates. The next day, dilutions of compounds in DMSO / doxycycline-containing media were added to the wells and incubated at 37°C, 5%. IF-2Q19-36422718-APN-A22P#INPI Page 223 of 25Q of CO2. 24 hours later, coelenterazine substrate was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro for potency determination. The results for the selected compounds provided here are shown in the table below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. Chart for HER3 activity No. 24hr Dox Inducible Her3 (ss + 4) Gluc 293FRT / TO: Mean IC50 (nM) A122 110.63 A120 31.42 A137 10.85 A151 276.03 A177 10.86 A179 399.69 A124 912.67 A182 A183 2145.26 A184 155.56 A185 85.5 A107 44.21 A187 802.1 No. 24hr Dox Inducible Her3 (ss+4) Gluc 293FRT / TO: Mean IC50 (nM) A188 88.04 A189 959.52 A190 35.6 A191 116.79 A192 1709.12 A193 50.85 A194 303.25 A195 381.8 96 78.19 A197 77.48 A198 44.08 A199 131.52 A200 29.08 No. 24hr Dox Inducible Her3(ss+4) Gluc 293FRT / TO: Mean IC50 (nM) A201 211.04 A202 129.54 A203 34.13 A204 134.41 A205 230.38 A206 38.19 A207 17.98 A208 427.53 A 209 497.91 A210 342.58 B22 57.77 IF-2019-36422718-APN-A22P#INPI Page 224 of 250 H929 Cell Viability Assay The human multiple myeloma cell line NCIH929 was cultured in RPMI advanced 1640 medium (Gibco®) supplemented with 6% fetal bovine serum, 2 mM glutamine, and 1x penicillin / streptomycin. On the day of assay, cells were resuspended in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2 mM glutamine, and 1x penicillin / strepticin and plated in 384-well tissue culture plates and treated with dilutions of compounds in DMSO / medium. The plates were incubated at 37°C, 5% CO2 for 48 hours. After 48 hours, Celltiter-Glo® (Promega) was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro for cell viability determination. The results for the selected compounds provided here are shown in Table 1, below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. U266 Cell Viability Assay The human multiple myeloma cell line U266B1 was cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2 mM glutamine, and 1x penicillin / streptomycin. Cells were plated into 384-well tissue culture plates and treated with IF-2019-36422718-APN-ANp#INPI Page 225 of 250 dilutions of compounds in DMSO / medium. The plates were incubated at 37°C, 5% CO2 for 48 hours. After 48 hours, Celltiter-Glo® (Promega) was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro for cell viability determination. The results for the selected compounds provided here are shown in Table 1, below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. In vitro microsome stability assays Potassium phosphate (423 μL of a 0.1 M solution) was added to 8-strip deep-well tubes followed by human, mouse, rat, or monkey microsomes (25 μL of a 20 mg / mL solution). The tubes were then placed on ice and the test article (2 μL of a 0.25 mM solution in DMSO) was added. The mixture was preincubated at 37°C for 3 to 5 minutes (shaking at 150 rpm) and then the reaction was started by adding 50 μl of NADPH. An aliquot of samples (100 pL) was collected at 0 and 30 min and 200 μL of an acetonitrile mixture containing IS (compound 914) was added to stop the reaction. After centrifugation for 10 minutes at 4000 rpm, a mixed solution of the 20 μL of the supernatant (20 pL) plus IF-2019-36422718-APN-A22P#INPI Page 226 of 250 100 μL of ACN / H2O (1:1) for LC-MS / MS analysis. The stability of the liver microsome is evaluated by the remaining % of the compound at 30 minutes, which is calculated using the following equation: [(AUCanalyteT= 30 / AUCIS) / (AUCanalyteT= 0 / AUCIS)]*100. The results for the selected compounds provided here are shown in Table 1, below. For chemical structures that include one or more stereoisomers, but are illustrated without indicating stereochemistry, the test data refer to a mixture of stereoisomers. Signal sequence assay induced by transiently expressed Dox Flp-In 293 T-Rex™ cells were transfected with 500 ng of pcDNA™5 / FRT / TO plasmids inserted with cDNA encoding Gaussia luciferase fused to the 3' end of the cDNA encoding target signal sequences plus 10 amino acids. The transfected cells were incubated overnight and then the cells were trypsinized and plated into 384-well tissue culture plates. The next day, dilutions of compounds in DMSO / doxycycline-containing media were added to the wells and incubated at 37°C, 5% CO2. 24 hours later, coelenterazine substrate was added to each well and the luciferase signal was quantified using Tecan Infinite M1000 Pro IF-2Q19-36422718-APN-A22I7#INPI Page 227 of 25Q for determining power. Target Signal Peptide Sequence + 10 Amino Acids A87 A137 A151 TNFR1 MGLSTVPDLLLPLVLLEL LVGIYPSGVIG (SEQ ID NO: 3) LVPHLGDREK (SEQ ID NO: 4) 307 152 1625 TNFR2 MAPVAVWAALAVGL E LWA AAHA (SEQ ID NO: 5) LPAQVAFTPY (SEQ ID NOT: 6) 564 186 2114 IL-17a MTPGKTSLVSLLLLLSLE AIVKA (SEQ ID NO: 7) GITIPRNPGC (SEQ ID NO: 8) 447 216 1816 IL-17Ra MGAARSPPSAVPGPLLGL LLLLLGVLAPGGAS (SEQ ID NO: 9) LRLLDHRALV (SEQ ID NO: 42) 4 176 1862 IL-23a MLGSRAVMLLLLLPWTAQ G (SEQ ID NO: 11) RAVPGGSSPA (SEQ ID NO: 12) 567 223 1924 IL-12b (p40) MCHQQLVISWFSLVFLAS PLVA (SEQ ID NO: 13) IWELKKDVYV (SEQ ID NO: 14) 155 74 913 IL-23R MNQVTIQWDAVIALYIL F SWCHG (SEQ ID NO: 15) GITNINCSGH (SEQ ID NO: 16) 111 47 666 IL-6 MNS FSTSAFGPVAFSLGL LLVLPAAFPAP (SEQ ID NO: 17) VPPGEDSKDV (SEQ ID NO: 18) 66 38 437 IL- 6R MLAVGCALLAALLAAPGA A (SEQ ID NO: 19) LAPRRCPAQE (SEQ ID NO: 20) 78 48 445 GP130 MLTLQTWLVQALFIFLTT ESTG (SEQ ID NO: 21) ELLDPCGYIS (SEQ ID NO: 22) 201 161 969 IF-2G19-36422718-APN-A22P#INPI Page 228 of 25G Target Signal Peptide Sequence + 10 Amino Acids A87 A137 A151 IL-1R1 MKVLLRLICFIALLISS (SEQ ID NO: 23) LEADKCKERE (SEQ ID NO: 24) 374 282 1474 IL-1R2 MLRLYVLVMGVSA (SEQ ID NO: 25) FTLQPAAHTG (SEQ ID NO: 26) 23 17 168 IL-IRa (isoform a 1) MEICRGLRSHLITLLLFL FHSETIC (SEQ ID NO: 27) RPSGRKSSKM (SEQ ID NO: 28) 111 47 666 IL-2Ra (CD25) MDSYLLMWGLLTFIMVPG CQA (SEQ ID NO: 29) ELCDDDPPEI ( SEQ ID NO: 30) 159 55 876 ​​IFN-al MAS P FAL LMVL WL SOKS SCSLG (SEQ ID NO: 31) CDLPETHSLD (SEQ ID NO: 32) 128 57 820 IFN-a2 MAL T FAL LVAL LVL S C KS SCSVG (SEQ ID NO: 33) CDLPQTHSLG (SEQ ID NO: 34) 51 44 404 IFN-a4 MALSFSLLMAVLVLSYKS ICSLG (SEQ ID NO: 35) CDLPQTHSLG (SEQ ID NO: 36) 221 89 1129 IFN-b MTNKCLLQIALLLCFSTT ALS (SEQ ID NO: 37) MSYNLLGFLQ (SEQ ID NO: 38) 818 288 4305 YTD (SEQ ID NO: 42) 133 42 778 CTLA-4 MACLGFQRHKAQLNLATR TWPCTLLFFLLFIPVFC (SEQ ID NO: 43) KAMHVAQPAV (SEQ ID NO: 44) 259 112 1145 PD-L1 MRIFAVFIFMTYWHLLNA (SEQ ID NO: 45) FTVTVPKDLY (SEQ ID NO: 46) 56 19 366 LAG3 MWEAQFLGLLFLQPLWVA PVKPLQPGAE (SEQ ID NO: 47) VPVVWAQEGA (SEQ ID NO: 48) 75 48 464 IF-2O19-36422718-APN-ANP#INPI Page 229 of 250 Objetivo Secuencia de péptido señal + 10 Aminoácidos A87 A137 A151 TIM3 MFSHLPFDCVLLLLLLLL TRS (SEQ ID NO: 49) SEVEYRAEVG (SEQ ID NO: 50) 282 132 1354 TIGIT MRWCLLLIWAQGLRQAPL ASG (SEQ ID NO: 51) MMTGTIETTG (SEQ ID NO: 52) 162 79 737 CD96 MEKKWKYCAVYYIIQIHF VKG (SEQ ID NO: 53) VWEKTVNTEE (SEQ ID NO: 54) 12 7 107 VIEW MGVPTALEAGSWRWGSLL FALFLAASLGPVAA (SEQ ID NO: 55) FKVATPYSLY (SEQ ID NO: 56) 211 150 911 B 7H3 MLRRRGS PGMGVHVGAAL GALWFCLTGA ( SEQ ID NO: 57) LEVQVPEDPV (SEQ ID NO: 58) 27 9 201 CD73 MCPRAARAPATLLLALGA VLWPAAGA (SEQ ID NO: 59) WELTILHTND (SEQ ID NO: 60) 58 44 375 PDGFRa MGTSHPAFLVLGCLLTGL SLILC (SEQ ID NO: 61) QLSLPSILPN ( SEQ ID NO: 62) 90 37 565 VGFR2 MQSKVLLAVALWLCVETR A (SEQ ID NO: 63) ASVGLPSVSL (SEQ ID NO: 64) 684 213 2591 IL-7R MTILGTTFGMVFSLLQW SG (SEQ ID NO: 65) ESGYAQNGDL (SEQ ID NO: 66) 58 16 392 EGFR MRP S GTAGAAL LAL LAAL CPASRA (SEQ ID NO: 67) LEEKKVCQGT (SEQ ID NO: 68) 60 47 412 HER3 MRANDALQVLGLLFSLAR G (SEQ ID NO: 69) SEVGNSQAVC (SEQ ID NO: 70) 89 57 522 VEGF MNFLLSWVHWSLALLLYL HHAKWSQA (SEQ ID NO: 71) APMAEGGGQN (SEQ ID NO: 72) 111 51 645 TACE (ADAMI7 ) MRQS LL FLT S WP FVLA (SEQ ID NO: 73) PRPPDDPGFG (SEQ ID NO: 74) 66 40 391 ADAM10 MVL L RVLILLL SWAAGMG G (SEQ ID NO: 75) QYGNPLNKYI (SEQ ID NO: 76) 231 127 849 IF-2G19-36422718-APN-A23P#INPI Page 23G of 25G Peripheral Blood Mononuclear Cell (PBMC) Cytokine Assay Human PBMCs were recently isolated from whole blood collections from 3 normal donors using density gradient centrifugation followed by red blood cell lysis. PBMCs from each donor were analyzed separately. Cells were suspended in RPMI 1640 medium supplemented with 5% fetal bovine serum, 2 mM L-glutamine, 10 mM HEPES, and 1X penicillin / streptomycin. PBMCs were seeded at 200,000 cells / well in 96-well round-bottom plates without stimulation or with stimulation with lipopolysaccharide (LPS, 1 pg / ml) or antibodies against human CD3 (plate-bound, 2 pg / ml) and CD28. human (soluble, 2 pg / ml). Serial dilutions of the compound in DMSO / medium were added simultaneously and PBMC were incubated at 37°C, 5% CO2 for 24 hours. After 24 hours, the plates were centrifuged and half of the supernatant volume was removed for cytokine analysis by electrochemical immunoassay (U-PLEX® Biomarker Multiplex, Meso Scale Discovery). For viability analysis, CellTiter-Glo® (Promega) was added to the remaining material in each well and quantified using a luminescent plate reader. IF-2019-36422718-APN-A2NP#INPI Page 231 of 250 A87 A137 A133 A177 Mean IC50 (nM) [Stimulation condition] GM-CSF [AntiCD3 / CD28] 165 25 404 19 IFNy [Anti-CD3 / CD28] 152 21 234 19 IL-Ιβ [LPS] >25000 >25000 >25000 >25000 IL-2 [Anti-CD3 / CD28] 31 8 197 10 IL-6 [LPS] 61 12 193 24 IL-23 [LPS] 200 79 1054 54 TNFa [Anti-CD3 / CD28] 82 17 216 13 CellTiter- Glo Viability [No stimulation] >25000 >25000 >25000 >25000 Efficacy study: Effect of compound A87 on tumor growth and body weight in a B16F10 model compartmentalized with anti-PD-1 therapy. Female C57BL / 6 mice (7-8 weeks old) were injected in the flank subcutaneously with 5x106 B16F10 cells in 0.1 ml on day 0. On day 3, compound A87 in 10% ETOH / 10 % Kolliphor EL IV 30 mg / kg QW, IV 10 mg / kg D1D2, or IP 15 mg / kg QOD. Anti-PD1 antibody treatment (RMP1-14 from Bioxcell, 200 pg) was administered i.p. on a QODx3 dosing schedule. Tumor size was monitored with a digital caliper (Fowler) every 2-3 d until reaching a size of 1.5-2.0 cm and was expressed as volume (length x width x height). B16F10, a melanoma line, was obtained from ATCC. C57 / BL6 mice were purchased from Charles Rivers Laboratories. IF-2019-36422718-APN-A232 / INPI Page 232 of 250 TABLE 1 Activities of the compounds No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A1 1026.3 1396.1 A.I. 1170.58 I.A. A.I. 0.21 0.12 0.18 0.18 A2 344.75 807.39 I.A. 10141 A.I. 0.09 0.59 0.09 0.04 A3 241.49 637.58 11412 5080.51 A.I. 0.09 0.37 0.83 0.25 A4 93.87 310.79 3763.69 1220.45 A.I. 0.56 1.17 1.17 0.25 A5 651.38 I.A. 8429.37 I.A. 0.27 0.24 0.31 0.24 A6 4747.33 I.A. 24073.2 A.I. 0.12 0.17 0.44 0.53 A7 2314.7 I.A. 22428.6 A.I. 0.17 0.23 0.99 0.29 A8 2681.93 A.I. A.I. A.I. 0.17 0.61 0.19 0.09 A9 1106.83 A.I. A.I. A.I. 0.34 0.14 0.66 0.09 A10 123.42 4687.09 2863.07 A.I. 0.2 8.85 0.14 0.77 A11 365.31 865.78 I.A. 623.7 I.A. A.I. 0.18 0.17 0.08 0.21 IF-2019-36422718-APN-ANp#INPI Page 233 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A12 857.59 I.A.I.A. A.I. 0.1 0.07 0.22 0.11 A13 25.01 1471.73 987.14 A.I. 0.04 0.1 0.1 0.65 A14 640.11 1234.03 I.A. 1163.27 I.A. A.I. 5.39 1.13 1.4 0.08 A15 95.1 3063.1 2955.87 14604.7 0.29 0.061 0.13 0.07 A16 108.07 6341.65 4977.83 A.I. 2.09 2.62 41.1 0.11 A17 942.97 I.A. I.A. A.I. 0.41 1.06 0.36 0.49 A18 I. A. I. A. I.A. 15473.2 0.05 0.11 0.05 0.04 A19 325.83 I. A. I.A. 21895.5 0.24 0.1 0.08 0.05 A20 206.77 I.A. 12798.2 I.A. 0.07 0.19 0.06 0.05 A21 184.02 10002.6 8288.81 A.I. 1.77 0.62 0.11 0.14 A22 155.66 404.42 6377.93 370.18 6673.8 A.I. 0.12 0.4 0.11 0.16 IF-2019-36422718-APN-ANP#INPI Page 234 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A23 758.88 I.A. A.I. A.I. 0.17 0.13 0.03 0.04 A24 A.I. A.I. A.I. A.I. 0.13 0.04 0.03 0.03 A25 435.17 I.A. A.I. A.I. 0.32 4.16 0.2 0.12 A26 224.49 I.A. 16068.5 A.I. 3.4 1.84 0.13 6.65 A27 492.55 I.A. A.I. A.I. 2.15 0.98 2.07 2.52 A28 5251.11 I.A. 10426 A.I. 0.06 0.14 0.06 — A29 241.1 591.29 A.I. 446.59 I.A. A.I. 32.4 43.3 19.5 39.6 A30 792.84 I.A. A.I. A.I. 0.35 0.28 0.03 0.12 A31 619.25 I.A. A.I. A.I. 0.25 0.09 0.03 0.05 A32 A.I. A.I. A.I. A.I. 0.51 0.27 0.09 0.06 A33 I.A. A.I. A.I. A.I. 0.08 0.13 0.07 0.05 IF-2G19-36422718-APN-ANp#INPI Page 235 of 25G No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A34 A.I. A.I. A.I. A.I. 0.24 0.12 0.09 0.03 A35 83.03 243.99 > 11897.98 A.I. A.I. 20.9 30 13.6 24.8 A36 118.49 319.35 >21809.41 300.59 > 15385.93 A.I. 1.85 0.94 1.54 6.69 A37 202.16 I.A. A.I. A.I. 6.03 13.5 5.69 8.26 A38 75.12 5490.99 > 11844.59 A.I. 12.6 24.2 9.04 11.4 A39 761.18 I.A. A.I. 10421.2 0.26 6 0.11 0.05 A40 308.26 > 15070.18 I.A. A.I. 0.19 0.12 0.04 0.04 A41 17532.8 A.I. A.I. A.I. 0.2 0.14 0.1 0.08 A42 696.43 I.A. A.I. A.I. 0.79 7.69 0.81 2.65 A43 46.87 160.55 1208.05 132.63 2974.53 A.I. 20.1 22.3 12 15.4 A44 132.1 12652.5 A.I. A.I. 43.8 54 38 47.6 IF-2019-36422718-APN-ANP#INPI Page 236 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A46 50.13 1758.33 3336.62 A.I. 3.63 4.46 1.44 6.12 A47 258.84 I.A. I.A. A.I. 5.68 10.7 1.68 12.6 A48 991.35 I.A. I.A. A.I. 0.07 0.4 0.1 0.19 A49 407.05 I.A. I.A. A.I. 11.8 16.4 9.36 3.5 A50 22.21 74.12 660.73 56.97 1007.74 6536.29 70.1 3.6 0.79 1.32 A51 61.36 3068.97 6153.41 A.I. 28 34.7 23.6 26.7 A52 45.56 1035.16 2105.88 A.I. 29.3 40.1 38.3 31 A53 35.33 1014.07 1717.71 > 10260.36 39.2 50.5 39 38 A54 26.51 952.37 1907.23 A.I. 34.6 42.4 30.5 33.8 A55 1540.39 I.A. I.A. A.I. 1.18 0.97 0.34 4.87 A56 32.76 1255.87 1634.05 I.A. 53.2 57.3 42.6 44.5 IF-2ü19-36422718-APN-AW#INPI Page 237 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A57 73.41 7807.65 A.I. A.I. 60.2 84 28.5 31.9 A58 72.14 8500.05 A.I. A.I. 72.8 66.7 53.1 31.6 A59 24.23 615.54 1442.63 A.I. 3.73 3.9 1.94 1.89 A60 18.54 886.17 1483.8 I.A. 60.8 50.3 38.7 46.7 A61 955.94 I.A. I.A. A.I. 17.9 19.6 8.96 13.3 A63 43.65 1873.85 7433.97 I.A. 85.2 88.2 84.4 76.4 A64 74.98 3293.48 6402.59 A.I. 53.1 63.1 48 53.3 A65 153.77 8715.63 A.I. A.I. 73.4 78 57.8 53.1 A66 187.59 3495.74 9211 A.I. 0.02 0.39 0.35 0.13 A67 40.77 937.29 2398.75 A.I. 28 45.4 27.6 33.2 A68 156.12 6440.61 A.I. A.I. 55.1 57.1 57.1 50.5 IF-2G19-36422718-APN-A2N8 / INPI Page 238 of 25G No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A69 136.39 I.A. I.A. A.I. 64.6 74.3 58.2 63 A70 46.08 1301.94 3023.7 A.I. 3.14 6.75 3.26 1.36 A71 63.32 2014.74 7724.78 I.A. 11.5 17.2 6.75 5.55 A72 96.18 6972.14 10286.3 A.I. 43.3 54.6 53.2 62.5 A73 37.27 1861.53 3471.61 A.I. 16.3 71.5 25.4 18.2 A74 77.38 257.97 I.A. 248.26 I.A. A.I. 53.7 55.7 60.6 56.3 A75 104.41 255.94 3782.3 233.05 3029.96 A.I. 2.75 7.54 0.28 3.08 A76 I. A. I. A. I. A. I. A. I.A. A.I. 28.6 33.9 35.7 53.1 A77 95.05 338 5544.21 359.68 4012.61 A.I. 37.3 32.5 20.8 30.1 A78 359.83 I.A. I.A. A.I. 0.15 0.25 0.11 0.2 A79 408.23 I.A. I.A. A.I. 10.6 0.1 0.06 0.16 A80 272.95 I.A. A.I. A.I. 13.4 14.1 2.56 10.8 IF-2G19-36422718-APN-ANl%INPI Page 239 of 25G No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH (%) Mouse Rat Monkey Human A81 476.93 I.A. A.I. A.I. 0.12 0.12 0.03 0.2 A82 30.52 1547.55 2298.14 A.I. 0.08 0.16 0.23 0.3 A83 28.17 961.05 959.61 A.I. 23.4 47.6 34.9 39.3 A84 175.94 I.A. A.I. A.I. 68.3 67.3 65.8 60.6 A85 87.46 A.I. A.I. A.I. 52.2 64.9 42.9 25.6 A86 428.72 A.I. 394.88 5625.91 A.I. 34.1 39.9 29.2 41.3 A87 19.15 492.19 50.23 223.57 A.I. 49.6 43.6 32.7 39.7 A88 4330.54 I.A. A.I. A.I. A.I. 15.9 15.2 1.33 11.7 A89 82.05 1208.13 186.53 1751.25 A.I. 17.1 22.2 13.5 18.5 A90 207.02 2413.57 493.18 3786.86 A.I. 28.2 20.2 14.1 20.1 A91 193.42 2459.27 376.81 3011.92 14653.1 25.4 21.6 21.8 23.7 A92 304.02 A.I. 518.65 I.A. A.I. 40.8 51.8 40.4 44.3 IF-2019-36422718-APN-A24PhNPI Page 240 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A93 670.27 I.A. 911.37 10427.9 I.A. 0.4 0.51 0.18 0.84 A94 36.37 550.17 78.29 800.16 A.I. 45.7 45.5 30.3 42.1 A95 198.02 4897.04 390.92 6711.7 A.I. 54.2 43.1 46.1 43.9 A96 121.85 1847.65 231.78 5104.13 A.I. 37.6 41.9 32.8 40.5 A97 41.78 565.68 87.04 725.76 A.I. 77.7 71.4 66.1 71.1 A98 201.79 7335.28 351.2 A.I. A.I. 55.2 32.8 26.9 57.5 A99 115.58 3535.19 349.8 A.I. A.I. 60.8 50.8 37 41.9 A100 1150.93 I.A. 1560.04 I.A. A.I. 0.1 2.18 0.04 0.22 A101 220.23 3425.89 564.3 A.I. A.I. 20.8 25.4 18.8 30.2 A102 33.39 477.31 90.53 558.29 A.I. 86.6 101.9 70 62.3 A103 445.68 I.A. 698.23 I.A. A.I. 42.2 36.5 38.5 31.6 IF-2019-36422718-APN-A2NP#INPI Page 241 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A106 52.35 1118.61 126.18 902.63 A.I. 8.81 18.9 30.7 7.18 A107 26.11 609.25 72.97 1176.64 A.I. 16.1 19.3 25.0 83.9 A108 29.58 546.31 68.29 420.52 A.I. 0.62 2.05 0.88 1.06 A118 67.79 2093.86 172.7 5345.11 A.I. 22.1 18.3 14.7 14.2 A119 52.34 1077.79 170.3 7675.81 A.I. 50.8 66.1 53.9 71.7 A120 15.58 238.67 27.34 672.16 A.I. 19.2 28.5 16.3 4.78 A122 51.93 885.26 134.57 2420.21 A.I. 36.4 0.17 0.15 0.38 A123 13.98 424.92 45.93 834.51 A.I. 6.13 7.41 3.47 5.02 A124 606.76 I.A. 802.05 I.A. A.I. 1.01 1.25 1.91 18.9 A125 829.42 11524.98 1090.55 A.I. A.I. 0.14 0.37 8.67 0.2 A131 145.44 2403.07 426.19 4744.68 A.I. 101 73.9 70.2 84.5 IF-2G19-36422718-APN-ANp#INPI Page 242 of 25G No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH (%) Mouse Rat Monkey Human A133 36.84 748.55 134.51 5121.95 LA. 82.2 87.3 67.3 71.3 A134 11.04 309.22 27.28 540.66 LA. 27.9 41.3 9.76 31.9 A135 21.58 625.08 48.58 1239.26 LA. 26.1 56.3 39.2 9.36 A136 26.46 543.65 101.39 1726.93 LA. 14.3 26.6 23.2 65.3 A137 8.30 191.24 21.45 281.93 LA. 28 31.6 14.2 48.8 A138 73.91 947.28 156.27 2396.92 LA. 13.2 17.1 12.5 8.84 A140 491.56 3009.42 808.08 LA. THE. 3.68 0.56 1.56 0.41 A141 431.02 4235.2 862.9 9106.16 LA. 0.48 1.14 0.66 0.26 A142 38.25 741.05 67.02 1446.85 LA. 16 22.6 3.89 11.8 A147 4122.89 LA. THE. THE. THE. 0.74 1.16 0.99 2.76 A148 925.61 A.I. 1117.32 I.A. A.I. 1.59 1.29 0.67 0.52 IF-2019-36422718-APN-A24P#INPI Page 243 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A149 A.I. A.I. A.I. A.I. A.I. 0.83 0.47 0.96 0.44 A150 30.29 467.79 41.34 2000.66 A.I. 1.38 2.02 2.2 4.6 A151 152.57 1216.54 305.64 2711.98 A.I. 4.55 4.2 3.98 4.28 A152 81.5 1028.9 173.82 2171.97 A.I. 5.06 3.6 3.22 3.69 A153 1293.98 I.A. 1255.35 I.A. A.I. 0.87 6.23 1.26 2.57 A154 14.94 504.45 58.66 749.43 A.I. 17.5 12.3 10.2 7.33 A155 1350.05 3484.03 7795.99 A.I. 16.8 38.8 4.86 17.8 A156 92.46 1825.18 206.72 3707.48 A.I. 75.6 82.1 80.6 81.3 A157 23.33 584.47 77.41 858.16 A.I. 23.3 32.2 27.3 21.1 A160 152.83 10687.02 452.72 A.I. A.I. 61.3 51.1 46.1 71.8 A161 577.46 A.I. 725.52 I.A. A.I. 26.5 27.3 16.7 20.2 IF-2G19-36422718-APN-ANP#INPI Page 244 of 25G No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A162 101.25 6263.53 200.98 A.I. A.I. 62.5 69.6 60.3 70.5 A163 55.56 1928.36 81.21 13622.1 A.I. 72.8 54.9 57.5 64.2 A164 454.69 I.A. 974.47 I.A. A.I. 69.0 57.9 40.9 64.8 A165 131.14 1857.05 293.51 4086.76 A.I. 14.9 11.9 12.8 2.23 A166 16.68 278.28 30.25 547.83 A.I. 26.4 31.3 18.7 14.0 A167 200.61 2656.44 412.45 6495.51 A.I. 18.3 9.19 73 5.68 A168 1491.98 I.A. 1144.17 I.A. A.I. 42 42.1 73 25.7 A169 81.52 1048.04 192.27 3272.71 A.I. 22.5 13.1 4.23 34.7 A170 56.13 797.63 133.66 1775.44 A.I. 3.65 10.8 1.37 7.2 A171 A.I. A.I. A.I. A.I. A.I. 0.91 0.90 0.26 0.60 A172 29.18 436.2 66.4 1750.08 A.I. 3.65 2.23 2.63 3.46 ΙΡ-2019-36422718-ΑΡ\-Λ\Ί5·Ι\ΡΙ Page 245 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A173 78.83 5638.24 248.3 A.I. A.I. 49.2 53.8 55.9 56.1 A174 15.79 565.56 53.31 1861.24 A.I. 36.9 44.4 28.4 41.7 A175 9.35 393.21 40.35 1436.98 A.I. 6.73 6.28 2.27 4.26 A176 17.11 631.2 62.1 3109.99 A.I. 32.4 23.0 15.2 31.9 A177 4.95 154.54 12.57 179.88 A.I. 11.6 14.5 2.8 13.7 A178 134.76 4820.51 255.26 A.I. A.I. 22.8 29.2 25.8 24.0 A179 269.79 3249.91 72.57 11347.74 A.I. 0.5 0.18 0.26 0.04 A180 2742.03 A.I. 13843.24 20179.62 A.I. 0.44 1.97 0.08 0.80 A181 38.69 983.85 122.41 1479.93 A.I. 17.1 22.0 27.9 23.3 A182 78.84 1957.98 255.55 A.I. A.I. 61.7 41.9 41.5 53.7 A183 1443.55 2524.48 6116.1 A.I. 7.39 3.17 0.75 10.1 IF-2O19-36422718-APN-ANP#INPI Page 246 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A184 100.13 1079.53 232.68 6916.08 A.I. 5.64 7.47 1.23 2.56 A185 43.18 573.1 85.38 1468.19 A.I. 30.1 37.8 10.0 21.8 A187 427.09 6171.01 1087.5 3866.88 A.I. 0.03 0.07 0.15 0.05 A188 38.94 714.46 99.28 1555.52 A.I. 4.48 27.8 12.4 27 A189 512.4 8138.23 1358.47 10609.19 A.I. 0.14 0.07 0.01 0.06 A190 16.23 294.54 45.7 867.11 A.I. 69.3 85.3 71.6 74.1 A191 57.62 1095.62 144.64 6734.93 A.I. 55.3 65.0 68.3 48.6 A192 1153.54 I.A. 2332.92 9362.89 A.I. 0.18 0.08 0.10 0.02 A193 23.8 748.16 81.77 6806.9 A.I. 10.1 11.3 7.72 34.2 A194 261.32 A.I. 401.51 I.A. A.I. 68.5 59.2 65.0 63.6 A195 210.96 11201.43 668.05 A.I. A.I. 58.5 63.3 32.8 53.6 A196 30.96 1474.7 104.78 I.A. A.I. IF-2ü19-36422718-APN-AW#INPI Page 247 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A197 34.25 666.07 95.53 4125.97 A.I. 65.4 76.6 92.8 70.7 A198 18.54 372.95 53.28 1170.31 A.I. 68.2 61.4 65.1 39.2 A199 80.8 1420.53 162.14 A.I. A.I. 23.7 28.3 25.5 8.0 A200 11.23 284.85 27.87 435.72 A.I. 71.9 83.1 73.9 78.1 A201 117.7 7086.36 282.88 A.I. A.I. 39.1 35.4 26.5 32.8 A202 56.59 2052.14 175.52 2914.63 A.I. 55.0 50.8 38.3 13.3 A203 14.76 434.38 30.44 396.26 A.I. 80.3 78.7 77.9 83.4 A204 58.42 981.88 157.89 1487.11 A.I. 62.6 58.3 49.7 48.4 A205 128.76 1806.9 305.32 2362.23 A.I. 38.9 38.7 31.7 37.2 A206 17.37 395.41 38.95 657.05 A.I. 84.3 80.5 65 54.7 A207 7.93 221.47 10.6 105.74 A.I. 84.3 98.8 63.0 62.7 IF-2O19-36422718-APN-ANP#INPI Page 248 of 250 No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human A208 343 A.I. 615.95 I.A. A.I. 51.8 68.9 37.5 23.3 A209 326.73 I.A. 672.98 I.A. A.I. 31.8 44.7 45.7 22.6 A210 202.76 I.A. 446.86 I.A. A.I. 76.0 54.6 55.4 47.4 B1 423.7 I.A. A.I. A.I. 0.02 0.01 0.02 0.04 B2 1721.99 I.A. A.I. A.I. 0.55 1.46 0.23 0.35 B3 7382.27 I.A. 9441.64 12597.4 0.15 0.1 0.08 0.26 B4 I.A. A.I. A.I. 16627.8 2.21 2.79 1.7 12.1 B5 1497.99 I.A. A.I. A.I. 0.24 7.08 0.21 0.54 B6 416.05 I.A. A.I. A.I. 81.8 13.2 4.57 7.66 B7 6900.19 24323 6858.59 7481.69 1.47 0.58 0.04 0.03 B8 I.A. A.I. A.I. A.I. 17.1 23.8 15.5 22.1 B9 3642.93 A.I. A.I. A.I. 0.36 3.74 0.26 0.49 IF-2G19-36422718-APN-A2NP#INPI Page 249 of 25G No. 24hr Inducible Dox PDIssGluc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox PDIFLFIuc 293FRT / TO: IC50 Mean (nM) 24hr Inducible Dox TNFaFLGIuc 293FRT / TO: IC50 mean (nM) 24hr Inducible Dox IL2FLGIuc 293FRT / TO: IC50 mean (nM) 48hr H929 Celltiter-Glo viability: mean EC50 (nM) 48hr U266 Celltiter-Glo viability: mean EC50 (nM) Liver chromosome stability - % left after 30min p / NADPH(%) Mouse Rat Monkey Human B10 16476.4 A.I. 6923.68 I.A. A.I. B11 A.I. A.I. A.I. A.I. A.I. B12 5655.74 I.A. A.I. A.I. A.I. B16 449.25 13885 825.91 I.A. A.I. 58.4 72.3 44.7 55.2 B19 220.99 15364.2 A.I. A.I. 13.5 15.7 0.98 9.46 B20 794.07 I.A. A.I. A.I. 3.41 11.1 1.73 5.43 B21 3951.77 I.A. A.I. A.I. A.I. 0.16 0.06 0.03 0.17 B22 31.31 519.36 80.48 1648.2 A.I. 8.31 10.1 1.77 1.77

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof: (FORMULA I) wherein: each of R a and R b is independently H or C1-3 alkyl; R 1 is H, OH, C1-3 alkyl, C1-3 O-alkyl, =CH2, or =NOR 5 ; or R 1 is C3-6 cycloalkyl or C3-6 heterocycloalkyl and forms a spiro group with the carbon ring to which it is attached; each of R 1a and R 1b is independently H or C1-3 alkyl; R 2 is C3-9 heterocycloalkyl or C3-9 heterocycloalkenyl and is not morpholino; R 3 is C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-7 heterocycloalkyl, C6-10 aryl or C2-6 heteroaryl; R4 is C6-10 aryl or C2-9 heteroaryl; each R5 is independently H, C1-3 alkyl, or C0-2 alkylene-C6-10 aryl; X is C1-3 alkylene; Y is SO or SO2; each heterocycloalkyl, heterocycloalkenyl, and heteroaryl group independently has 1, 2, or 3 ring heteroatoms selected from N, O, and S. 14 Claims follow