Macrocyclic TAK1 Inhibitors

Abstract

The present invention provides compounds of formula (I), or a tautomer thereof, wherein R 1 , R 2 , R 3 , W1, W2, W3, A, X, and Y are as defined in the specification. The compound is a potent inhibitor of TAK1, a serine / threonine kinase. The present invention further provides a pharmaceutical composition comprising a compound of formula (I) and at least one pharma- ceutically acceptable excipient; a compound of formula (I) for use as a medicament (e.g., for the treatment or prevention of a condition selected from cancer, inflammatory disease, autoinflammatory disease, and autoimmune disease); and a method for treating or preventing a disease or disorder, comprising administering a pharma- ceutically effective amount of a compound of formula (I) to a subject in need thereof. [Formula 1] TIFF2024527464000160.tif50114

Description

[Technical Field]

[0001] The present invention relates to compounds of formula (I) and compositions comprising compounds of formula (I). The compounds and compositions of the present invention are useful for treating or preventing diseases or disorders that can be treated or prevented by inhibition of the serine / threonine kinase TAK1. [Background technology]

[0002] TAK1 (transforming growth factor β-activated kinase 1, mitogen-activated protein kinase kinase kinase 7, MAP3K7) is a serine / threonine kinase belonging to the MAPK kinase kinase (MAP3K) family. TAK1 was originally identified as a kinase involved in TGF-β signaling (Non-Patent Document 1). It was subsequently shown to mediate the activation of immune processes stimulated by proinflammatory cytokines such as tumor necrosis factor alpha (TNFα), Toll-like receptor (TLR) ligands, and interleukin-1 beta (IL-1β) (Non-Patent Document 2). In response to activation, TAK1 mediates the activation of nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), and p38 pathways (reviewed in Non-Patent Document 3).

[0003] TAK1 inhibitors have shown promise in models of rheumatoid arthritis (Non-Patent Document 4), pancreatic cancer (Non-Patent Document 5), and colitis (Non-Patent Document 6). Inhibition of TAK1 has also shown promise in the treatment of KRAS (Kirsten rat sarcoma viral oncogene homolog)-dependent cancers (Non-Patent Document 7).

[0004] Various inhibitors of TAK1 have been described in the art; for example, a series of TAK1 inhibitors are disclosed in Non-Patent Document 8, Patent Document 1 (Derbyshire et al.), and Patent Document 2 (Derbyshire et al.). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent Application Publication No. 2018 / 0105500 [Patent Document 2] U.S. Patent Application Publication No. 2019 / 0263759 [Non-Patent Document]

[0006] [Non-Patent Document 1] Yamaguchi et al., Science, 1995, 270, 2008 - 2011 [Non-Patent Document 2] Sato et al., Nat Immunol, 2005, 6 (11), 1087 - 95 [Non-Patent Document 3] Dai et al., Life, 2012, 64(10), 825 - 834 [Non-Patent Document 4] Scarneo et al., Arthritis Research & Therapy, 2019, 21(292) [Non-Patent Document 5] [[ID=​​​​​​​​​​​​​​​​​​​​​However, many of the known TAK1 inhibitors exhibit poor aqueous solubility, poor selectivity for TAK1, and / or poor cellular activity. Thus, there is a need in the art for additional TAK1 inhibitors with beneficial properties. [Means for solving the problem]

[0008] The present invention provides compounds of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0009] [ka]

[0010] [In the formula, A is a 6-membered aromatic ring or a 5-6-membered aromatic heterocycle containing 1 or 2 atoms selected from the group consisting of N, S, and O; W1, W2, and W3 are independently selected from CH and N; X is a linear C 2-8 Alkylene, optionally halogen; OH; C 3-6 Cycloalkyl; C optionally substituted with one or more halogens or OH 1-6 alkyl; and the linear C 2-8 The linear C alkylene groups, taken together with the alkylene atoms, form a 3- or 4-membered cycloalkyl group. 2-8 and / or optionally, one or more carbon atoms of said alkylene are substituted with a group independently selected from O, NH, and S. 2-8 is alkylene; Y is NH or O; R 1 and R 2 is H;C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;OC 1-6 Alkyl;OC 2-6 Alkenyl;OC 2-6 Alkynyl; -Ra ;C(O)R a ;C(O)OR a ;OCR a ;OC(O)(R a );-C 1-6 Alkylene-R a ;-C(O)C 1-6 Alkylene-R a ;-C(O)OC 1-6 Alkylene-R a ;-OC 1-6 Alkylene-R a ;OC(O)C 1-6 Alkylene-R a ; and -R b wherein said alkyl, alkenyl, or alkynyl is optionally selected from one or more R b substituted with a group; R 3 H, halogen, OH, C 1-6 Alkyl or OC 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogens; where: R a is C 3-8 cycloalkyl or a 3-12 membered heterocycle containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O; said cycloalkyl or heterocycle optionally being selected from C 1-4 Alkylene-bridged and / or C 1-4 alkyl; 3-6 membered heterocycles (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O); C 3-6 Cycloalkyl;OC 1-4 Alkyl; O-(3- to 6-membered heterocycle (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O)); OC 3-6 Cycloalkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl; C(O)NH2; and -C 1-4 Alkylene-OC 1-4 substituted with one or more groups independently selected from alkyl;a wherein the alkyl, alkylene, heterocycle, or cycloalkyl is optionally selected from the group consisting of halogen; OH; O; SH; NH; NHC 1-4 alkyl; or N(C 1-4 substituted by one or more groups independently selected from alkyl); Each R b is C(O)R c ;C(O)OR c ;OC(O)R c ;SR c ;SO2R c ;NO2;CN;NR c R d ;N(R c )SO2C 1-3 Alkyl; N(R c )C(O)R d ;C(O)NR c R d ;SO2NR c R d halogen; SH; NH; and OH; wherein the alkyl is optionally substituted with one or more groups independently selected from halogen, SH, NH, and OH, and / or optionally one or more carbon atoms of the alkyl is substituted with a group independently selected from O, NH, and S; and R c and R d is H;C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;-C 1-4 Alkylene-OC 1-4 Alkyl; and C 3-8 cycloalkyl; wherein said alkyl, alkylene, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more groups selected from halogen, SH, NH, OH, and =0, and / or optionally one or more carbon atoms of the alkyl is substituted with an atom independently selected from O, N, and S.

[0011] The present inventors have discovered that the compound of formula (I) is a potent inhibitor of the serine / threonine kinase TAK1. In particular, the present inventors have demonstrated that the compound of formula (I) exhibits excellent cellular potency in an in vitro cell-based p38 phosphorylation assay. Selectivity is important for kinase inhibitors. The compounds of the present invention exhibit good selectivity for TAK1. For example, the compounds of the present invention have better selectivity for TAK1 than for interleukin-1 receptor-associated kinase (IRAK).

[0012] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable excipient.

[0013] The present invention further provides a compound of formula (I) or a pharmaceutical composition of the invention for use as a medicament.

[0014] The present invention further provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutical composition of the present invention. The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows a Western blot obtained in a cell-based p38 phosphorylation assay using compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present inventors have discovered a new class of inhibitors of TAK1, a serine / threonine kinase. As described in the Examples section, various exemplary compounds of the present invention have been synthesized and their ability to inhibit TAK1 activity has been evaluated using an in vitro TAK1 biochemical assay and an in vitro cell-based p38 phosphorylation assay. The present inventors have discovered that the compounds of the present invention are highly potent inhibitors of TAK1 activity in the in vitro biochemical assay. Furthermore, the present inventors have found that the compounds of the present invention exhibit excellent cellular activity in the p38 phosphorylation assay (see, e.g., the experimental results in Biological Examples 1 and 2 below). Thus, the compounds of the present invention are of particular interest for use in the treatment or prevention of diseases or disorders associated with abnormal TAK1 activity.

[0017] Furthermore, the compounds of the present invention exhibit high solubility in aqueous solution, achieving a maximum solubility of about 90 μM in solubility assays.

[0018] The present invention provides compounds of formula (I):

[0019] [ka]

[0020] In the compounds of formula (I), A is a 6-membered aromatic ring or a 5-6-membered aromatic heterocycle containing one or two atoms selected from the group consisting of N, S, and O. For example, A can be selected from the group consisting of phenyl, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, thiazole, isoxazolyl, and isothiazolyl. In compounds where A is an aromatic heterocycle containing three heteroatoms, the ring can be a triazinyl group (R 3 (bearing no substituents). In an exemplary embodiment, A is phenyl, pyridyl, thiazole, or thienyl. Preferably, A is phenyl or thienyl. More preferably, A is phenyl.

[0021] In embodiments where A is phenyl, the compound of formula (I) is preferably according to formula (Ia):

[0022] [ka]

[0023] In embodiments where A is pyridyl, the compound of formula (I) is preferably according to formula (Ib):

[0024] [ka]

[0025] In embodiments where A is thiazole, the compound of formula (I) is preferably according to formula (Ic):

[0026] [ka]

[0027] In embodiments where A is thienyl, the compound of formula (I) is preferably according to formula (Id):

[0028] [ka]

[0029] In compounds of formula (I) (and similarly throughout this section compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), and (If)), R 3 is H, halogen (e.g., F, Cl, Br, or I), OH, C 1-6 Alkyl or OC 1-6 alkyl, wherein said alkyl is optionally substituted with one, two, or three halogens (e.g., F, Cl, Br, or I). For example, R 3 are H, F, Cl, Br, I, and C 1-4 Alkyl or OC 1-4alkyl, wherein said alkyl is optionally substituted with one or two, preferably one, F or Cl. Preferably, R 3 is H, F, Cl, methyl, ethyl, or methoxy. More preferably, R 3 is H or F.

[0030] In compounds of Formula (I) (and similarly, compounds of Formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If) throughout this section), W1, W2, and W3 are independently selected from CH and N. For example, one of W1, W2, and W3 can be N, and the remaining can be CH. In certain exemplary embodiments, each of W1, W2, and W3 is CH. In other exemplary embodiments, each of W1 and W2 is CH, and W3 is N. In alternative exemplary embodiments, each of W1 and W3 is CH, and W2 is N. Preferably, each of W1, W2, and W3 is CH.

[0031] In the compounds of formula (I) (and similarly throughout this section the compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If)), X is a linear C 2-8 Alkylene, optionally with halogen (e.g., F, Cl, Br, I); OH; C 3-6 Cycloalkyl; C optionally substituted with one or more halogens or OH 1-6 Alkyl; and linear C 2-8 A straight-chain C alkylene group which, together with the alkylene atoms, forms a 3- or 4-membered cycloalkyl group. 2-8 The alkylene is substituted with one or more groups independently selected from two groups bonded to the same carbon atom of the alkylene. For example, X can be F, Cl, OH, and C 1-6 a linear C substituted with one or two groups independently selected from alkyl; 4-8 It can be alkylene. 4-8 The alkylene is the linear C 2-8 A straight-chain C alkylene group which, together with the alkylene atoms, forms a 3- or 4-membered cycloalkyl group. 2-8When substituted with two groups bonded to the same carbon atom of the alkylene, the cycloalkyl group is preferably cyclopropyl. In certain embodiments, the alkylene of X is substituted with one methyl group or one ethyl group. In certain preferred embodiments, the alkylene of X is substituted with one methyl group.

[0032] Optionally, one or more carbon atoms of the alkylene at position X are substituted with a group independently selected from O, NH, and S (e.g., atoms independently selected from O and S). For example, one or two carbon atoms of the alkylene at position X can be substituted with a group independently selected from O, NH, and S. In certain exemplary embodiments, one carbon atom of the alkylene is substituted with O or NH, more preferably O.

[0033] The inventors have found that an alkylene at the X position, which forms the bond between the imidazole moiety and A of the compound of formula (I), provides compounds that exhibit superior potency in inhibiting TAK1 compared to corresponding compounds that do not contain an alkylene linker at the X position that connects to Y. Without wishing to be bound by theory, the inventors believe that the surprising potency exhibited by the compounds of the present invention is a result of the rigidity imparted to the compounds by the alkylene linker at the X position, which holds the compounds in a configuration that is particularly effective for binding to and inhibiting TAK1. The alkylene at the X position, which has 4 to 8 carbon atoms (i.e., C 4-8 The alkylene linker at the X position provides the necessary rigidity to the compound. The inventors have also surprisingly found that an alkylene linker at the X position also increases the aqueous solubility of the compound. Optimally, the alkylene at the X position is an alkylene having 4 to 8 carbon atoms. Alkylene linkers at the X position that are 5 or 6 carbons in length have been found to be particularly effective. Thus, in preferred embodiments, X is a linear C5 alkylene or C6 alkylene. In particularly preferred embodiments, X is a linear C5 alkylene.

[0034] In certain embodiments, the alkylene of X is F, Cl, Br, I, OH, C 3-6Cycloalkyl and C optionally substituted with one or more halogens or OH 1-6 For example, the alkylene of X can be substituted with one, two, or three groups independently selected from F, Cl, OH, methyl, or ethyl. 1-6 In embodiments substituted with alkyl groups, C 1-6 The alkyl group may be substituted with one or more F, Cl, or OH. For example, a substituent may be present on the first carbon of the X alkylene chain at the benzimidazole (or variant thereof) end of the X group. In such compounds, when a single substituent is present, a chiral center results. In preferred compounds, the substituent is oriented into the page of the compound depicted herein. When the substituent is methyl, the chiral center is in the (S) configuration. In preferred compounds, the substituent is oriented within the compound of formula (I) as shown herein:

[0035] [ka]

[0036] Furthermore, for compounds where X has a C5 alkyl chain length, the structure is:

[0037] [ka]

[0038] Thus, for example, in a compound where X has a C5 alkyl chain length, the substituent is methyl, and W1, W2 and W3 are all CH, the structure is preferably:

[0039] [ka]

[0040] Substitution of the alkylene of X with one or more groups described herein affects the biological activity and / or physicochemical properties of the compounds of formula (I). For example, compounds of formula (I) in which the alkylene of X is substituted with methyl exhibit improved aqueous solubility. Thus, in certain preferred embodiments, the alkylene of X is substituted with one methyl group. For example, X can be -CH(CH)(CH)-. In such compounds, the CH substituent creates a chiral center. In preferred compounds, the chiral center is in the (S) configuration.

[0041] In certain embodiments, one, two, or three carbon atoms of the alkylene of X are substituted with a group independently selected from O, NH, and S. For example, one or two carbon atoms of the alkylene of X are substituted with a group independently selected from O or NH. The substitution of one or more atoms of the alkylene of X with O, NH, or S affects the biological activity and / or physicochemical properties of the compound of formula (I). For example, a compound of formula (I) in which one carbon atom is substituted with O exhibits significantly improved aqueous solubility. Thus, in certain preferred embodiments, one carbon atom in the alkylene of X is substituted with O. For example, X is -(CH2)2-O-(CH2)2- It is possible.

[0042] In compounds of formula (I) (and similarly throughout this section compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), and (If)), Y is NH or O. Preferably, Y is NH.

[0043] In compounds of formula (I) (and similarly throughout this section compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), and (If)), R 1 and R 2 is H;C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;OC 1-6 Alkyl;OC 2-6 Alkenyl;OC 2-6Alkynyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-6 Alkylene-R a ;C(O)C 1-6 Alkylene-R a ;-C(O)OC 1-6 Alkylene-R a ;-OC 1-6 Alkylene-R a ;OC(O)C 1-6 Alkylene-R a ; and -R b wherein said alkyl, alkenyl, or alkynyl is optionally selected from one or more R b In certain embodiments, R 1 and R 2 are both H. In certain other embodiments, R 1 and R 2 At least one of them is not H.

[0044] R 1 and R 2 Compounds of formula (I) in which at least one of is not H exhibit improved aqueous potency of TAK1 inhibition and / or improved aqueous solubility.

[0045] Thus, in certain preferred embodiments, R 1 is H and R 2 is C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;OC 1-6 Alkyl;OC 2-6 Alkenyl;OC 2-6 Alkynyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-6 Alkylene-R a ; and -R b wherein said alkyl, alkenyl, or alkynyl is optionally selected from one or more Rb For example, R 2 is C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-6 Alkylene-R a ; and -R b wherein said alkyl, alkenyl, or alkynyl is optionally selected from one or more R b For example, R 2 is C 1-4 Alkyl; C 2-4 Alkenyl; C 2-4 Alkynyl;OC 1-4 Alkyl;OC 2-4 Alkenyl;OC 2-4 Alkynyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-4 Alkylene-R a ; and R b wherein the alkyl, alkenyl, or alkynyl may optionally be one, two, or three R b For example, R 2 is C 1-4 Alkyl; C 2-4 Alkenyl; C 2-4 Alkynyl; R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-4 Alkylene-R a ; and -R b wherein the alkyl, alkenyl, or alkynyl may optionally be one, two, or three R b Preferably, R 1 is H and R 2 -R a ;C(O)R a;C(O)OR a ;OC(O)(R a );-Methylene-R a ; or -R b More preferably, R 1 is H and R 2 -R a ;C(O)R a ; or -R b In certain exemplary embodiments, R 1 is H and R 2 Ha-R a is.

[0046] In another preferred embodiment, R 2 is H and R 1 is C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;OC 1-6 Alkyl;OC 2-6 Alkenyl;OC 2-6 Alkynyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-6 Alkylene-R a ; and -R b wherein said alkyl, alkenyl, or alkynyl is optionally selected from one or more R b For example, R 2 is H and R 1 is C 1-4 Alkyl; C 2-4 Alkenyl; C 2-4 Alkynyl;OC 1-4 Alkyl;OC 2-4 Alkenyl;OC 2-4 Alkynyl; R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-4 Alkylene-R a ; and -R bwherein the alkyl, alkenyl, or alkynyl may optionally be one, two, or three R b Preferably, R 2 is H and R 1 is methyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-Methylene-R a ; or -R b More preferably, R 2 is H and R 1 is methyl; -R a ;C(O)R a or -methylene-R a is.

[0047] In another preferred embodiment, R 1 and R 2 is C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;OC 1-6 Alkyl;OC 2-6 Alkenyl;OC 2-6 Alkynyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C 1-6 Alkylene-R a ; and -R b wherein said alkyl, alkenyl, or alkynyl is optionally selected from one or more R b For example, R 1 and R 2 independently, C 1-4 Alkyl; C 2-4 Alkenyl; C 2-4 Alkynyl;OC 1-4 Alkyl;OC 2-4 Alkenyl;OC 2-4 Alkynyl; R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-C1-4 Alkylene-R a ; and -R b wherein the alkyl, alkenyl, or alkynyl may optionally be one, two, or three R b Preferably, R 1 and R 2 are independently methyl; -R a ;-C(O)R a ;C(O)OR a ;OC(O)(R a );-Methylene-R a ; or -R b In one exemplary embodiment, R 1 Ha-methylene-R a and R 2 Ha-R b is.

[0048] In the compounds of formula (I), R 1 is at the 5- or 6-position of the compound of formula (I). 1 When is in the fifth place, R 1 is preferably methyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-Methylene-R a ; or -R b and R 2 is preferably H or -R b R 1 is at the 6-position of the compound of formula (I), R 1 is preferably methyl; -R a ;C(O)R a ;C(O)OR a ;OC(O)(R a );-Methylene-R a ; or -R b and R 2 is preferably H.

[0049] In a further preferred embodiment, R 1 is in fifth place, and R 2 is not H. In such embodiments, R 1is preferably C 1-6 Alkyl; C 2-6 Alkenyl, and C 2-6 alkynyl, wherein said alkyl, alkenyl, or alkynyl optionally comprises one or more R b For example, it may be substituted with one or more R b groups, in particular one or more R selected from SH, NH, and OH b a branched C optionally substituted with a group 3-6 It can be an alkyl group. For example, R 1 is a branched C substituted with OH 3-6 It may be an alkyl group, for example, -CH(CH3)OH.

[0050] In compounds of formula (I) (and similarly throughout this section compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), and (If)), R a is C 3-8 cycloalkyl or a 3-12 membered heterocycle containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O (preferably N and O); said cycloalkyl or heterocycle is optionally selected from C 1-4 Bridged with alkylene and / or one or more C 1-4 alkyl; a 3-6 membered heterocycle containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O (preferably N and O); C 3-6 Cycloalkyl;OC 1-4 Alkyl; O-(3- to 6-membered heterocycle (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O)); OC 3-6 Cycloalkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl; C(O)NH2; or -C 1-4 Alkylene-OC 1-4 substituted with alkyl; where R a wherein the alkyl, alkylene, heterocycle, or cycloalkyl is optionally selected from the group consisting of halogen (preferably F or Cl); OH; O; SH; NH; NHC1-4 alkyl; or N(C 1-4 and substituted with one or more groups independently selected from alkyl).

[0051] In certain embodiments, R a is selected from a 3- to 8-membered non-aromatic carbocycle; a 3- to 8-membered heterocycle or a 6- to 12-membered spiroheterocycle containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O; said non-aromatic carbocycle, heterocycle, or spiroheterocycle may optionally be selected from C 1-4 Alkylene-bridged and / or C 1-4 alkyl; 3-6 membered heterocycles (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O); C 3-6 Cycloalkyl;OC 1-4 Alkyl; O-(3- to 6-membered heterocycle (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O)); OC 3-6 Cycloalkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl; C(O)NH2; or -C 1-4 Alkylene-OC 1-4 and substituted with one or more groups independently selected from alkyl, alkylene, heterocycle, or cycloalkyl, wherein said alkyl, alkylene, heterocycle, or cycloalkyl is optionally substituted with one or more groups independently selected from F, Cl; OH; O; SH; NH; NHC 1-4 alkyl; or N(C 1-4 and substituted with one or more groups independently selected from alkyl).

[0052] For the avoidance of doubt, the term "heterocycle," as used herein, includes any aromatic or non-aromatic cyclic group containing one or more heteroatoms (i.e., N, O, or S). The term "heterocycle," as used herein, unless otherwise specified, includes bicyclic heterocyclic groups such as spirocyclic heterocycles, fused heterocycles, and bridged heterocycles. For the avoidance of doubt, a "spirocyclic heterocycle" is a heterocycle containing two ring structures fused at a single atom, where at least one of the ring structures contains one or more heteroatoms; a "fused heterocycle" is a heterocycle containing two ring groups having two atoms in common, where at least one of the ring structures contains one or more heteroatoms; and a "bridged heterocycle" is a heterocycle containing two ring groups having three or more atoms in common, where the two bridgehead atoms are separated by a bridge containing at least one atom, and where at least one of the ring structures contains one or more heteroatoms.

[0053] For the avoidance of doubt, the term "alkyl," as used herein, includes straight-chain, branched-chain, and cyclic (i.e., cycloalkyl) alkyl groups, unless otherwise specified. The term cycloalkyl, as used herein, includes bicyclic cycloalkyl groups, such as spirocyclic cycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups, unless otherwise specified. For the avoidance of doubt, a "spirocyclic cycloalkyl" is a cycloalkyl containing two ring structures fused at a single carbon atom; a "fused cycloalkyl" is a cycloalkyl containing two ring groups having two carbon atoms in common; and a "bridged cycloalkyl" is a heterocycle containing two ring groups having three or more carbon atoms in common, where the two bridgehead carbon atoms are separated by a bridge containing at least one carbon atom.

[0054] In certain preferred embodiments, R a is a 5- to 11-membered heterocycle (e.g., a 5- to 8-membered heterocycle or a 9- to 11-membered spiroheterocycle) containing one or two atoms selected from the group consisting of N and O, and the heterocycle is optionally 1-2Alkylene-bridged and / or C 1-4 Alkyl; 3-6 membered heterocyclic ring containing 1 or 2 atoms selected from the group consisting of N and O; C 3-6 Cycloalkyl;OC 1-4 Alkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl; C(O)NH2; or -C 1-4 Alkylene-OC 1-4 and wherein said alkyl, alkylene, heterocycle, or cycloalkyl is optionally substituted with one or two groups independently selected from F, Cl, OH, , SH, NH2;NHC 1-4 alkyl; or N(C 1-4 and substituted with one or more groups independently selected from alkyl).

[0055] For example, R a is a heterocycle selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxopiperidinyl, homopiperazinyl, pyridinyl, oxodihydropyridinyl, pyrrolidinyl, azetidineyl, triazolyl, oxadiazolenyl, imidazolyl, oxazolidinoneyl, or a 9-11 membered spirocyclic heterocycle (containing one or two atoms selected from the group consisting of N and O), wherein said heterocycle or spirocyclic heterocycle is optionally selected from C 1-4 Bridged with alkylene and / or methyl, ethyl, 3-4 membered heterocycle (containing one atom selected from the group consisting of N, S, and O); C 3-6 Cycloalkyl; O-(3- to 6-membered heterocycle containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O)); OC 1-4 Alkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl; C(O)NH2; or -C 1-4 Alkylene-OC1-4 substituted with one group independently selected from alkyl; wherein said alkyl, alkylene, heterocycle, spirocyclic heterocycle (e.g., non-aromatic spirocyclic heterocycle), or cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and OH.

[0056] Compounds of formula (I) (and similarly compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If) throughout this section) are represented by R 1 and R 2 At least one of the a ;C(O)R a ;C(O)OR a ;OC(O)(R a ); or -methylene-R a and wherein R a is piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxopiperidinyl, homopiperazinyl, pyridinyl, oxodihydropyridinyl, pyrrolidinyl, azetidinyl, triazole, oxadiazolenyl, imidazolyl, oxazolidinoneyl, or a 9-11 membered spirocyclic heterocycle containing one or two atoms selected from the group consisting of N and O; said heterocycle or spirocyclic heterocycle is optionally selected from C 1-4 Bridged with alkylene and / or methyl, ethyl, 3-4 membered heterocycle (containing one atom selected from the group consisting of N, S, and O); C 3-6 Cycloalkyl; O-(3- to 6-membered heterocycle containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O)); OC 1-4 Alkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl; C(O)NH2; or -C 1-4 Alkylene-OC 1-4substituted with one group independently selected from alkyl; wherein said alkyl, alkylene, heterocycle, spirocyclic heterocycle (e.g., non-aromatic spirocyclic heterocycle), or cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and OH.

[0057] For example, R 1 and R 2 One or both of (e.g., R 1 ) is methylene-R a or C(O)R a where R a is as defined immediately above.

[0058] R a In an embodiment where the heterocycle in is a bridged 5- to 11-membered heterocycle, the heterocycle is preferably bridged by a C1 alkylene.

[0059] In certain embodiments, R a optionally C 1-4 Bridged with alkylene and / or one or more C 1-4 alkyl; 3-6 membered heterocycles (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O); C 3-6 Cycloalkyl;OC 1-4 Alkyl; O-(3- to 6-membered heterocycle (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O)); OC 3-6 Cycloalkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl; C(O)NH2; or -C 1-4 Alkylene-OC 1-4 alkyl (F; Cl; OH; methyl; 3-4 membered heterocycle containing one atom selected from N or O; OC 1-4 Alkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl; or -C 1-2and alkylene-substituted with aryl, aryl- ...

[0060] In one particular exemplary embodiment, R a is selected from the group consisting of:

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] In compounds of formula (I) (and similarly throughout this section compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), and (If)), R b is C(O)R c ;C(O)OR c ;OC(O)R c ;SR c ;SO2R c ;NO2;CN;NR c R d ;N(R c )SO2C 1-3 Alkyl; N(R c )C(O)R d ;C(O)NR c R d ;SO2NR c R d and OH; wherein the alkyl is optionally substituted with one or more groups independently selected from halogen (e.g., F, Cl, Br, I), SH, NH, and OH. For example, R b is C(O)R c ;C(O)ORc ;OC(O)R c ;SR c ;SO2R c ;NO2;CN;NR c R d ;N(R c )SO2C 1-3 Alkyl; N(R c )C(O)R d ;C(O)NR c R d or OH; wherein the alkyl is optionally substituted with one or two groups independently selected from F, Cl, SH, NH, and OH. For example, R b HA;C(O)R c ;C(O)OR c ;OC(O)R c ;SR c ;SO2R c ;NO2;CN;NR c R d ;N(R c )SO2C 1-3 Alkyl; N(R c )C(O)R d ;C(O)NR c R d ; SH; NH; or OH; wherein said alkyl is optionally substituted with one or two groups independently selected from F, Cl, SH, NH, and OH. Preferably, R b is C(O)R c or C(O)NR c R d is.

[0065] In compounds of formula (I) (and similarly throughout this section compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), and (If)), R c and R d is H;C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;-C 1-4 Alkylene-OC 1-4 Alkyl; and C 3-8wherein said alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more groups selected from halogen, SH, NH, OH, and =0, and / or optionally one or more carbon atoms of the alkyl is replaced with an atom independently selected from O, N, and S. For example, R c and R d are independently H;-C 1-3 Alkylene-OC 1-3 Alkyl, C 1-3 Alkyl, C 2-3 Alkenyl; C 2-3 and alkynyl, wherein the alkyl, alkenyl, or alkynyl has 1 or 2 carbon atoms optionally substituted with 1 or 2 groups selected from F, Cl, SH, NH, and OH, and / or optionally substituted with atoms independently selected from O, N, and S. In an exemplary embodiment, R c and R d is H, methyl, ethyl, propyl, -C 1-2 Alkylene-OCH3, -C 1-2 alkylene (O)OCH3 (e.g., -CH2(O)OCH3).

[0066] Compounds of Formula (I) (and similarly, compounds of Formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If) throughout this section) may contain isotopic atoms. As defined herein, an isotopic atom is an atom that is not the most common naturally occurring isotope of an element. Deuterium is a safe, stable isotope of hydrogen. In certain embodiments, compounds of Formula (I) have a deuterium abundance level that is greater than the naturally occurring deuterium abundance. The naturally occurring deuterium abundance is 0.0156 mole %, where mole % is the fraction of deuterium out of the total moles of hydrogen in a sample. Thus, in one mole of naturally occurring hydrogen, 0.156 millimoles are deuterium, or 6.022 x 10 23 9.39 × 10 naturally occurring hydrogen atoms in a sample 19deuterium atoms are present, or 1 deuterium atom is present in a sample of 6413 naturally occurring hydrogen atoms. A deuterium abundance level greater than the naturally occurring deuterium abundance can be at least 1 mol% deuterium, 5 mol%, 10 mol%, 50 mol%, 90 mol%, or 98 mol% deuterium. In certain embodiments, the compound of Formula (I) has a deuterium abundance level of at least 1 mol%, 5 mol%, 10 mol%, 50 mol%, 90 mol%, or 98 mol%. Procedures for preparing deuterated compounds are known in the art. See, for example, Sajiki, New Horizons of Process Chemistry (2017), Springer, pg 29-40 and Hanson, The Organic Chemistry of Isotopic Labelling (2011), Chapter 3, RSC Publishing. In one exemplary embodiment, R in the compound of Formula (I) 2 is R b where R b is C(O)NR c R d and R c and R d Each of the is -CD3.

[0067] Preferred compounds of the present invention are: The compound is selected from the group consisting of: 1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacyclododecaphane-3,5-dione (Example 1); 1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 2); 1 5 -((4-methylpiperazin-1-yl)methyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 3); 1 5-methyl-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 4); 1 1 H-9-oxa-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 5); 11-methyl-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 6); 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylate (Example 7); 11-methyl-1 7 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 8); 4-(11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carbonyl)piperazine-1-carboxylate tert-butyl (Example 9); 1 7 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 10); 1 5 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 11); 1 5-(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 12); 4-(3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5 -carbonyl)piperazine-1-carboxylate tert-butyl (Example 13); 4-(3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carbonyl)piperazine-1-carboxylate tert-butyl (Example 14); 11-methyl-1 7 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 15); 1 5 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 16); 1 7 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 17); (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid (Example 18); (E)-1 7 -(4-(oxetan-3-yl)piperazine-1-carbonyl)-12 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 19); (R,E)-1 7 -(2,4-dimethylpiperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 20); (S,E)-1 7 -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 21); (E)-1 7 -((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 22); (R,E)-1 7 -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 23); (S,E)-1 7 -(2,4-dimethylpiperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 24); (E)-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 25); (E)-1 7 -(4-methyl-1,4-diazepane-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 26); (E)-N,N-dimethyl-1 5 -((4-methylpiperazin-1-yl)methyl)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 27); (E)-1 7 -(2-Methoxypyridin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 28); (R,E)-11-methyl-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 29); (S,E)-11-methyl-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 30); (E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamides (Examples 31 and 32); ((E)-3-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)pyridine 1-oxide (Example 33); (E)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 34); (E)-11-methyl-1 7 -(2-oxo-1,2-dihydropyridin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 35 and 36); (E)-1 7-(3,3-difluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 37); (E)-N-methyl-N-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carbonyl)methyl glycinate (Example 38); (E)-N-Cyclobutyl-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 39); (E)-1 7 -(3,3-difluoroazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 40); (E)-N-(3-hydroxycyclobutyl)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 41); (E)-11-methyl-1 7 -(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 42); (E)-1 7 -(azetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 43); (S,E)-N,N,7-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 44); (E)-N-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)acetamide (Example 45); (R,E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 sulfonamide (Example 46); (E)-N-Isopropyl-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamides (Examples 47 and 48); (E)-1 7 -(3-Methoxy-3-methylazetidine-1-carbonyl)-11-methyl-12 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 49 and 50); (E)-N,N,10-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 51 and 52); (S,E)-1 6 -chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 53 and 54); (R,E)-1 6 -chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 55 and 56); (R,E)-1 7 -(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 57); (E)-11-methyl-1 7 -(2-oxopiperidin-3-yl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 58 to 61); (E)-11-methyl-1 7 -(2-oxo-1,2-dihydropyridin-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 62 and 63); (R,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 64); (R,E)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 65); (R,E)-11-methyl-1 7 -(1-methyl-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 66); (E)-11-ethyl-N,N-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 67 and 68); (R,E)-1 5 -(2-hydroxypropan-2-yl)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 69); (E)-N-(2-fluoroethyl)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 70 and 71); (E)-N-(2,2-difluoroethyl)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamides (Examples 72 and 73); (S,E)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 74); (E)-11-methyl-1 7 -((R)-3-methylmorpholine-4-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 75 and 76); (E)-11-methyl-1 7 -((S)-3-methylmorpholine-4-carbonyl)-12 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 77 and 78); (E)-11-methyl-1 7 -(1-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 79 and 80); (E)-1 7 -(3-Methoxyazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 81 and 82); (R,E)-11-methyl-1 7 -(1-methyl-1H-1,2,4-triazol-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 83 and 84) (R,E)-11-methyl-1 7 -(1-methyl-1H-1,2,4-triazol-5-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 85 and 86); (S,E)-11-methyl-1 7 -(1-methyl-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 87); (E)-1 7 -((S)-3-Fluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 88 and 89); (E)-11-methyl-1 7 -(1-methyl-1H-imidazol-2-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 90 and 91); (E)-1 7 -((R)-3-fluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 92 and 93); (R,E)-1 7 -(3-hydroxy-3-methylazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 94); (S,E)-1 7 -(3-hydroxy-3-methylazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 95); (S,E)-1 7 -(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 96); (E)-1 6 -(4-methylpiperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 97); (E)-1 6 -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 98); (E)-1 5 -Fluoro-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 99); (E)-1 6 -(piperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 100); (E)-1 6 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 101); (E)-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(2,6)-pyridineacycloundecaphane-3,5-dione (Example 102); (E)-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(2,6)-pyridineacycloundecaphane-3,5-dione (Example 103); (1 2 E,4 2 Z)-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(4,2)-thiopheneacycloundecaphane-3,5-dione (Example 104); (E)-4 6 -Fluoro-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 105); (S,E)-1 7 -((R)-3-hydroxy-3-methylpyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 106); (S,E)-1 7 -(3-cyclopropoxyazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 107); (1 2 Z,4 2 E)-N,N,5-trimethyl-2,11-dioxo-4 2 ,4 3 -dihydro-4 1 H-3,10-diaza-1(4,2)-thiazola-4(2,1)-benzo[d]imidazole acycloundecaphane-4 7 - carboxamides (Examples 108 and 109); (S,E)-11-methyl-1 7 -(3-(trifluoromethoxy)azetidine-1-carbonyl)-1 2 ,1 3 -dihydro-11H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 110); (S,E)-1 7 -((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 111); (S,E)-1 7 -((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 112); (S,E)-11-methyl-17 -(2-oxopyrrolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 113); (S,E)-11-methyl-1 7 -(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 114); (S,E)-11-methyl-1 7 -(2-oxa-6-azaspiro[3.4]octane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 115); (S,E)-11-methyl-1 7 -(5-oxa-2-azaspiro[3.4]octane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 116); (S,E)-1 7 -(7,7-difluoro-5-oxa-2-azaspiro[3.4]octane-2-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 117); (S,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1 2 ,1 3-dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 118); (S,E)-11-methyl-1 4 -(2-oxopyrrolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 119); (11S,E)-11-methyl-1 7 -(1-oxa-6-azaspiro[3.4]octane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 120 and 121); (S,E)-1 4 -(3-cyclopropyl-2-oxoimidazolidin-1-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 122); (S,E)-1 5 -(2-hydroxypropan-2-yl)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 123); (S,E)-N,N,11-trimethyl-1 5 -((4-methylpiperazin-1-yl)methyl)-3,5-dioxo-1 2 ,1 3 -dihydro-11 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 124); (S,E)-N,N,11-trimethyl-1 5 -(morpholinomethyl)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 125); (11S,E)-1 4 -(3-fluoro-2-oxopyrrolidin-1-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 126 and 127); (S,E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-1 4 - carboxamide (Example 128); (S,E)-11-methyl-1 7 -(1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 129); (S,E)-11-methyl-1 4 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 130); (E)-N,N-Dimethyl-3',5'-dioxospiro[cyclopropane-1,11'-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane]-7'-carboxamide (Example 131); (E)-11-methyl-1 7 -(5-methyl-1,3,4-oxadiazol-2-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 132 and 133); (S,E)-1 7 -(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 134); (E)-11-methyl-1 7 -(1-methyl-1H-imidazol-2-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 135 and 136); (E)-1 7 -(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 137 and 138); (E)-1 7-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 139 and 140); (E)-1 7 -(3-cyclopropyl-2-oxoimidazolidin-1-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 141 and 142); (E)-11-methyl-1 7 -(3-(oxetan-3-yl)-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 143 and 144); ((S,E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 145); (11S,E)-1 7 -(3-fluoro-2-oxopyrrolidin-1-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 146); and (S,E)-11-methyl-1 7 -(3-methyl-1,2,4-oxadiazol-5-yl)-1 2,1 3 -dihydro-1 1 H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 147) Or a pharmaceutically acceptable salt or solvate thereof.

[0068] The following compounds are further specific compounds of the invention: (S,E)-1 5 -(2-hydroxypropan-2-yl)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 5 -(2-hydroxypropan-2-yl)-11-methyl-1 7 -(2-oxopyrrolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 5 -(2-hydroxypropan-2-yl)-11-methyl-1 7 -(1-methyl-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 5 -(2-hydroxypropan-2-yl)-11-methyl-1 7 -(1-methyl-1H-1,2,4-triazol-5-yl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 5 -(2-hydroxypropan-2-yl)-11-methyl-1 7 -(2-oxooxazolidin-3-yl)-1 2 ,1 3 -dihydro-1 1 H -2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; and (S,E)-1 7 -((S)-3-fluoropyrrolidine-1-carbonyl)-1 5 -(2-hydroxypropan-2-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione.

[0069] Preferred compounds include: 1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 2); 1 5 -((4-methylpiperazin-1-yl)methyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 3); 1 5 -methyl-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 4); 1 1 -methyl-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 6); 11 -methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylate (Example 7); 1 1 -methyl-1 7 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 8); 4-(11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carbonyl)piperazine-1-carboxylate tert-butyl (Example 9); 1 7 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 10); 1 5 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 11); 1 5 -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 12); 4-(3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5 -carbonyl)piperazine-1-carboxylate tert-butyl (Example 13); 1 1 -methyl-1 7-(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 15); 1 5 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 16); 1 7 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 17); (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid (Example 18); (E)-1 7 -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 19); (S,E)-1 7 -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 21); (E)-1 7 -((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 22); Example 23: (R,E)-1 7 -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 23); (S,E)-1 7 -(2,4-dimethylpiperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 24); (E)-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 25); (E)-1 7 -(4-methyl-1,4-diazepane-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 26); (E)-N,N-dimethyl-1 5 -((4-methylpiperazin-1-yl)methyl)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 27); (R,E)-11-methyl-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 29); (S,E)-11-methyl-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 30); (E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamides (Examples 31 and 32); (E)-3-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)pyridine 1-oxide (Example 33); (E)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 34); (E)-11-methyl-1 7 -(2-oxo-1,2-dihydropyridin-3-yl)-1 2 ,13 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 35 and 36); (E)-1 7 -(3,3-difluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 37); (E)-N-methyl-N-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carbonyl)methyl glycinate (Example 38); (E)-N-Cyclobutyl-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 39); (E)-1 7 -(3,3-difluoroazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 40); (E)-N-(3-hydroxycyclobutyl)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7- carboxamide (Example 41); (E)-11-methyl-1 7 -(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 42); (E)-1 7 -(azetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 43); (E)-N-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)acetamide (Example 45); (R,E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 sulfonamide (Example 46); (E)-N-Isopropyl-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamides (Examples 47 and 48); (E)-1 7 -(3-Methoxy-3-methylazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-11 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 49 and 50); (S,E)-1 6 -chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 53 and 54); (R,E)-1 6 -chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 55 and 56); (R,E)-1 7 -(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 57); (E)-11-methyl-1 7 -(2-oxopiperidin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 58-61); (E)-11-methyl-1 7 -(2-oxo-1,2-dihydropyridin-4-yl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 62 and 63); (R,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamide (Example 64); (R,E)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 65); (R,E)-11-methyl-1 7 -(1-methyl-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 66); (E)-11-ethyl-N,N-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 67 and 68); (R,E)-1 5 -(2-hydroxypropan-2-yl)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7-carboxamide (Example 69); (E)-N-(2-fluoroethyl)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 - carboxamides (Examples 70 and 71); (E)-N-(2,2-difluoroethyl)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamides (Examples 72 and 73); (S,E)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 74); (E)-11-methyl-1 7 -((S)-3-methylmorpholine-4-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 77 and 78); (E)-11-methyl-1 7 -(1-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 79 and 80); (E)-1 7-(3-Methoxyazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 81 and 82); (R,E)-11-methyl-1 7 -(1-methyl-1H-1,2,4-triazol-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 83 and 84) (R,E)-11-methyl-1 7 -(1-methyl-1H-1,2,4-triazol-5-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 85 and 86); (S,E)-11-methyl-1 7 -(1-methyl-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 87); (E)-1 7 -((S)-3-Fluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 88 and 89); (E)-11-methyl-1 7 -(1-methyl-1H-imidazol-2-yl)-1 2 ,1 3 -dihydro-11 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 90 and 91); (E)-1 7 -((R)-3-fluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Examples 92 and 93); (R,E)-1 7 -(3-hydroxy-3-methylazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 94); (S,E)-1 7 -(3-hydroxy-3-methylazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 95); (E)-1 6 -(4-methylpiperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 97); (E)-1 6 -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 98); (E)-1 5 -Fluoro-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 99); (E)-1 6 -(piperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 100); (E)-1 6 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 101); (E)-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(2,6)-pyridineacycloundecaphane-3,5-dione (Example 102); (E)-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(2,6)-pyridineacycloundecaphane-3,5-dione (Example 103); (1 2 E,4 2 Z)-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(4,2)-thiopheneacycloundecaphane-3,5-dione (Example 104); (E)-4 6 -Fluoro-1 5 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 105); (S,E)-1 7 -((R)-3-hydroxy-3-methylpyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 106); (S,E)-1 7 -(3-cyclopropoxyazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 107); (1 2 Z,4 2 E)-N,N,5-trimethyl-2,11-dioxo-4 2 ,4 3 -dihydro-4 1 H-3,10-diaza-1(4,2)-thiazola-4(2,1)-benzo[d]imidazole acycloundecaphane-4 7 - carboxamides (Examples 108 and 109); (S,E)-11-methyl-1 7 -(3-(trifluoromethoxy)azetidine-1-carbonyl)-1 2 ,1 3-dihydro-11H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 110); (S,E)-1 7 -((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 111); (S,E)-1 7 -((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 112); (S,E)-11-methyl-1 7 -(2-oxopyrrolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 113); (S,E)-11-methyl-1 7 -(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 114); (S,E)-11-methyl-1 7 -(2-oxa-6-azaspiro[3.4]octane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 115); (S,E)-11-methyl-1 7 -(5-oxa-2-azaspiro[3.4]octane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 116); (S,E)-1 7 -(7,7-difluoro-5-oxa-2-azaspiro[3.4]octane-2-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 117); (S,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 118); and (S,E)-11-methyl-1 4 -(2-oxopyrrolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-Diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 119).

[0070] Particularly preferred compounds include: (R,E)-11-methyl-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,13 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 29); (S,E)-11-methyl-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 30); (S,E)-11-methyl-1 7 -(1-methyl-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 87); (S,E)-11-methyl-1 7 -(2-oxopyrrolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 113); (S,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (Example 118); and (S,E)-11-methyl-1 4 -(2-oxopyrrolidin-1-yl)-1 2 ,1 3 -dihydro-1 1H-2,6-Diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 119).

[0071] Further preferred compounds include: 1 5 -((4-methylpiperazin-1-yl)methyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 3); 1 1 -methyl-1 7 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 8); 1 7 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (Example 10).

[0072] For the avoidance of doubt, when a compound structure is depicted or a name is presented herein, the compound structure or name is deemed to encompass all stereoisomers of that compound unless otherwise specified. For example, if the stereochemistry of a compound is not depicted in the compound structure or name, the compound structure or name encompasses all stereoisomers of that compound.

[0073] Also, for the avoidance of doubt, when a compound structure or name is shown herein, the compound structure or name is deemed to encompass all tautomeric forms of that compound unless otherwise specified. For example, a compound of formula (Ie) below is encompassed by formula (I):

[0074] [ka]

[0075] In certain embodiments, the compound of formula (I) is according to formula (If) or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0076] [ka]

[0077] [In the formula, A is a 6-membered aromatic ring or a 5-6-membered aromatic heterocycle containing 1 or 2 atoms selected from the group consisting of N, S, and O; W is CH or N; X is optionally selected from halogen, OH, and C 1-6 a linear C substituted with one or more groups independently selected from alkyl 2-8 alkylene and / or optionally, one or more carbon atoms in the alkylene are replaced with an atom independently selected from O, N, and S; Y is NH or O; R 1 and R 2 is H;C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;OC 1-6 Alkyl;OC 2-6 Alkenyl;OC 2-6 Alkynyl; -R a ;C(O)R a ;C(O)OR a ;OCR a ;OC(O)(R a );-C 1-6 Alkylene-R a ;-C(O)C 1-6 Alkylene-R a ;-C(O)OC 1-6 Alkylene-R a ;-OC 1-6 Alkylene-R a ;OC(O)C 1-6Alkylene-R a ; and -R b wherein said alkyl, alkenyl, or alkynyl is optionally selected from one or more R b substituted with a group; R 3 H, halogen, OH, C 1-6 Alkyl or OC 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogens; where: R a is selected from a 3- to 8-membered non-aromatic carbocycle; a 3- to 8-membered heterocycle or a 6- to 12-membered spiroheterocycle containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O; said non-aromatic carbocycle, heterocycle, or spiroheterocycle may optionally be bridged and / or contain a halogen; OH; O; SH; NH; NHC 1-4 Alkyl;N(C 1-4 alkyl)2;C 1-4 Alkyl; 3-6 membered heterocycles (containing 1, 2, or 3 atoms selected from the group consisting of N, S, and O); OC 1-4 Alkyl; C(O)C 1-4 Alkyl; C(O)OC 1-4 Alkyl;OC(O)C 1-4 Alkyl;C(O)NH2;-C 1-4 Alkylene-OC 1-4 Alkyl; or -C 1-4 substituted with one or more groups independently selected from alkylene-OH; Each R b is C(O)R c ;C(O)OR c ;OC(O)R c ;SR c ;SO2R c ;NO2;CN;NR c R d ;N(R c )SO2C 1-3 Alkyl; N(R c )C(O)R d ;C(O)NR c R d ;SO2NR c Rd halogen; SH; NH; and OH; wherein the alkyl is optionally substituted with one or more groups independently selected from halogen, SH, NH, and OH, and / or optionally one or more carbon atoms of the alkyl are substituted with an atom independently selected from O, N, and S; and R c and R d is H;C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;-C 1-4 Alkylene-OC 1-4 and a 3- to 8-membered non-aromatic carbocyclic ring; wherein said alkyl, alkenyl, alkynyl, or carbocyclic ring is optionally substituted with one or more groups selected from halogen, SH, NH, OH, and =0, and / or optionally, one or more carbon atoms of the alkyl are replaced with an atom independently selected from O, N, and S.

[0078] For the avoidance of doubt, references herein to the compounds of formula (I) are intended to include all tautomeric forms, salts and solvates thereof, unless otherwise stated.

[0079] Salts of compounds of formula (I) suitable for use in the present invention are those in which the counterion is pharmaceutically acceptable. However, salts having pharmaceutically unacceptable counterions are also within the scope of the invention, for example, for use as intermediates in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts.

[0080] Salts suitable for use in accordance with the present invention include salts formed with organic or inorganic acids. In particular, suitable salts formed with acids according to the present invention include salts formed with mineral acids, strong organic carboxylic acids (unsubstituted or substituted, e.g., by halogens, alkanecarboxylic acids of 1 to 4 carbon atoms, e.g., saturated or unsaturated dicarboxylic acids, e.g., hydroxycarboxylic acids, e.g., amino acids), or organic sulfonic acids (unsubstituted or substituted, e.g., by halogens, such as (C1-C4)-alkylsulfonic acids or arylsulfonic acids). Pharmaceutically acceptable acid addition salts include those formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxalic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, isethionic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid, glutamic acid, lysine, and arginine. Suitable cations that may be present in the salt include alkali metal cations, particularly sodium, potassium, and calcium, as well as ammonium or amino cations.

[0081] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, such as potassium and sodium salts, alkaline earth metal salts (e.g., calcium and magnesium salts), and salts with organic bases (e.g., dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines, such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethyl-propylamine, or mono-, di-, or trihydroxy lower alkylamines, such as mono-, di-, or triethanolamine). Corresponding internal salts may also be formed.

[0082] Those skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." The complex may incorporate the solvent in stoichiometric or non-stoichiometric amounts. Solvates are described in Water-Insoluble Drug Formulation, 2 nd ed. R. Lui CRC Press, page 553, and Byrn et al. Pharm Res 12(7), 1995, 945-954. Before being prepared into a solution, the compound of formula (I) may be in the form of a solvate. Solvates of the compound of formula (I) suitable for use as a medicament according to the present invention are those in which the associated solvent is pharmaceutically acceptable. For example, hydrates are pharmaceutically acceptable solvates. However, solvates with pharmaceutically unacceptable associated solvents may potentially be used as intermediates in the preparation of the compound of formula (I) and its pharmaceutically acceptable esters, amides, carbamates, and / or salts.

[0083] A compound that can be converted into a compound of formula (I) or its active metabolite or residue upon administration to a recipient is known as a "prodrug." Thus, in certain embodiments, a compound of formula (I) can be provided in the form of a prodrug. For example, a prodrug can be converted into an active form with medical effects in the body, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series (1976); "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

[0084] Compounds of formula (I) may have suitable groups converted to esters, amides, or carbamates. Thus, typical ester and amide groups formed from acid groups in compounds of formula (I) include -COOR G , -CONR G 2, -SO2OR G , or -SO2N(R G )2, while -OH or -NHR in the compound of formula (I) G Typical ester, amide, and carbamate groups formed from groups include -OC(O)R G , -NR G C(O)R G , -NR G CO2R G , -OSO2R G , and -NR G SO2R G where R G is C 1-8 Alkyl, C 2-8 Alkenyl, C2-8 Alkynyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 Alkyl, HaloC 1-8 Alkyl, dihalo C 1-8 Alkyl, trihalo C 1-8 Alkyl, phenyl and phenyl C 1-4 alkyl; preferably, R G is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, and C 3-8 Cycloalkyl C 1-6 alkyl; more preferably, R G is C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, and C 3-8 Cycloalkyl C 1-4 alkyl.

[0085] Pharmaceutical Composition Although the compound of formula (I) can be administered alone, it is preferred that it be present in a composition, particularly a pharmaceutical composition. The pharmaceutical composition of the present invention comprises a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0086] Pharmaceutical compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intraosseous injection, intramuscular, intravascular (bolus or infusion), and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend, for example, on the type of disease or condition being treated or prevented.

[0087] Pharmaceutical compositions of the present invention suitable for oral administration can be provided as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The compound of formula (I) can also be provided as a bolus, electuary, or paste. Various pharmaceutically acceptable carriers and their formulations are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by EW Martin. See also Wang, YJ and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S, 1988.

[0088] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the recipient's blood; and aqueous and non-aqueous sterile suspensions, which contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain a suitable non-toxic, parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid or cremaphor.

[0089] Compositions for nasal, aerosol, or inhalation administration include saline solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other solubilizing or dispersing agents as are known in the art.

[0090] Formulations for rectal administration may be presented as suppositories containing conventional carriers such as cocoa butter, synthetic glyceride esters, or polyethylene glycols. Such carriers are usually solid at ordinary temperatures but liquefy and / or melt in the rectal cavity to release the drug.

[0091] Formulations for topical administration in the mouth, e.g., buccal or sublingually, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0092] Preferred unit dosage compositions are those comprising a test dose or therapeutic dose, or an appropriate fraction thereof, of a compound of Formula (I).

[0093] In a preferred embodiment, the compositions of the present invention consist essentially of a compound of formula (I) and at least one pharmaceutically acceptable excipient.

[0094] It will be understood that in addition to the ingredients particularly mentioned above, compositions for use in the present invention may include other agents conventional in the art having regard to the type of composition in question.

[0095] The compositions of the present invention may comprise one or more additional therapeutic agents. Examples of additional therapeutic agents that may be present in the compositions of the present invention include, but are not limited to, one or more Hsp90 inhibitors (e.g., 2-(((1r,4r)-4-hydroxycyclohexyl)amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide), one or more Hsp70 inhibitors, one or more MEK, BRAF, or RAF inhibitors, or one or more other additional anti-cancer / chemotherapeutic agents.

[0096] treatment The compounds of formula (I) and compositions of the present invention are used as pharmaceuticals. In particular, the compounds and compositions of the present invention are used in the treatment and / or prevention of cancer, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases. Additionally or alternatively, the compounds and compositions of the present invention are used to treat or prevent diseases or disorders associated with abnormal TAK1 activity. Abnormal TAK1 activity can occur, for example, due to the presence of a gain-of-function mutation in the TAK1 pathway. For example, frontometaphyseal dysplasia type 2 (FMD2) can be caused by a mutation in the MAP3K7 gene. Additionally or alternatively, the compounds and compositions of the present invention are used to treat or prevent diseases or disorders that can be treated or prevented by inhibiting TAK1.

[0097] Cancers that can be treated or prevented by administering the compounds or compositions of the present invention include, but are not limited to, cancers associated with mutations in the KRAS gene, particularly cancers classified as KRAS-dependent cancers. Such cancers include cancers classified as refractory cancers, recurrent cancers, or refractory-recurrent cancers, particularly refractory cancers.

[0098] Conditions that may be treated or prevented by administering the compounds or compositions of the invention include, but are not limited to, diseases caused by CYLD deficiency, absence (cylindromatosis), or mutations in the CYLD gene, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Brooke-Spiegler syndrome, multiple familial trichoepithelioma, and familial cylindromatosis.

[0099] Specific examples of cancers that can be treated or prevented by administering the compounds or compositions of the present invention include carcinoma, sarcoma, myeloma, leukemia, lymphoma, or mixed-type cancer. Further exemplary cancers that can be treated or prevented by administering the compounds or compositions of the present invention include, for example, anal cancer; bile duct cancer; extrahepatic bile duct cancer; appendix cancer; carcinoid tumor, gastrointestinal cancer; colon cancer; colorectal cancer, including pediatric colorectal cancer; esophageal cancer, including pediatric esophageal cancer; gallbladder cancer; gastric (abdominal) cancer, including pediatric gastric (abdominal) cancer; hepatocellular (liver) cancer, including adult (primary) hepatocellular (liver) cancer and pediatric (primary) hepatocellular (liver) cancer; pancreatic cancer, including pediatric pancreatic cancer; sarcoma, rhabdomyosarcoma; pancreatic islet cell carcinoma; Digestive / gastrointestinal cancers such as rectal cancer and small intestine cancer; e.g., pancreatic islet cell carcinoma (endocrine pancreas); adrenocortical carcinoma, including pediatric adrenocortical carcinoma; gastrointestinal carcinoid tumors; parathyroid carcinoma; pheochromocytoma; pituitary tumors; thyroid cancer, including pediatric thyroid cancer; pediatric multiple endocrine neoplasia syndrome; endocrine cancers such as pediatric carcinoid tumors; eye cancers, e.g., intraocular melanoma and retinoblastoma; e.g., Ewing's family of tumors; osteosarcoma / pleomorphic malignant fibrous histiocytoma of bone; pediatric rhabdomyosarcoma; soft tissue sarcomas, including adult and pediatric soft tissue sarcomas Musculoskeletal cancers, such as fibrosarcoma; clear cell sarcoma of the tendon sheath; and uterine sarcoma; breast cancer, including, for example, pediatric breast cancer and male pediatric breast cancer, and breast cancer during pregnancy; for example, pediatric brain stem glioma; brain tumors; pediatric cerebellar astrocytoma; pediatric cerebral astrocytoma / malignant glioma; pediatric ependymoma; pediatric medulloblastoma; pediatric pineal and supratentorial primitive neuroectodermal tumors; pediatric optic nerve and hypothalamic gliomas; other pediatric brain tumors; adrenocortical carcinoma; central nervous system lymphoma, primary; pediatric cerebellar astrocytoma; neuroblastoma; craniopharyngioma; spinal cord tumors; central nervous system dysplasia teratoid / rhabdoid tumors; central nervous system embryonal tumors; and neurological cancers such as pediatric supratentorial primitive neuroectodermal tumors and pituitary tumors; bladder cancer, including pediatric bladder cancer; renal cell (kidney) cancer; ovarian cancer, including pediatric ovarian cancer; epithelial ovarian cancer; borderline ovarian tumors; penile cancer; prostate cancer; renal cell carcinoma, including pediatric renal cell carcinoma; transitional cell carcinoma of the renal pelvis and ureter; testicular cancer; urethral cancer; vaginal cancer; vulvar cancer; cervical cancer; Wilms' tumor and other pediatric kidney tumors; uterine cancer; and genitourinary cancers, such as gestational trophoblastic neoplasia.For example, childhood extracranial germ cell tumors; extragonadal germ cell tumors; germ cell cancers such as ovarian germ cell tumors; for example, lip and oral cavity cancer; oral cancer, including childhood oral cancer (e.g., oral squamous cell carcinoma); hypopharyngeal cancer; laryngeal cancer, including childhood laryngeal cancer; metastatic cervical squamous cell carcinoma of unknown primary; oral cancer cancer); cancer of the paranasal sinuses and nasal cavity; nasopharyngeal cancer, including pediatric nasopharyngeal cancer; oropharyngeal cancer; parathyroid cancer; pharyngeal cancer; salivary gland cancer, including pediatric salivary gland cancer; throat cancer; and head and neck cancers, such as thyroid cancer; for example, leukemia (e.g., adult and childhood acute lymphocytic leukemia; acute lymphocytic leukemia, including adult and childhood acute myeloid leukemia; chronic lymphocytic leukemia, such as B-cell chronic lymphocytic leukemia; chronic myeloid leukemia; and hairy cell leukemia); lymphoma (e.g., AIDS-related lymphoma; cutaneous T-cell lymphoma; Hodgkin's lymphoma, including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma in pregnancy; non-Hodgkin's lymphoma, including adult and childhood non-Hodgkin's lymphoma and Hodgkin's lymphoma in non-pregnancy); mycosis fungoides; Sézary syndrome; Waldenstrom's macroglobulinemia; primary mediastinal megaloblastoma and primary central nervous system lymphoma); and blood / blood cell cancers such as B-cell lymphoma; mantle cell lymphoma; diffuse large B-cell lymphoma; and primary central nervous system lymphoma; and other hematological cancers (e.g., chronic myeloproliferative disorders; multiple myeloma / plasma cell neoplasms; myelodysplastic syndromes; and myelodysplastic / myeloproliferative disorders); lung cancers such as non-small cell lung cancer and small cell lung cancer; cancers of the respiratory tract such as adult malignant mesothelioma; pediatric malignant mesothelioma; malignant thymoma; pediatric thymoma; thymic carcinoma; bronchial adenoma / carcinoid, including pediatric bronchial adenoma / carcinoid; pleuropulmonary blastoma; non-small cell lung cancer; and small cell lung cancer; skin cancers such as Pozi's sarcoma; Merkel cell carcinoma; melanoma; and pediatric skin cancer; AIDS-related malignancies; other childhood cancers, unusual childhood cancers, and cancers of unknown primary site; and metastases of the foregoing cancers. Further examples of cancer include breast cancer, colorectal cancer, leukemia, neurofibroma, or non-small cell lung cancer, or a combination thereof;

[0100] Inflammatory, autoinflammatory, and autoimmune diseases that can be treated or prevented by administering the compounds or compositions of the present invention include systemic lupus erythematosus (SLE), Sjögren's syndrome, rheumatoid arthritis, osteoarthritis, gout, psoriatic arthritis, psoriasis, ankylosing spondylitis, diabetes, malaria, Crohn's disease, ulcerative colitis, inflammatory bowel disease, familial Mediterranean fever (FMF), cryopyrin-associated periodic fever syndrome (CAPS), IL-1 receptor antagonist deficiency (DIRA) and hyper-IgD syndrome (HIDS), myocardial infarction, reperfusion, ischemia, or stroke. Multiple sclerosis and systemic sclerosis may also be mentioned. Pulmonary diseases, including idiopathic pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease (COPD), can also be treated or prevented by administering the compounds or compositions of the present invention.

[0101] Additional inflammatory diseases and conditions that can be treated or prevented by administering a compound or composition of the invention include ocular allergies, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, autoimmune blood disorders, hemolytic anemia, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenia, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, periodontal disease, hyaline membrane disease, kidney disease, glomerular disease, and alcoholic liver disease. , endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis (anterior or posterior), interstitial pulmonary fibrosis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephrotic syndrome, chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle fatigue, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic urticarial dysplasia, Behcet's disease Disease, incontinentia pigmenti, Paget's disease, pancreatitis, periodic fever syndrome, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, fibrosis, gastritis, gastroenteritis, sinusitis, silica-induced disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, thyroiditis, Addison's disease, lichen planus, appendicitis, atopic dermatitis, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, cystitis, dacryoadenitis, dermatitis, juvenile rheumatoid arthritis, encephalitis , endocarditis, endometritis, enteritis, enteritis, epicondylitis, epididymitis, fasciitis, Schoenlein-Henoch syndrome, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, bacterial meningitis, myelitis, myocarditis, myositis, oophoritis, orchitis, osteitis, otitis media, parotitis, pericarditis, peritonitis, pharyngitis, urticaria, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tenosynovitis, tonsillitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, vitiligo, hypersensitivity vasculitis, bullous pemphigoid, pemphigus vulgaris,Pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute or chronic gout, chronic gouty arthritis, and Hashimoto's thyroiditis, type 1 diabetes, autoimmune syndromes including allergic encephalomyelitis, post-infectious autoimmune disorders including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pemphigus complex, epidermolysis bullosa, angioedema, erythema, cutaneous eosinophilia, lupus erythematosus, acne, keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigoid, Moore's disease, ulcer, scleritis, Graves' eye disease, Vogt-Koyanagi-Harada syndrome, pollen allergy, reversible airway obstructive disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or habitual asthma, late-onset asthma and airway hyperresponsiveness, gastric ulcer, vascular damage due to ischemic disease and thrombosis, ischemic bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, eosinophilic gastroenteritis, mastocytosis, migraine, dermatitis, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, polyneuropathy Neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, true erythroid aplasia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, pulmonary fibrosis, idiopathic interstitial pneumonia, albinism, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, Wegener's granuloma, fat, eosinophilic fasciitis, gingival lesions, periodontium, alveolar bone, cementum, prevention of hair loss androgenetic alopecia or senile alopecia due to the prevention or promotion of hair growth and / or promotion of hair growth and development, muscular dystrophy, pyoderma and Sezary syndrome, ischemia-reperfusion injury of organs occurring during storage, transplant or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis due to drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug intoxication, lung cancer, emphysema, siderosis, retinitis pigmentosa, senile macular degeneration, vitreous scar, corneal alkali burn, linear IgA bullous dermatitis and cement dermatitis, gingivitis, sepsis, diseases caused by environmental pollution, aging, carcinogenesis, altitude sickness,These include diseases caused by the release of histamine or leukotriene-C4, autoimmune hepatitis, sclerosing cholangitis, partial liver resection, acute liver necrosis, toxic necrosis, viral hepatitis, shock, or anoxia, hepatitis B virus, non-A non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, delayed liver failure, acute exacerbation of chronic liver failure, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, senile dementia, Parkinson's disease, psychological trauma, and chronic bacterial infections.

[0102] In certain embodiments, inflammatory diseases and conditions that can be treated or prevented by administering a compound or composition of the invention include lupus nephritis, type II diabetes, hyperimmunoglobulinemia D and periodic fever syndrome, Schnitzler syndrome, adult-onset Still's disease, pseudogout, SAPHO syndrome, Castleman's disease, and Alzheimer's disease. Further conditions that may benefit from the administration of the compounds or compositions of the present invention include Huntington's disease, renal fibrosis, liver fibrosis, non-alcoholic steatohepatitis (NASH), and neuroinflammation. It should be noted that fibrosis is often a pathological feature of most chronic inflammatory diseases, and therefore fibrosis and inflammation frequently occur together.

[0103] The compounds and compositions of the present invention are also useful in methods for treating or preventing a disease or disorder, said methods comprising administering a compound of formula (I) or a composition of the present invention to a subject in need thereof. Thus, the compounds or compositions of the present invention can be administered to a subject suffering from or at risk of developing cancer, an inflammatory disease, an autoinflammatory disease, and / or an autoimmune disease.

[0104] The compounds of formula (I) of the present invention can also be used in the manufacture of a medicament, in particular a medicament to be administered to a subject suffering from or at risk of developing cancer, an inflammatory disease, an autoinflammatory disease, and / or an autoimmune disease.

[0105] The amount of a compound of formula (I) required to achieve a therapeutic effect will vary depending on the particular route of administration and the characteristics of the subject being treated, such as the species, age, weight, sex, medical condition, the particular disease or condition and its severity, and other relevant medical and physical factors. An ordinarily skilled physician can readily determine and administer the effective amount of a compound of formula (I) required to treat or prevent the disease or condition.

[0106] The compounds of formula (I) can be administered daily (including several times daily), every two or three days, every two, three, or four weeks, or even as a single high dose, depending on the subject and the disease or disorder being treated.

[0107] Preferably, the compound of formula (I) (excluding the mass of any counterion or solvent) can be administered in an amount of about 1 to 1000 mg per dose, for example, 1, 5, 10, 15, 20, 25, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 300, 400, 500, 600, 700, 800, 900, and 1000 mg.

[0108] In certain embodiments, the compound of formula (I) is administered as a composition. Preferably, the composition is a pharmaceutical composition of the present invention.

[0109] The compound of formula (I) can be used as the sole active ingredient in the present invention, but can also be used in combination with one or more additional therapeutic agents, and the use of such a combination provides one embodiment of the present invention. Such additional therapeutic agents can be drugs useful for treating or preventing diseases or conditions, or other pharmaceutically active substances. Such drugs are known in the art. Examples of additional therapeutic agents for use in the present invention include those described herein.

[0110] The one or more additional therapeutic agents can be administered simultaneously, sequentially, or separately from the administration of a dose of a compound of Formula (I). The individual components of such combinations can be administered separately at different times during the course of treatment or simultaneously in divided or single combination forms. An ordinarily skilled physician can readily determine and administer the effective amount of one or more therapeutic agents required to achieve the desired therapeutic effect.

[0111] Preferred unit dosage compositions for use in accordance with the present invention are those containing an effective dose, or an appropriate fraction thereof, of a compound of formula (I).

[0112] kit The present invention provides kits comprising a compound of formula (I), one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents, examples of such additional therapeutic agents include those described herein as suitable for use in the present invention and optionally present in the pharmaceutical compositions of the present invention as additional therapeutic agents.

[0113] The kit of the present invention is used for the treatment and / or prevention of cancer, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0114] For the avoidance of doubt, the compound of formula (I) included in the kits according to the invention is in a form and amount suitable for use according to the invention. Suitable pharmaceutical compositions and formulations are described herein. Those skilled in the art can readily determine the amount of the compound of formula (I) suitable for inclusion in the kits of the invention and for use according to the invention.

[0115] Exemplary Procedures for the Preparation of Compounds of Formula (I) The compounds of the present invention can be prepared using methods known to those skilled in the art of organic chemistry. Exemplary procedures for the preparation of compounds of formula (I) are shown in Schemes 1 to 4 below. The present invention provides methods for preparing compounds of the present invention by the process shown in any one of Schemes 1 to 4. Similar procedures can be used for all compounds of formula (I) in claim 1, including compounds having groups W1, W2, and W3 rather than W, or alternative structures of the cyclic group "A". For the avoidance of doubt, the group R of intermediate compounds (II) to (XVIII) described herein can be used. 1 , R 2 , R 3 , W, X, Y, and A are R groups as described herein for formula (I). 1 , R 2 , R 3 , W, X, Y, and A groups.

[0116] [ka]

[0117] As shown in Scheme 1, compounds of formula (I) can be obtained by cyclization of the carboxylic acid intermediate (II). The cyclization can be achieved using a coupling reagent (HOBT, HATU, etc.) under dilute conditions. Preferably, this step is carried out using HATU (1.2 equivalents) and DIPEA (3 equivalents) in THF (final starting material concentration 0.5 mM or less) with heating at 70° C. for more than 2 hours. The reaction mixture is then cooled and filtered through silica gel.

[0118] An alternative approach to compounds of formula (I) is described below in Scheme 2. The approach involves cyclization of the carboxylic acid intermediate (III) using a suitable amide coupling agent such as HATU.

[0119] [ka]

[0120] A further approach to compounds of formula (I) is shown below in Scheme 3. The approach involves a ring-closing metathesis reaction of intermediate (IV), where Z 1 and Z 2 is reacted with a bond or C to form intermediate (V) using a suitable catalyst (e.g., Grubbs catalyst). 1-3 The intermediate (V) is then hydrogenated to form a compound represented by formula (I) below, where X is independently selected from the group consisting of -Z 1 -Ethylene-Z 2 Compounds of formula (I) can be obtained in which

[0121] [ka]

[0122] A further exemplary procedure for the preparation of compounds of formula (I) is shown in Scheme 4 below.

[0123] [ka]

[0124] Intermediate (VI), where Q is a halogen, boronic acid, boronic ester, or triflate, can be prepared by methods similar to the above chemical reactions shown in Schemes 1-3. Intermediates (VII) and (VIII) or compounds of formula (I) can be prepared from intermediate (VI) through a transition metal coupling reaction. For example, intermediate (VII) can be produced through Pd-catalyzed carbonylation of intermediate (VI). Compounds of formula (I) can be prepared from intermediate (VII) or intermediate (VIII) through an amide coupling reaction, reductive amination, or nucleophilic substitution reaction. Compounds of formula (I) can also be prepared directly from intermediate (VI).

[0125] An exemplary procedure for the preparation of intermediate (II) is described in Scheme 5 below.

[0126] [ka]

[0127] Intermediate (XI) can be prepared by coupling a compound corresponding to intermediate (IX) with an appropriate monoprotected diacid, intermediate (X), using a suitable coupling reagent (e.g., HATU, HOBT). Finally, (XI) can be deprotected to give intermediate (II).

[0128] For the avoidance of doubt, the group "PG," as used herein, represents a suitable protecting group. Protecting groups can be added to, and subsequently removed from, various reactants and intermediates in a manner readily understood by those skilled in the art of organic synthesis. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are known in the art. Furthermore, such procedures and groups can be found in references such as "Protective Groups in Organic Synthesis," 3rd ed., T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York (1999).

[0129] An exemplary procedure for the preparation of intermediates of formula (III) is set forth in Scheme 6 below.

[0130] [ka]

[0131] Intermediate (XI) can be prepared by coupling a compound corresponding to intermediate (XII) with a suitable protected diacid, intermediate (XIII), using a suitable coupling reagent (e.g., HATU, HOBT). Finally, intermediate (XIV) can be deprotected to obtain intermediate (III).

[0132] An exemplary procedure for the preparation of intermediate (IX) is described below in Scheme 7.

[0133] [ka]

[0134] The amine corresponding to intermediate (XVI) can be reacted with a fluoronitro derivative corresponding to intermediate (XV) via a nucleoaromatic substitution reaction in the presence of a suitable base (e.g., TEA, KOtBu) at room temperature or under heat. The resulting nitroaniline intermediate (XVII) can be reduced (e.g., using hydrogen and a suitable catalyst, such as Zn in AcOH, SnCl, or Fe in HCl) to give intermediate (XVIII). Treatment of intermediate (XVIII) with cyanogen bromide (CNBr) induces cyclization to give intermediate (IX).

[0135] equivalent The present invention has been described broadly and generically herein. Those skilled in the art will readily recognize that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Accordingly, it is to be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, combinations of two or more such features, systems, articles, materials, kits, and / or methods are included within the scope of the invention, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent. Furthermore, each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the general description of the invention with a proviso or negative limitation that removes the subject matter from the genus, regardless of whether the excised material is specifically described herein.

[0136] Incorporation by Reference The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein are incorporated herein by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicant reserves the right to physically incorporate into this application any and all materials and information from such articles, patents, patent applications, or other physical and electronic documents.

[0137] The following examples illustrate the invention. [Example]

[0138] Reagents and solvents were purchased from commercial suppliers and used as received. Reactions were stirred using Teflon-coated magnetic stir bars in glass vials or round-bottom flasks and heated using conventional stir plates.

[0139] The solvent was removed by rotary evaporation, Genevac EZ-2 vacuum centrifuge, or freeze-drying.

[0140] Reaction progress was monitored by LC-MS or thin-layer chromatography (TLC) using aluminum-backed plates (Merck 60F254). TLC plates were visualized under UV light (254 nm). LC-MS data were acquired on either an Agilent 1100 system (using a Purosphere STAR RP-18, 2.1 x 50 mm, end-capped 3 μm column, eluting with solution A (water containing 0.1% TFA) and B (acetonitrile)) coupled to an Agilent MSD mass spectrometer operating in ES (+) ionization mode, or an Agilent 1260 Infinity II system (using a Gemini NX-C18, 3.0 x 50 mm, 110 Å column, eluting with solution A (water containing 0.2% NH4OH) and B (acetonitrile)) coupled to an Agilent MSD XT mass spectrometer operating in ES (+ or -) ionization mode. UV traces were recorded at 220 or 254 nm. HPLC was performed on an Agilent 1100 system using a Kromasil Eternity-5-C 18, 4.6 x 150 mm column and eluted with solutions A (water with 0.1% TFA) and B (acetonitrile). UV traces were recorded at 220 or 254 nm.

[0141] Preparative HPLC was performed either on a Gilson system using a Kromasil 100-5C18, 21.1 × 250 mm column and eluting with solutions A (water with 0.1% TFA) and B (acetonitrile), or on an Agilent 1200 system using a Phenomenex Gemini NX-C18 110 Å, 21.2 × 150 mm, 5 μm column and eluting with solutions A (50 mM aqueous NH4OH) and B (acetonitrile).

[0142] Flash chromatography on silica gel or C18-functionalized silica was performed on a Biotage Isolera One system equipped with a diode array detector using the solvent systems indicated. UV traces were recorded between 200 and 400 nm.

[0143] Nuclear magnetic resonance (NMR) spectra were obtained at 5 mm 1 H / 13 C 400 MHz ( 1 H NMR: 400MHz, 13 C NMR was recorded at 25 °C using a 101 MHz Varian Inova spectrometer or a 500 MHz Bruker Avance Neo spectrometer equipped with a 5 mm iProbe BBF / H / D probe. Spectra were processed using MestReNova v.12.0. Chemical shifts are reported in ppm (δ) using residual solvent as the internal standard. Peak multiplicities, given in Hz, are expressed as follows: s, singlet; d, doublet; dd, double doublet; ddd, double double doublet; t, triplet; dt, double triplet; q, quartet; dq, double quartet; p, pentet; h, heptet; m, multiplet; br, broad singlet.

[0144] The abbreviations used here are: DIPEA N,N-Diisopropylethylamine; DMAP 4-(dimethylamino)pyridine; DMF N,N-dimethylformamide; DMP Dess-Martin periodinane; DMSO dimethyl sulfoxide; EDC N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide; HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl hydrochloric acid; HOBT 1-hydroxybenzotriazole; IPA isopropyl alcohol; on overnight; pet.ether petroleum ether; quant. Quantitatively; rt room temperature; Rt retention time; sat. saturated; SFC supercritical fluid chromatography; SiO2 silica gel; TBAF tetrabutylammonium fluoride; tBuOK potassium tert-butoxide; TCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TEA triethylamine; TFA trifluoroacetic acid; THF tetrahydrofuran; TIPSOTf Triisopropylsilyl trifluoromethanesulfonate; TLC thin layer chromatography; TMS tetramethylsilane.

[0145] The chemical structures of the exemplary compounds disclosed herein are shown as having the tautomeric forms shown in Formula (I) or Formula (Ie). Specific tautomeric forms are shown below, but the exemplary compounds may have tautomeric forms other than those shown herein. Compound names were obtained using the IUPAC nomenclature module in ChemDraw 20.0.

[0146] Example 1:1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacyclododecaphane-3,5-dione

[0147] [ka]

[0148] Step 1: Preparation of methyl 3-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of aminobenzimidazole (1.07 g, 8.00 mmol) and 3-(methoxycarbonyl)benzoic acid (1.44 g, 8.0 mmol) in 10 mL of CHCl was added HOBT monohydrate (1.23 g, 8.0 mmol), EDC (1.53 g, 8.00 mmol), DMAP (98 mg, 0.8 mmol), and DIPEA (2.58 g, 8.0 mmol). The reaction was stirred overnight at room temperature and then concentrated to dryness under vacuum. The residue was dissolved in 45 mL of EtOH. The product precipitated and was collected by filtration as a white solid, yielding 532 mg (21% yield). 1 H NMR (DMSO-d6) δ:12.47 (s, 1H), 8.78 (m, 1H), 8.39 (m, 1H), 8.12 (m, 1H), 7.66 (m, 1H), 7.45 (m, 2H), 7.17 (m, 2H), 3.91 (s, 3H);LC / MS:M+H=296.1.

[0149] Step 2: Preparation of methyl 3-((1-(6-bromohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of methyl 3-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (348 mg, 1.18 mmol) and KOtBu (139 mg, 1.24 mmol) in 8 mL of THF and 2 mL of DMSO was added 1,6-dibromohexane at room temperature. The reaction was stirred overnight and diluted with 60 mL of water. The mixture was extracted three times with EtOAc (20 mL). The organic phases were combined, dried, and concentrated. The residue was subjected to flash chromatography to give the desired methyl 3-((1-(6-bromohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (374 mg, 69%) as an oil. LC / MS: M+H=460.1, R t :5.4 minutes.

[0150] Step 3: Preparation of methyl 3-((1-(6-aminohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate Sodium azide (58 mg, 0.9 mmol) was added to a solution of 3-((1-(6-bromohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (374 mg, 0.82 mmol) in 2 mL of DMF at room temperature. The reaction was stirred overnight and then diluted with 1.0 mL of EtOH. Pd / C (87 mg, 0.08 mmol) was added, and the reaction mixture was placed under an atmosphere of H2. The reaction was stirred overnight, filtered through Celite with the aid of EtOH, and the filtrate was concentrated. The residue was dissolved in MeCN and water (2 mL) and purified by reverse-phase chromatography (Biotage 12G Ultra C18 column) on a C18 flash cartridge using 5-80% MeCN in water with 1% TFA. Fractions were collected and lyophilized to give a pink solid (229 mg). This material was used in the next step without further purification. LC / MS: M+H=395.2, R t :3.9 minutes.

[0151] Step 4: Preparation of 3-((1-(6-aminohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a stirred solution of methyl 3-((1-(6-aminohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (217 mg, 0.55 mmol) in 3 mL of MeOH was added KOH (93 mg, 1.65 mmol). After 4 h at room temperature, the reaction was heated at 65° C. for 1.5 h. The reaction was diluted with 1 mL of water and cooled to room temperature. The reaction mixture was concentrated overnight using a stream of nitrogen. The residue was dissolved in 1 M HCl and MeCN to a volume of 1 mL and purified by reverse-phase chromatography (Biotage 12G Ultra C18 column) on a C18 flash cartridge using 5-80% MeCN in water with 1% TFA. Fractions were collected and lyophilized to give a white solid (96 mg, 35% yield). LC / MS: M+H=381.1, R t :3.7 minutes.

[0152] Step 5:1 1Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacyclododecaphane-3,5-dione To a solution of 3-((1-(6-aminohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (45 mg, 0.09 mmol), HOBT monohydrate (15 mg, 0.1 mmol), EDC (19 mg, 0.1 mmol), and DMAP (1.1 mg, 0.009 mmol) was added DIPEA (63 μL, 0.36 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in water and MeCN to a volume of 1 mL and purified by reverse-phase chromatography (Biotage 12G Ultra C18 column) on a C18 flash cartridge using 5-95% MeCN in water with 1% TFA. Fractions were collected and lyophilized to give a white solid (4.8 mg, 11% yield, 80% purity by HPLC). 1 H NMR (DMSO-d6) δ:12.47 (bs, 1H), 9.22 (s, 1H), 8.30 (s, 1H), 8.05 (m, 1H), 7.69 (d, 1H), 7.53 (m, 2H), 7.48 (m, 1H), 7.28-7.17 (m, 2H), 4.23 (bs, 2H), 3.28 (bs, 2H), 1.86 (bs, 2H), 1.72 (bs, 2H), 1.66-1.51 (m, 4H);LC / MS:M+H=363.1.

[0153] Example 2:1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0154] [ka]

[0155] Step 1: Preparation of methyl 3-((1-(5-bromopentyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of methyl 3-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (1.68 g, 5.57 mmol) and KOtBu (688 mg, 6.13 mmol) in 20 mL of DMF was added 1,5-dibromopentane at room temperature. The reaction was stirred overnight and diluted with 200 mL of water. The mixture was extracted three times with EtOAc / petroleum ether. The aqueous phase was extracted with CHCl. ​​The organic phases were combined, dried, and concentrated. The residue was subjected to flash chromatography to give the desired methyl 3-((1-(6-bromohexyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (1.45 g, 58%) as an oil. 1 H NMR (DMSO-d6) δ:12.78 (s, 1H), 8.82 (s, 1H), 8.49 (d, 1H), 8.09 (d, 1H), 7.95 (s, 1H), 7.63 (m, 12H), 7.55 (m, 2H), 7.25 (m, 2H), 4.30 (m, 2H), 3.91 (s, 3H), 3.50 (m, 2H), 1.86 (m, 4H), 1.49 (m, 2H);LC / MS:M+H=458.1.

[0156] Step 2: Preparation of methyl 3-((1-(5-aminopentyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of methyl 3-((1-(5-bromopentyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (889 mg, 2 mmol) in 5 mL of DMF was added sodium azide (143 mg, 2.20 mmol) at room temperature. The reaction was stirred overnight and then diluted with 2.5 mL of EtOH. Pd / C (218 mg, 0.2 mmol) was added, and the reaction mixture was placed under an atmosphere of H2. The reaction was stirred overnight, filtered through Celite with EtOH, and the filtrate was concentrated. The residue was dissolved in MeCN and water (2 mL) and purified by reverse-phase chromatography (Biotage 12G Ultra C18 column) on a C18 flash cartridge using 0-70% MeCN in water with 1% TFA. Fractions were collected and lyophilized to give a white solid (439 mg, 44% yield as the TFA salt).1 H NMR (DMSO-d6) δ:8.81 (s, 1H), 8.49 (d, 1H), 8.10 (d, 1H), 7.60 (m, 3H), 7.26 (m, 2H), 4.29 (m, 2H), 3.91 (s, 3H), 2.76 (s, 2H), 1.86 (s, 2H), 1.61 (d, 2H), 1.41 (s, 2H); LC / MS:M+H=381.2.

[0157] Step 3: Preparation of 3-((1-(5-aminopentyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a stirred solution of methyl 3-((1-(5-aminopentyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (342 mg, 0.9 mmol) in 5 ml of THF was added aqueous LiOH (67 mg, 2.79 mmol in 1 ml of water) at room temperature. The reaction mixture was heated at 45° C. overnight, cooled to room temperature, and concentrated to dryness under vacuum. The residue was dissolved in 1 M HCl and MeCN to a volume of 1 ml and purified by reverse-phase chromatography (Biotage 12G Ultra C18 column) on a C18 flash cartridge using 5-80% MeCN in water with 1% TFA. Fractions were collected and lyophilized to give a white solid (620 mg), which was used without further purification. LC / MS: M+H=367.1; R t :3.2 minutes.

[0158] Step 4:1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione DIPEA (249 μl, 1.43 mmol) was added to a solution of 3-((1-(5-aminopentyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (150 mg, 0.41 mmol) and HATU (171 mg, 0.45 mmol) in 8 ml of DMF at room temperature. The reaction was stirred overnight. The reaction mixture was purified by reverse-phase chromatography (Biotage 12G Ultra C18 column) on a C18 flash cartridge using 0-80% MeCN in water with 1% TFA. Fractions were collected and lyophilized. The product was further purified by precipitation from EtOH to give a white solid (2.5 mg, 2% yield). 1 H NMR (DMSO-d6) δ:12.51 (s, 1H), 9.04 (s, 1H), 8.11 (d, 1H), 7.88 (m, 1H), 7.74 (d, 1H), 7.58 (m, 1H), 7.53 - 7.48 (m, 2H), 7.23 LC / MS:M+H=349.1.

[0159] Example 3:1 5 -((4-methylpiperazin-1-yl)methyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0160] [ka]

[0161] Step 1: Preparation of ((4-fluoro-3-nitrobenzyl)oxy)triisopropylsilane TIPSOTf (2.02 mL, 7.50 mmol) was slowly added to a solution of (4-fluoro-3-nitrophenyl)methanol (856 mg, 5.0 mmol) and 2,6-lutidine (1.74 mL, 15 mmol) in 5 mL of CHCl. ​​The reaction was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in CHCl and purified using flash chromatography (SiO, 0–25% EtOAc in petroleum ether) to give the product as a yellow oil (1.27 g, 77% yield). 1 H NMR (DMSO-d6) δ:8.12 (d, 1H), 7.83 - 7.70 (m, 1H), 7.59 (m, 1H), 4.88 (s, 2H), 1.17 (m, 3H), 1.09 - 1.02 (m, 18H).

[0162] Step 2: Preparation of tert-butyl (5-((4-(hydroxymethyl)-2-nitrophenyl)amino)pentyl)carbamate To a stirred solution of tert-butyl (5-aminopentyl)carbamate (445 mg, 2.20 mL) in 4 mL of DMF was added ((4-fluoro-3-nitrobenzyl)oxy)triisopropylsilane (600 mg, 1.83 mmol), followed by DIPEA (1.55 mL, 3.66 mmol) at room temperature. The mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was purified using flash chromatography (SiO, 10–60% EtOAc in petroleum ether) to give the product as a red oil (605 mg, 93% yield). 1 H NMR (DMSO-d6) δ:8.11 (m, 1H), 8.01 (s, 1H), 7.49 (m, 1H), 7.05 (d, 1H), 6.79 (m, 1H), 5.20 (m, 1H), 4.40 (d, 2H), 3.41 - 3.33 (m, 2H), 2.92 (m, 2H), 1.62 (m, 2H), 1.50 - 1.29 (m, 13H).

[0163] Step 3: Preparation of tert-butyl (5-((2-nitro-4-(((triisopropylsilyl)oxy)methyl)phenyl)amino)pentyl)carbamate TIPSOTf (0.35 μl, 1.28 mmol) was slowly added to a solution of tert-butyl (5-((4-(hydroxymethyl)-2-nitrophenyl)amino)pentyl)carbamate (302 mg, 0.86 mmol) and 2,6-lutidine (0.3 mL, 2.56 mmol) in 3 mL of CHCl. ​​The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in CHCl and purified using flash chromatography (SiO, 0-25% EtOAc in petroleum ether) to give the product as a yellow oil (326 mg, 75% yield). LC / MS: M+Na=532.3, R t :7.0 minutes.

[0164] Step 4: Preparation of tert-butyl (5-(2-amino-5-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate To a stirred solution of tert-butyl (5-((2-nitro-4-(((triisopropylsilyl)oxy)methyl)phenyl)amino)pentyl)carbamate (326 mg, 0.64 mmol) in 35 mL of MeOH was added Pd / C (68 mg, 0.064 mmol) under a nitrogen atmosphere. The nitrogen was replaced with hydrogen and the reaction was stirred at room temperature for 2 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of water / MeOH / MeCN (1:3:1) and CNBr (81 mg, 0.77 mmol) was added at room temperature. The resulting solution was heated at 50 °C overnight in a sealed flask. The reaction mixture was diluted with 50 mL of Na2CO3 (sat. aq.) and extracted with EtOAc (3 × 30 mL). The organic phases were combined, dried, and concentrated. The residue was dissolved in CH2Cl2 and purified using flash chromatography (SiO2, 1-7% MeOH in CH2Cl2) to give the product as an oil film (137 mg, 42% yield). LC / MS: M+H=505.4, R t :5.6 minutes.

[0165] Step 5: Preparation of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate HATU (114 mg, 0.3 mmol) was added to a stirred solution of 3-(methoxycarbonyl)benzoic acid (59 mg, 0.33 mmol) in 5 mL of DMF. The resulting solution was added to a stirred solution of tert-butyl (5-(2-amino-5-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate (137 mg, 0.27 mmol) in 5 mL of DMF, followed by the addition of DIPEA (141 μL, 0.82 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness under vacuum. The residue was dissolved in CHCl and purified using flash chromatography (SiO, 0–30% EtOAc in petroleum ether) to give the product as an oil film (160 mg, 88% yield). LC / MS: M+H = 667.4, R t :6.6 minutes.

[0166] Step 6: Preparation of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate A solution of TBAF (0.66 ml 1 M in THF, 0.66 mmol) was added to a stirred solution of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (88 mg, 0.13 mmol) in 6 ml of THF at room temperature. The reaction was stirred for 40 min and concentrated to dryness in vacuo. The residue was dissolved in CHCl and purified using flash chromatography (SiO, 1-6% MeOH in CHCl with 1% TEA) to give the product as a foam (56 mg, 83% yield). 1H NMR (DMSO-d6) δ:12.75 (s, 1H), 8.82 (m, 1H), 8.48 (d, J=7.7 Hz, 1H), 8.09 (m, 1H), 7.63 (m, 1H), 7.54 - 7.52 (m, 1H), 7.47 (d, 1H), 7.21 (m, 1H), 6.71 (m, 1H), 5.23 (m, 1H), 4.56 (m, 2H), 4.26 (m, 2H), 3.91 (s, 3H), 2.89 (m, 2H), 1.82 (m, 2H), 1.47 (m, 2H), 1.39 - 1.22 (m, 9H), LC / MS: M+H=511.2.

[0167] Step 7: Preparation of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-formyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate DMP (47 mg, 0.11 mmol) was added to a stirred solution of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (47 mg, 0.09 mmol) in 5 mL of CHCl. ​​The reaction was stirred at room temperature for 30 min, diluted with 20 mL of CHCl, washed with 1 M NaOH (aq) (3 × 10 mL), dried, and concentrated to an oil. The crude product was used without further purification.

[0168] Step 8: Preparation of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate N-Methylpiperazine (27 mg, 0.27 mmol) was added to a slurry of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-formyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (46 mg, 0.09 mmol) in 5 mL of MeOH. The reaction mixture was diluted with 5 mL of CHCl to give a clear solution. Sodium triacetoxyborohydride (58 mg, 0.027 mmol) was added. The mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated in vacuo, diluted with 30 mL of EtOAc, and washed with NaCO (sat. aq., 3 × 20 mL). The organic phase was dried and concentrated to give an oil (58 mg). The crude product was used without further purification.

[0169] Step 9: Preparation of methyl 3-((1-(5-aminopentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate TFA (1.0 mL, 8.61 mmol) was added to a solution of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (54 mg, 0.09 mmol) in 10 mL of CHCl. ​​The reaction was stirred at room temperature for 45 minutes and then concentrated to give an oil. The crude product was used without further purification.

[0170] Step 10: Preparation of 3-((1-(5-aminopentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid KOH (31 mg, 0.55 mmol) was added to a stirred solution of methyl 3-((1-(5-aminopentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (86 mg, 0.09 mmol) in 10 mL of MeOH at room temperature. The reaction was stirred at room temperature for 1 hour before heating to 60 °C. After an additional 3 hours, 5 mL of water was added and heating was continued overnight. The reaction was cooled to room temperature and concentrated to dryness under vacuum. The residue was dissolved in MeCN and water (1 mL) and purified by reverse-phase chromatography (Biotage 12G Ultra C18 column) on a C18 flash cartridge using 5-50% MeCN in water with 0.1% TFA. Fractions were collected and lyophilized to give a white solid (36 mg, 49% yield as the TFA salt). LC / MS: M+H=479.3, R t :3.2 minutes.

[0171] Step 11:1 5 -((4-methylpiperazin-1-yl)methyl)-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione To a solution of 3-((1-(5-aminopentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (20 mg, 0.024 mmol) and DIPEA (21 μL, 0.12 mmol) in 10 mL of DMF was added HATU (11 mg, 0.029 mmol). After 70 min, the reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in MeCN and water (1 mL) and purified by reverse-phase chromatography on a C18 flash cartridge (Biotage 12G Ultra C18 column) using 5-40% MeCN in water with 0.1% TFA. Fractions were collected and lyophilized to give a gray solid (2.2 mg, 13% yield as the TFA salt). 1H NMR (DMSO-d6) δ:12.54 (s, 1H), 9.03 (s, 1H), 8.10 (d, 1H), 7.89 (m, 1H), 7.75 (d, 1H), 7.58 (m, 1H), 7.51 (d, 1H), 7.46 (s, 1H), 7.24 (d, 1H), 4.28 (s, 2H), 3.81 (s, 2H), 3.68- 3.25 (m, 4H), 3.20 (s, 2H), 3.02 (s, 4H), 2.77 (s, 3H), 2.04 (s, 2H), 1.82 (s, 2H), 1.43 (s, 2H). LC / MS: M+H=461.2.

[0172] Example 4:1 5 -methyl-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0173] [ka]

[0174] Step 1: Preparation of tert-butyl (5-((4-methyl-2-nitrophenyl)amino)pentyl)carbamate 1-Fluoro-4-methyl-2-nitrobenzene (776 mg, 5.0 mmol) and DIPEA (4.24 mL, 10.0 mmol) were added to a solution of tert-butyl (5-aminopentyl)carbamate (1.01 g, 5.0 mmol) in 10 mL of DMF at room temperature. The reaction mixture was heated to 80 °C and stirred for 2.5 h. The reaction mixture was cooled to room temperature, diluted with 150 mL of water, and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried and concentrated. The residue was dissolved in CHCl and purified using flash chromatography (SiO, 10-50% EtOAc in petroleum ether) to give the product as a red oil (1.18 g, 70% yield). LC / MS: M+Na = 360.1, R t :5.4 minutes.

[0175] Step 2: Preparation of tert-butyl (5-(2-amino-5-methyl-1H-benzo[d]imidazol-1-yl)pentyl)carbamate To a stirred solution of tert-butyl (5-((4-methyl-2-nitrophenyl)amino)pentyl)carbamate (1.18 g, 3.51 mmol) in 35 mL of MeOH was added Pd / C (373 mg, 0.35 mmol) under a nitrogen atmosphere. The nitrogen was replaced with hydrogen, and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of water / MeOH / MeCN (1:3:1), and CNBr (446 mg, 4.21 mmol) was added at room temperature. The resulting solution was heated at 50 °C overnight in a sealed flask. The reaction mixture was diluted with 50 mL of Na2CO3 (sat. aq.) and extracted with EtOAc (3 x 30 mL). The organic phases were combined, dried, and concentrated. The residue was dissolved in CH2Cl2 and purified using flash chromatography (SiO2, 1-10% MeOH in CH2Cl2 with 1% NH3 (28% aq.)) to give the product as a reddish-brown solid (855 mg, 73% yield). LC / MS: M+H=333.2, R t :3.2 minutes.

[0176] Step 3: Preparation of tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-methyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate tert-Butyl (5-(2-amino-5-methyl-1H-benzo[d]imidazol-1-yl)pentyl)carbamate (33 mg, 0.1 mmol), 3-(tert-butoxycarbonyl)benzoic acid (22 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), and TEA (28 μL, 0.2 mmol) were dissolved in 0.4 mL of MeCN and stirred overnight at 50° C. The reaction mixture was cooled to room temperature, diluted with water and MeOH, and purified by reverse-phase chromatography (C18, 50 mM NHOH (aq) / MeCN gradient) to give the product (34 mg, 63% yield). 1H NMR (DMSO-d6) δ:12.69 (s, 1H), 8.78 (s, 1H), 8.43 (d, 1H), 8.02 (d, 1H), 7.59 (m, 1H), 7.41 (d, 1H), 7.34 (s, 1H), 7.08 (d, 1H), 6.68 (m, 1H), 4.23 (m, 2H), 2.87 (m, 2H), 2.39 (s, 3H), 1.81 (m, 2H), 1.58 (s, 9H), 1.45 (m, 2H), 1.37 - 1.26 (m, 9H). LC / MS:M+H=537.3.

[0177] Step 4: Preparation of 3-((1-(5-aminopentyl)-5-methyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a stirred solution of tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-methyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (34 mg, 0.063 mmol) in 2 ml dioxane and 1 ml water was added 1 ml of HCl (conc.). The reaction was stirred overnight and concentrated in vacuo. The residue was dissolved in toluene and concentrated to dryness in vacuo. The product was used in the next step without further purification.

[0178] Step 5:1 5 -methyl-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione To a stirred solution of 3-((1-(5-aminopentyl)-5-methyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (from Step 4) in MeCN was added TEA (27 μl, 0.19 mmol) and HATU (24 mg, 0.063 mmol). The reaction mixture was heated to 50 °C and stirred overnight. The reaction mixture was diluted with DMSO / dioxane / methanol / water, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 min, 25 ml / min). Pure fractions were pooled and concentrated to give the product as a white solid (9 mg, 39% yield). 1 H NMR (DMSO-d6) δ:12.41 (s, 1H), 9.03 (s, 1H), 8.09 (d, 1H), 7.87 (tm, 1H), 7.73 (d, 1H), 7.57 (m, 1H), 7.38 (d, 1H), 7.29 (s, 1H), 7.06 (d, 1H), 4.25 (m, 2H), 3.23 - 3.13 (m, 2H), 2.38 (s, 3H), 2.03 (m, 2H), 1.81 (m, 2H), 1.42 (m, 2H). LC / MS:M+H=363.2.

[0179] Example 5:1 1 H-9-Oxa-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0180] [ka]

[0181] Step 1: Preparation of tert-butyl (2-(2-((2-nitrophenyl)amino)ethoxy)ethyl)carbamate A solution of 1-fluoro-2-nitrobenzene (28 mg, 0.2 mmol), tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (49 mg, 0.24 mmol), and K2CO3 (83 mg, 0.6 mmol) in 2 mL of MeCN was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc. The organic phase was washed with water and concentrated to give the product as a yellow oil (54 mg, 83% yield). 1 H NMR (DMSO-d6) δ:8.17 (m, 1H), 8.06 (m, 1H), 7.57 - 7.51 (m, 1H), 7.09 (d, 1H), 6.75 (m, 1H), 6.73 - 6.66 (m, 1H), 3.65 (m, 2H), 3.50 (m, 2H), 3.44 (m, 2H), 3.09 (m, 2H), 1.36 (s, 9H). LC / MS: M+Na=348.1.

[0182] Step 2: Preparation of tert-butyl (2-(2-(2-amino-1H-benzo[d]imidazol-1-yl)ethoxy)ethyl)carbamate To a stirred solution of tert-butyl (2-(2-((2-nitrophenyl)amino)ethoxy)ethyl)carbamate (50 mg, 0.15 mmol) in 10 mL of EtOH was added 5% Pd / C (8 mg, 0.007 mmol) under a nitrogen atmosphere. The nitrogen was replaced with hydrogen, and the reaction was stirred at room temperature for 2 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of water / MeOH / MeCN (1:3:1), and CNBr (21 mg, 0.2 mmol) was added at room temperature. The resulting solution was heated at 40 °C overnight in a sealed flask. The reaction mixture was diluted with 50 mL of Na2CO3 (sat. aq.) and extracted with EtOAc (3 × 30 mL). The organic phases were combined, dried, and concentrated. The crude product was used directly in the next step without further purification. 1H NMR (DMSO-d6) δ:12.59 (s, 1H), 8.46 (s, 2H), 7.56 - 7.50 (m, 1H), 7.37 (m, 1H), 7.29 - 7.23 (m, 2H), 6.70 (m, 1H), 4.28 (m, 2H), 3.70 (m, 2H), 3.41 - 3.36 (Overlap with DMSO, m, 2H), 3.00 (m, 2H), 1.35 (s, 9H). LC / MS:M+H=321.2.

[0183] Step 3: Preparation of tert-butyl 3-((1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of tert-butyl (2-(2-(2-amino-1H-benzo[d]imidazol-1-yl)ethoxy)ethyl)carbamate (65 mg, 0.16 mmol) in 5 mL of MeCN was added 3-(tert-butoxycarbonyl)benzoic acid (36 mg, 0.16 mmol), HATU (61 mg, 0.16 mmol), and TEA (68 μL, 0.49 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic phase was washed with 0.1 M NaOH, 0.1 M HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated. The crude product (74 mg) was used directly in the next step without further purification. 1 H NMR (DMSO-d6) δ: 12.79 (s, 1H), 8.77 (s, 1H), 8.44 (d, 1H), 8.03 (d, 1H), 7.59 (m, 1H), 7.58 - 7.50 (m, 2H), 7.30 - 7.18 (m, 2H), 6.59 (m, 1H), 4.43 (m, 2H), 3.84 (m, 2H), 3.47 - 3.41 (overlapping with water peak, m, 2H), 2.97 (m, 2H), 1.58 (s, 9H), 1.31 (s, 9H). LC / MS: M+H = 523.3.

[0184] Step 4: Preparation of 3-((1-(2-(2-aminoethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid tert-Butyl 3-((1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (74 mg, 0.14 mmol) was dissolved in 2 ml of dioxane and 1 ml of water, and 1 ml of HCl (conc.) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated. The residue was dissolved in toluene and concentrated to dryness in vacuo. The product was used in the next step without further purification.

[0185] Step 5:1 1 Preparation of H-9-oxa-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione To a stirred solution of 3-((1-(2-(2-aminoethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (from the previous step) in 10 mL of MeCN was added HATU (80 mg, 0.21 mmol) and TEA (59 μl, 0.42 mmol). The reaction mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature, diluted with DMSO / dioxane / methanol / water, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 minutes, 25 mL / min). Pure fractions were pooled and concentrated to give the product as a white solid (8 mg, 16 percent yield). 1 H NMR (DMSO-d6) δ:12.35 (s, 1H), 9.42 (s, 1H), 8.06 (d, 1H), 7.70 (d, 2H), 7.55 (m, 1H), 7.48 (m, 2H), 7.20 (m, 2H), 4.47 (m, 2H), 3.83 (m, 2H), 3.76 (m, 2H). LC / MS:M+H=351.1.

[0186] Example 6:11 -methyl-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0187] [ka]

[0188] Step 1: Preparation of tert-butyl (5-((2-nitrophenyl)amino)hexyl)carbamate A solution of 1-fluoro-2-nitrobenzene (42 mg, 0.3 mmol), tert-butyl (5-aminohexyl)carbamate (78 mg, 0.36 mmol), and K2CO3 (124 mg, 0.9 mmol) in 50 mL of MeCN was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc. The organic phase was washed with water, 0.1 M HCl, NaHCO3 (sat.), and brine, dried, and concentrated to give the product as a yellow oil (91 mg, 83% yield). 1 H NMR (DMSO-d6) δ:8.06 (m, 1H), 7.91 (d, 1H), 7.53 (m, 1H), 7.09 (d, 1H), 6.76 (m, 1H), 6.67 (m, 1H), 3.80 (m, 1H), 2.90 (m, 2H), 1.67 - 1.49 (m, 2H), 1.44 - 1.26 (m, 9H), 1.21 (d, 3H). LC / MS: M+Na=360.2.

[0189] Step 2: Preparation of tert-butyl (5-(2-amino-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To a stirred solution of tert-butyl (5-((2-nitrophenyl)amino)hexyl)carbamate (91 mg, 0.27 mmol) in 5 mL of EtOH under a nitrogen atmosphere was added 10% Pd / C (14 mg, 0.013 mmol). The nitrogen was replaced with hydrogen, and the reaction was stirred under hydrogen at room temperature for 4 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of water / MeOH / MeCN (1:3:1), and CNBr (37 mg, 0.35 mmol) was added at room temperature. The resulting solution was heated at 40 °C overnight in a sealed flask. The reaction mixture was diluted with 50 mL of Na2CO3 (sat. aq.) and extracted with EtOAc (3 × 30 mL). The organic phases were combined, dried, and concentrated. The crude product (87 mg) was used directly in the next step without further purification. 1 H NMR (DMSO-d6) δ:7.28 (d, 1H), 7.12 (d, 1H), 6.91 (m, 1H), 6.83 (m, 1H), 6.70 (m, 1H), 6.32 (s, 2H), 4.37 (h, J=6.7 Hz, 1H), 2.81 (m, 2H), 2.06 - 1.93 (m, 1H), 1.83 - 1.71 (m, 1H), 1.44 (d, 3H), 1.34 (s, 9H), 1.24 - 1.11 (m, 1H), 1.03 - 0.90 (m, 1H);LC / MS:M+H=333.2.

[0190] Step 3: Preparation of tert-butyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-1H-benzo[d]imidazol-2-yl)carbamoylbenzoate To a stirred solution of tert-butyl (5-(2-amino-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (33 mg, 0.10 mmol) in 0.4 mL of MeCN, 3-(tert-butoxycarbonyl)benzoic acid (22 mg, 0.10 mmol), HATU (38 mg, 0.10 mmol), and TEA (28 μL, 0.20 mmol) were added. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, diluted with methanol / water, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 minutes, 25 mL / min). Pure fractions were pooled and concentrated to give the product as a white solid (25 mg, 47 percent yield). 1 H NMR (DMSO-d6) δ:12.84 (s, 1H), 8.79 (s, 1H), 8.41 (d, 1H), 8.03 (d, 1H), 7.66 - 7.55 (m, 3H), 7.27 - 7.20 (m, 2H), 6.63 (m, 1H), 5.09 (s, 1H), 2.81 (m, 2H), 2.27 (s, 1H), 1.95 - 1.85 (m, 1H), 1.63 - 1.55 (m, 9H), 1.46 - 1.33 (m, 2H), 1.30 - 1.17 (s, 9H), 1.13 - 1.00 (m, 1H). LC / MS: M+H=537.3.

[0191] Step 4: 11-methyl-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione tert-Butyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-1H-benzo[d]imidazol-2-yl)carbamoylbenzoate (23 mg, 0.043 mmol) was dissolved in 2 ml of dioxane and 1 ml of water, and 1 ml of HCl (conc.) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated. The residue was dissolved in toluene and concentrated to dryness in vacuo. The residue was dissolved in 10 ml of MeCN, and to the resulting solution were added HATU (24 mg, 0.06 mmol) and TEA (18 μl, 0.13 mmol). The reaction mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature, diluted with DMSO / dioxane / methanol / water, filtered, and purified by reverse phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM Purified with NH4OH (aq) / acetonitrile, gradient over 12 minutes, 25 ml / min. Pure fractions were pooled and concentrated to give the product as a white solid (6 mg, 39 percent yield). 1 H NMR (DMSO-d6) δ:12.43 (s, 1H), 9.02 (s, 1H), 8.10 (d, 1H), 7.88 (m, 1H), 7.73 (d, 1H), 7.61 - 7.54 (m, 2H), 7.54 - 7.46 (m, 1H), 7.24 - 7.14 (m, 2H), 5.46 - 5.33 (m, 1H), 3.19 - 2.98 (m, 2H), 2.29 - 2.15 (m, 2H), 1.91 - 1.76 (m, 1H), 1.66 (d, 3H), 1.64 - 1.58 (m, 1H), 1.42 - 1.30 (m, 1H), 1.24 - 1.12 (m, 1H);LC / MS:M+H=363.1.

[0192] Example 7:1 1 -methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Methyl carboxylate

[0193] [ka]

[0194] Step 1: Preparation of methyl 2-((6-((tert-butoxycarbonyl)amino)hexan-2-yl)amino)-3-nitrobenzoate A solution of methyl 2-fluoro-3-nitrobenzoate (300 mg, 1.51 mmol), tert-butyl (5-aminohexyl)carbamate (391 mg, 1.81 mmol), and K2CO3 (625 mg, 4.52 mmol) in 50 mL of MeCN was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc. The organic phase was washed with water, 0.1 M HCl, NaHCO3 (sat.), and brine, dried, and concentrated to give the product as a yellow oil (580 mg, 97 percent yield). 1 H NMR (DMSO-d6) δ:8.04 (m, 1H), 8.01 - 7.96 (m, 2H), 6.83 (m, 1H), 6.72 (m, 1H), 3.86 (s, 3H), 3.20 - 3.11 (m, 1H), 2.84 (m, 2H), 1.45 - 1.38 (m, 2H), 1.35 (s, 9H), 1.33 - 1.25 (m, 2H), 1.24 - 1.14 (m, 2H), 1.05 (d, 3H);LC / MS:M+Na=418.1.

[0195] Step 2: Preparation of methyl 2-amino-1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-1H-benzo[d]imidazole-7-carboxylate To a stirred solution of methyl 2-((6-((tert-butoxycarbonyl)amino)hexan-2-yl)amino)-3-nitrobenzoate (580 mg, 1.47 mmol) in 10 mL of MeOH was added 10% Pd / C (14 mg, 0.013 mmol) under a nitrogen atmosphere. The nitrogen was replaced with hydrogen, and the reaction was stirred under hydrogen at room temperature for 2 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of water / MeOH / MeCN (1:3:1), and CNBr (202 mg, 1.91 mmol) was added at room temperature. The resulting solution was heated at 40 °C overnight in a sealed flask. The reaction mixture was diluted with 50 mL of Na2CO3 (sat. aq.) and extracted with EtOAc (3 × 30 mL). The organic phases were combined, dried, and concentrated. The crude product (550 mg) was used directly in the next step without further purification. 1 H NMR (DMSO-d6) δ:7.29 (m, 1H), 7.16 (m, 1H), 6.98 (m, 1H), 6.68 (m, 1H), 6.31 (s, 2H), 4.44 (m, 1H), 3.86 (s, 3H), 2.79 (m, 2H), 2.02 - 1.91 (m, 1H), 1.81 - 1.70 (m, 1H), 1.48 (d, J=7.0 Hz, 3H), 1.39 - 1.23 (m, 11H), 1.07 - 0.94 (m, 1H), 0.90 - 0.76 (m, 1H);LC / MS:M+H=391.2.

[0196] Step 3: Preparation of methyl 1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-7-carboxylate To a stirred solution of methyl 2-amino-1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-1H-benzo[d]imidazole-7-carboxylate (350 mg, 0.90 mmol) in 10 mL of MeCN was added 3-(tert-butoxycarbonyl)benzoic acid (199 mg, 0.90 mmol), HATU (340 mg, 0.90 mmol), and TEA (250 μL, 1.79 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc, and the organic phase was washed with 0.1 M NaOH, 0.1 M HCl, NaHCO (sat.), and brine, dried, and concentrated. The crude product was purified by flash chromatography (SiO 2 , 10-30% EtOAc / petroleum ether) to give the product as a light brown oil (390 mg, 73 percent yield). 1 H NMR (DMSO-d6) δ:8.82 (s, 1H), 8.37 (d, 1H), 8.05 (d, 1H), 7.75 (d, 1H), 7.63 (m, 1H), 7.50 (d, 1H), 7.29 (m, 1H), 6.61 (m, 1H), 3.94 (s, 3H), 2.76 (m, 2H), 1.74 (d, 3H), 1.58 (s, 9H), 1.28 (s, 9H). LC / MS:M+H=595.3.

[0197] Step 4: 11-methyl-3,5-dioxo-1 1 Preparation of methyl H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-17-carboxylate Methyl 1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-7-carboxylate (390 mg, 0.66 mmol) was dissolved in 5 ml of dioxane and 2 ml of water, and 2 ml of HCl (conc.) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated. The residue was dissolved in toluene and concentrated to dryness in vacuo. The residue was dissolved in 300 ml of dioxane, and HATU (298 mg, 0.79 mmol) and TEA (573 μl, 3.28 mmol) were added to the resulting solution. The reaction mixture was heated at room temperature overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc, and the organic phase was washed with 0.1 M NaOH, 0.1 M HCl, NaHCO3 (sat.), and brine, dried, and concentrated. The crude product was purified by flash chromatography (SiO 2 , 100% EtOAc) to give the product as a light brown oil (58 mg, 21% yield). 1 H NMR (DMSO-d6) δ:12.86 (s, 1H), 8.81 (s, 1H), 8.11 (d, 1H), 7.83 - 7.69 (m, 3H), 7.60 (m, 1H), 7.50 (d, 1H), 7.28 (m, 1H), 4.93 (bs, 1H), 3.93 (s, 3H), 3.49 (bs, 1H), 3.10 (bs, 1H), 2.91 (bs, 1H), 1.90 (bs, 3H), 1.67 - 1.56 (m, 4H), 1.45 (bs, 1H). LC / MS:M+H=421.2.

[0198] Example 8:1 1 -methyl-1 7 -(4-Methylpiperazine-1-carbonyl)-11H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0199] [ka]

[0200] Step 1: 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxylic acids 11-methyl-3,5-dioxo-1 in 10 ml of water 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 A solution of methyl 2-carboxylate (55 mg, 0.13 mmol) and NaOH (37 mg, 0.92 mmol) was stirred at room temperature overnight. The reaction mixture was acidified with 2 ml of 1 M HCl. The precipitate was collected and washed with water. The product was used in the next step without further purification. LC / MS: M+H=407.1, R t :4.0 minutes.

[0201] Step 2: 11-methyl-1 7 Preparation of -(4-methylpiperazine-1-carbonyl)-11H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 A solution of -carboxylic acid (25 mg, 0.062 mmol), methylpiperazine (9 mg, 0.092 mmol), HATU (23 mg, 0.062 mmol), and TEA (26 μl, 0.19 mmol) was stirred overnight at 50° C. The reaction mixture was diluted with water and MeOH and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 min, 25 ml / min). Pure fractions were pooled and concentrated to give the product as a white solid (15 mg, 50 percent yield). 1H NMR (DMSO-d6) δ:12.62 (bs, 1H), 8.77 (s, 1H), 8.11 (d, 1H), 7.74 (d, 1H), 7.62 - 7.52 (m, 2H), 7.22 (m, 1H), 7.03 (d, 1H), 4.56 (bs, 1H), 4.15 - 2.91 (m, 10H), 3.29 (s, 3H), 2.19 (d, 3H), 2.66 - 1.33 (m, 6H). LC / MS:M+H=489.2.

[0202] Example 9: 4-(11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 (-carbonyl)piperazine-1-carboxylate tert-butyl

[0203] [ka]

[0204] Step 1: 4-(11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 Preparation of tert-butyl ((carbonyl)piperazine-1-carboxylate) 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7A solution of 1-(2-methyl-2-pyrazine-1-carboxylic acid (25 mg, 0.062 mmol), tert-butyl piperazine-1-carboxylate (17 mg, 0.092 mmol), HATU (23 mg, 0.062 mmol), and TEA (26 μl, 0.19 mmol) was stirred overnight at 50 °C. The reaction mixture was diluted with water and MeOH and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 min, 25 ml / min). Pure fractions were pooled and concentrated to give the product as an off-white solid (18 mg, 51% yield). 1 H NMR (DMSO-d₆) δ: 12.70 (bs, 1H), 8.77 (bs, 1H), 8.11 (d, 1H), 7.86 - 7.76 (m, 1H), 7.75 (d, 1H), 7.64 - 7.53 (m, 2H), 7.24 (m, 1H), 7.09 (m, 1H), 4.53 (bs, 1H), 3.90 - 2.91 (overlapping with water peak, m, 10H), 2.07 - 1.44 (m, 9H), 1.40 (s, 9H); LC / MS: M+H = 575.3.

[0205] Example 10:1 7 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0206] [ka]

[0207] Step 1: Preparation of methyl 2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate A solution of methyl 2-fluoro-3-nitrobenzoate (500 mg, 2.51 mmol), tert-butyl (5-aminopentyl)carbamate (610 mg, 3.01 mmol), and K2CO3 (1.05 g, 7.53 mmol) in 20 mL of MeCN was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc. The organic phase was washed with water, 0.1 M HCl, NaHCO3 (sat.), and brine, dried, and concentrated to give the product as a yellow oil (960 mg, 100% yield). 1 H NMR (DMSO-d6) δ:8.24 (m, 1H), 8.06 - 8.02 (m, 2H), 6.82 - 6.72 (m, 2H), 3.86 (s, 3H), 2.91 - 2.81 (m, 4H), 1.56 (m, 2H), 1.38 - 1.32 (m, 11H), 1.31 - 1.22 (m, 2H);LC / MS:M+H=382.2.

[0208] Step 2: Preparation of methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-7-carboxylate To a stirred solution of methyl 2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate (500 mg, 1.31 mmol) in 10 mL of MeOH was added 5% Pd / C (70 mg, 0.066 mmol) under a nitrogen atmosphere. The nitrogen was replaced with hydrogen and the reaction was stirred under hydrogen at room temperature for 2 hours. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of water / MeOH / MeCN (1:3:1) and CNBr (181 mg, 1.70 mmol) was added at room temperature. The resulting solution was heated at 40 °C overnight in a sealed flask. The reaction mixture was diluted with 50 mL of NaHCO3 (sat. aq.) and extracted with EtOAc (3 x 30 mL). The organic phases were combined, washed with brine and NaHCO3 (sat.), dried, and concentrated. The crude product (550 mg) was used directly in the next step without further purification. 1H NMR (DMSO-d6) δ:7.33 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.73 (m, 1H), 6.56 (s, 2H), 4.12 (m, 2H), 3.87 (s, 3H), 2.85 (m, 2H), 1.43 (m, 2H), 1.38 - 1.29 (m, 11H), 1.21 - 1.10 (m, 2H). LC / MS:M+H=377.2.

[0209] Step 3: Preparation of methyl 1-(5-((tert-butoxycarbonyl)amino)pentyl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-7-carboxylate To a stirred solution of methyl 2-amino-1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-1H-benzo[d]imidazole-7-carboxylate (500 mg, 1.33 mmol) in 10 mL of MeCN was added 3-(tert-butoxycarbonyl)benzoic acid (295 mg, 1.33 mmol), HATU (504 mg, 1.33 mmol), and TEA (555 μl, 3.98 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc, and the organic phase was washed with 0.1 M NaOH, 0.1 M HCl, NaHCO (sat.), and brine, dried, and concentrated. The crude product was purified by flash chromatography (SiO 2 , 10-30% EtOAc / petroleum ether) to give the product as a light brown oil (530 mg, 69% yield). 1H NMR (DMSO-d6) δ:13.10 (s, 1H), 8.79 (s, 1H), 8.45 (d, 1H), 8.05 (d, 1H), 7.80 (d, 1H), 7.65 - 7.57 (m, 2H), 7.32 (m, 1H), 6.69 (m, 1H), 4.47 (m, 2H), 3.94 (s, 3H), 2.87 (m, 2H), 1.67 - 1.60 (m, 2H), 1.59 (s, 9H), 1.42 (m, 2H), 1.32 (s, 9H), 1.31 - 1.25 (m, 2H);LC / MS:M+H=581.3.

[0210] Step 4: 3,5-Dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 Preparation of methyl carboxylate Methyl 1-(5-((tert-butoxycarbonyl)amino)pentyl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-7-carboxylate (530 mg, 0.91 mmol) was dissolved in 5 ml of dioxane, and 5 ml of 5 M HCl was added. The reaction mixture was stirred at 35° C. overnight. The reaction mixture was concentrated. The residue (LC / MS: M+H=425.2) was dissolved in 150 ml of THF, and HATU (415 mg, 1.10 mmol) and DIPEA (797 μl, 4.56 mmol) were added to the resulting solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in water / MeCN at 80° C. After cooling to room temperature, the precipitate was collected by filtration. The recovered product (280 mg, 76% yield) was used without further purification.

[0211] Step 5:1 7 -(4-methylpiperazine-1-carbonyl)-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione 3,5-dioxo-1 in 4 ml of dioxane / water (1:1) 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a stirred solution of methyl 2-carboxylate (41 mg, 0.1 mmol) was added NaOH (20 mg, 0.5 mmol). The reaction mixture was stirred overnight at room temperature. The solution was acidified with 1 mL of 1 M HCl, and the reaction was concentrated to dryness by repeated addition and evaporation of MeCN and toluene. The residue was dissolved in 5 mL of MeCN and HATU (38 mg, 0.15 mmol), and TEA (42 μL, 0.3 mmol) was added. The reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with DMSO / methanol / water, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NH4OH (aq) / acetonitrile, gradient over 12 min, 25 mL / min). Pure fractions were pooled and concentrated to give the product as a white solid (26 mg, 55 percent yield). 1 H NMR (DMSO-d6) δ:8.92 (s, 1H), 8.11 (d, 1H), 7.76 (m, 1H), 7.64 (d, 1H), 7.54 (d, 1H), 7.50 (m, 1H), 6.97 (bs, 1H), 6.75 (bs, 1H), 4.12 (bs, 2H), 3.78 (bs, 1H), 3.65 (bs, 1H), 3.30 - 3.20 (m, 4H), 2.47 (bs, 1H), 2.32 (bs, 2H), 2.19 (s, 3H), 2.13 (bs, 1H), 1.94 (bs, 2H), 1.84 (bs, 1H), 1.69 (bs, 1H), 1.43 (bs, 2H); LC / MS:M+H=475.2.

[0212] Example 11:1 5 -(4-methylpiperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0213] [ka]

[0214] Step 1: Preparation of methyl 4-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate A solution of methyl 4-fluoro-3-nitrobenzoate (755 mg, 3.50 mmol), tert-butyl (5-aminopentyl)carbamate (850 mg, 4.20 mmol), and K2CO3 (1.45 g, 10-50 mmol) in 50 mL of MeCN was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc. The organic phase was washed with water, 0.1 M HCl, NaHCO3 (sat.), and brine, dried, and concentrated to give the product as a yellow oil (1300 mg, 97% yield). 1 H NMR (DMSO-d6) δ:8.62 (d, 1H), 8.53 (m, 1H), 7.96 (m, 1H), 7.15 (d, 1H), 6.77 (m, 1H), 3.82 (s, 3H), 3.40 (m, 2H), 2.91 (m, 2H), 1.62 (m, 2H), 1.46 - 1.30 (m, 13H);LC / MS:M+Na=404.1# Step 2: Preparation of methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of methyl 4-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate (700 mg, 1.84 mmol) in 10 mL of MeOH was added 5% Pd / C (98 mg, 0.092 mmol) under a nitrogen atmosphere. The nitrogen was replaced with hydrogen and the reaction was stirred under hydrogen at room temperature for 2 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of water / MeOH / MeCN (1:3:1) and CNBr (253 mg, 1.70 mmol) was added at room temperature. The resulting solution was heated at 30 °C overnight in a sealed flask. The reaction mixture was concentrated under reduced pressure and partitioned between NaHCO3 (sat) and EtOAc. The organic phase was washed with brine and NaHCO3 (sat), dried, and concentrated. The crude product (590 mg) was used directly in the next step without further purification. 1 H NMR (DMSO-d6) δ:7.69 (d, 1H), 7.57 (m, 1H), 7.23 (d, 1H), 6.75 (m, 1H), 6.65 (s, 2H), 3.97 (m, 2H), 3.81 (s, 3H), 2.88 (m, 2H), 1.61 (m, 2H), 1.43 - 1.34 (m, 11H), 1.31 - 1.22 (m, 2H);LC / MS:M+H=377.2.

[0215] Step 3: Preparation of methyl 1-(5-((tert-butoxycarbonyl)amino)pentyl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-5-carboxylate (590 mg, 1.57 mmol) in 10 mL of MeCN was added 3-(tert-butoxycarbonyl)benzoic acid (348 mg, 1.57 mmol), HATU (594 mg, 1.57 mmol), and TEA (655 μL, 4.70 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc, and the organic phase was washed with 0.1 M NaOH, 0.1 M HCl, NaHCO (sat.), and brine, dried, and concentrated. The crude product was purified by flash chromatography (SiO 2 , 10-30% EtOAc / petroleum ether) to give the product as a light brown oil (610 mg, 67 percent yield). 1 H NMR (DMSO-d6) δ:12.96 (s, 1H), 8.79 (s, 1H), 8.44 (d, 1H), 8.13 (s, 1H), 8.05 (d, 1H), 7.89 (d, 1H), 7.67 - 7.58 (m, 2H), 6.69 (m, 1H), 4.28 (m, 2H), 3.87 (s, 3H), 2.88 (m, 2H), 1.83 (m, 2H), 1.59 (s, 9H), 1.45 (m, 2H), 1.38 - 1.32 (m, 2H), 1.31 (s, 9H);LC / MS:M+H=581.3.

[0216] Step 4: 3,5-Dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5 -Preparation of carboxylic acids Methyl 1-(5-((tert-butoxycarbonyl)amino)pentyl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-5-carboxylate (610 mg, 1.05 mmol) was dissolved in 5 ml of dioxane and 2 ml of water, and 2 ml of HCl (conc.) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in 150 ml of dioxane, and HATU (478 mg, 1.26 mmol) and DIPEA (918 μl, 5.25 mmol) were added to the resulting solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc. The organic phase was washed with 0.1 M NaOH, 0.1 M HCl, NaHCO3 (sat.), and brine, dried, filtered, and concentrated. The insoluble residue was recovered from the combined aqueous phases and washed with water. The insoluble residue was mixed with 5 ml of dioxane and 5 ml of water. Sodium hydroxide (126 mg, 3.15 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was acidified with 5 ml of 1 M HCl and the precipitate was recovered by centrifugation, washed repeatedly with water and dried in vacuo. The recovered product (140 mg) was used without further purification. LC / MS: M+H=393.1, R t :4.0 minutes.

[0217] Step 5:1 5 -(4-methylpiperazine-1-carbonyl)-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione 3,5-dioxo-1 in 0.5 ml of MeCN 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5A solution of -carboxylic acid (20 mg, 0.050 mmol), N-methylpiperazine (7.5 mg, 0.075 mmol), HATU (19 mg, 0.050 mmol), and TEA (21 μL, 0.15 mmol) was stirred overnight at 50° C. The reaction mixture was diluted with water and methanol, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 min, 25 ml / min). Pure fractions were pooled and concentrated to give the product as a white solid (1.5 mg, 6 percent yield). 1 H NMR (DMSO-d6) δ:12.57 (s, 1H), 9.03 (s, 1H), 8.11 (d, 1H), 7.89 (m, 1H), 7.75 (d, 1H), 7.58 (m, 1H), 7.55 (d, 1H), 7.51 (s, 1H), 7.28 (d, 1H), 4.29 (m, 2H), 3.48 (bs, 4H), 3.23 - 3.15 (m, 2H), 2.33 (bs, 2H), 2.20 (s, 3H), 2.04 (bs, 2H), 1.83 (bs, 2H), 1.43 (bs, 2H);LC / MS:M+H=475.2.

[0218] Example 12:1 5 -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0219] [ka]

[0220] 3,5-dioxo-1 in 0.5 ml of MeCN 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5A solution of 1-(oxetan-3-yl)piperazine (11 mg, 0.075 mmol), HATU (19 mg, 0.050 mmol), and TEA (21 μL, 0.15 mmol) was stirred at 50° C. overnight. The reaction mixture was diluted with water and methanol, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 min, 25 mL / min). Pure fractions were pooled and concentrated to give the product as a white solid (2.1 mg, 8 percent yield). 1 H NMR (DMSO-d6) δ:9.03 (s, 1H), 8.11 (d, 1H), 7.89 (m, 1H), 7.75 (d, 1H), 7.62 - 7.53 (m, 2H), 7.51 (s, 1H), 7.29 (d, 1H), 4.54 (m, 2H), 4.45 (m, 2H), 4.29 (m, 2H), 3.52 (bs, 4H), 3.45 (m, 1H), 3.23 - 3.14 (m, 2H), 2.30 (bs, 4H), 2.04 (bs, 2H), 1.83 (bs, 2H), 1.43 (bs, 2H); LC / MS:M+H=517.2.

[0221] Example 13: 4-(3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5 (-carbonyl)piperazine-1-carboxylate tert-butyl

[0222] [ka]

[0223] 3,5-dioxo-1 in 0.5 ml of MeCN 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5A solution of 1-(2-methyl-2-pyrazine-1-carboxylic acid (20 mg, 0.050 mmol), tert-butyl piperazine-1-carboxylate (14 mg, 0.075 mmol), HATU (19 mg, 0.050 mmol), and TEA (21 μl, 0.15 mmol) was stirred overnight at 50° C. The reaction mixture was diluted with water and methanol, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 min, 25 ml / min). Pure fractions were pooled and concentrated to give the product as a white solid (1 mg, 4 percent yield). 1 H NMR (DMSO-d6) δ:12.62 (s, 1H), 9.03 (s, 1H), 8.11 (d, 1H), 7.88 (m, 1H), 7.75 (d, 1H), 7.62 - 7.50 (m, 3H), 7.30 (d, 1H), 4.29 LC / MS:M+H=561.3.

[0224] Example 14: 4-(3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 (-carbonyl)piperazine-1-carboxylate tert-butyl

[0225] [ka]

[0226] NaOH (20 mg, 0.5 mmol) was dissolved in 4 ml of dioxane / water (1:1) and 3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7To a solution of tert-butyl piperazine-1-carboxylate (41 mg, 0.100 mmol) was added. The reaction mixture was stirred overnight at room temperature and then acidified with 1 mL of 1 M HCl. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeCN and toluene and repeatedly concentrated to dryness under reduced pressure. The residue was dissolved in 5 mL of MeCN, and tert-butyl piperazine-1-carboxylate (28 mg, 0.150 mmol), HATU (38 mg, 0.100 mmol), and TEA (42 μL, 0.30 mmol) were added. The resulting solution was stirred overnight at 50° C. The reaction mixture was diluted with water and methanol, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NH4OH (aq) / acetonitrile, gradient over 12 minutes, 25 mL / min). Pure fractions were pooled and concentrated to give the product as a white solid (15 mg, 27 percent yield). 1 H NMR (DMSO-d6) δ:12.72 (s, 1H), 8.97 (s, 1H), 8.11 (d, 1H), 7.86 (m, 1H), 7.76 (d, 1H), 7.61 - 7.54 (m, 2H), 7.25 (m, 1H), 7.13 (d, 1H), 4.29 - 4.20 (m, 1H), 4.13 - 4.04 (m, 1H), 3.76 - 3.67 (m, 2H), 3.53 - 3.40 (m, 2H), 3.30 - 3.22 (m, 5H), 3.19 - 3.09 (m, 1H), 2.03 - 1.93 (m, 2H), 1.80 - 1.70 (m, 2H), 1.41 (s, 11H); LC / MS:M+H=561.3.

[0227] Example 15:1 1 -methyl-1 7 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0228] [ka]

[0229] 4-(11-methyl-3,5-dioxo-1-methylpropional) in 0.3 ml of CH2Cl2 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a stirred solution of tert-butyl (-carbonyl)piperazine-1-carboxylate (13 mg, 0.023 mmol) was added 0.2 ml of TFA. The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The reaction mixture was diluted with water and methanol, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NH4OH (aq) / acetonitrile, gradient over 12 minutes, 25 ml / min). Pure fractions were pooled and concentrated to give the product as a white solid (6 mg, 56 percent yield). 1 H NMR (DMSO-d6) δ:8.76 (s, 1H), 8.11 (d, 1H), 7.80 (d1H), 7.74 (d, 1H), 7.59 (tm, 1H), 7.54 (d, 1H), 7.23 (m, 1H), 7.04 (d, 1H), 4.58 (bs, 1H), 2.68 (m, 2H); LC / MS:M+H=475.2.

[0230] Example 16:1 5 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0231] [ka]

[0232] 4-(3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 5To a stirred solution of tert-butyl (-carbonyl)piperazine-1-carboxylate (3 mg, 0.005 mmol) was added 0.2 ml of TFA. The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The reaction mixture was diluted with water and methanol, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NHOH (aq) / acetonitrile, gradient over 12 minutes, 25 ml / min). Pure fractions were pooled and concentrated to give the product as a white solid (2 mg, 81 percent yield). 1 H NMR (DMSO-d6) δ:9.03 (s, 1H), 8.11 (d, 1H), 7.88 (m, 1H), 7.75 (d, 1H), 7.58 (m, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 7.27 (d1H), 4.29 (m, 2H), 3.42 (s, 4H), 3.23 - 3.16 (m, 2H), 2.69 (s, 4H), 2.03 (s, 2H), 1.83 (s, 2H), 1.43 (s, 2H). LC / MS:M+H=461.2.

[0233] Example 17:1 7 -(piperazine-1-carbonyl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0234] [ka]

[0235] 4-(3,5-dioxo-1-methyl-1,4 ... 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7To a stirred solution of tert-butyl (-carbonyl)piperazine-1-carboxylate (15 mg, 0.027 mmol) was added 0.2 ml of TFA. The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The reaction mixture was diluted with water and methanol, filtered, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, 50 mM NH4OH (aq) / acetonitrile, gradient over 12 minutes, 25 ml / min). Pure fractions were pooled and concentrated to give the product as a white solid (10 mg, 81 percent yield). 1 H NMR (DMSO-d6) δ:8.96 (s, 1H), 8.11 (d, 1H), 7.86 (m, 1H), 7.75 (d, 1H),7.58 (m, 1H), 7.54 (d, 1H), 7.24 (m, 1H), 7.08 (d, 1H), 4.28 - 4.07 (m, 2H), 2.85 - 2.53 (m, 4H), 1.99 (bs, 2H), 1.76 (bs, 2H), 1.40 (bs, 2H). LC / MS:M+H=461.2.

[0236] Example 18: (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid

[0237] [ka]

[0238] Step 1: Preparation of methyl 2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate A mixture of methyl 2-fluoro-3-nitrobenzoate (1.0 g, 5.02 mmol), N-boc-1,5-diaminopentane (1.22 g, 6.03 mmol), and K2CO3 (2.08 g, 15.1 mmol) in acetonitrile (20 mL) was stirred at 80 °C overnight. The solvent was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was washed with 0.1 M NaOH, 0.1 M HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated. The crude methyl 2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate was used in the next step without further purification.

[0239] 1 H NMR (DMSO-d6) δ:(m, 1H), 8.05 (m, 1H), 8.04 - 8.02 (m, 1H), 6.82 - 6.73 (m, 2H), 3.86 (s, 3H), 2.90 - 2.81 (m, 4H), 1.56 (m, 2H), 1.39 - 1.31 (m, 11H), 1.30 - 1.22 (m, 2H);LC / MS:M+H=382.1.

[0240] Step 2: Preparation of methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-7-carboxylate 5% Pd / C (265 mg, 249 μmol) was added to a solution of methyl 2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate (1.90 g, 4.98 mmol) in methanol (20 mL). The reaction flask was evacuated and flushed with hydrogen twice. The mixture was stirred under hydrogen for 2 hours. The mixture was filtered through Celite, cyanogen bromide (686 mg, 6.48 mmol) was added to the solution, and the mixture was stirred at 40° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between saturated NaHCO and ethyl acetate. The organic phase was washed with saturated NaHCO and brine, dried over MgSO, filtered, and concentrated. The crude methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-7-carboxylate was used directly in the next step without further purification.

[0241] 1 H NMR (DMSO-d6) δ:7.33 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.74 (m, 1H), 6.57 (s, 2H), 4.16 - 4.08 (m, 2H), 3.87 (s, 3H), 2.85 (m, 2H), 1.43 (p, J=7.7 Hz, 2H), 1.39 - 1.29 (m, 11H), 1.15 (m, 2H);LC / MS:M+H=377.2.

[0242] Step 3: Preparation of methyl 1-(5-((tert-butoxycarbonyl)amino)pentyl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-7-carboxylate A solution of methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-7-carboxylate (1.0 g, 2.66 mmol), 3-(tert-butoxycarbonyl)benzoic acid (590 mg, 2.66 mmol), HATU (1.01 g, 2.66 mmol), and TEA (1.11 mL, 7.97 mmol) in THF (100 mL) was stirred at 50° C. overnight. The solvent was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was washed with 0.1 M NaOH, 0.1 M HCl, saturated NaHCO 3 , and brine, dried over MgSO 4 , filtered, and concentrated. The residue was dissolved in acetonitrile and precipitated by the addition of water. The solid was collected by filtration and washed with acetonitrile / water. Methyl 1-(5-((tert-butoxycarbonyl)amino)pentyl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-7-carboxylate was used without further purification.

[0243] 1 H NMR (DMSO-d6) δ:13.11 (s, 1H), 8.79 (s, 1H), 8.45 (d, 1H), 8.05 (d, 1H), 7.80 (m, 1H), 7.64 - 7.58 (m, 2H), 7.32 (m, 1H), 6.70 (m, 1H), 4.48 (m, 2H), 3.95 (s, 3H), 2.88 (m, 2H), 1.64 (m, 2H), 1.59 (s, 9H), 1.43 (m, 2H), 1.36 - 1.25 (m, 11H);LC / MS:M+H=581.3.

[0244] Step 4: Preparation of 1-(5-aminopentyl)-2-(3-carboxybenzamido)-1H-benzo[d]imidazole-7-carboxylic acid Methyl 1-(5-((tert-butoxycarbonyl)amino)pentyl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazole-7-carboxylate (1.20 g, 2.07 mmol) was dissolved in dioxane (10 ml) and water (5 ml) and concentrated HCl (5 ml) was added. The reaction mixture was stirred at room temperature overnight. The solution was concentrated to dryness and the residue was refluxed in diethyl ether / methanol until a fine precipitate formed. The solid was collected by filtration and dried under vacuum. 1-(5-aminopentyl)-2-(3-carboxybenzamido)-1H-benzo[d]imidazole-7-carboxylic acid was used without further purification.

[0245] 1 H NMR (DMSO-d6) δ:8.81 (m, 1H), 8.46 (m, 1H), 8.10 (m, 1H), 7.89 (br. s, 3H), 7.82 (m, 1H), 7.67 - 7.60 (m, 2H), 7.33 (m, 1H), 4.50 - 4.44 (m, 2H), 3.96 (s, 3H), 2.76 (m, 2H), 1.70 (m, 2H), 1.62 (m, 2H), 1.37 (m, 2H);LC / MS:M+H=425.2.

[0246] Step 5: Methyl 3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 Preparation of methyl carboxylate A slurry of 1-(5-aminopentyl)-2-(3-carboxybenzamido)-1H-benzo[d]imidazole-7-carboxylic acid (220 mg, 477 μmol) and TEA (333 μL, 2.39 mmol) in THF (200 mL) was added dropwise over 1 hour to a solution of Pybrop (334 mg, 716 μmol) in THF (200 mL). The reaction mixture was stirred overnight at room temperature and at 60°C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was slurried in water and concentrated. The remaining solid was slurried in methanol and collected by filtration. The solid was washed with methanol and a water / methanol mixture. 3,5-Dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 The methyl-carboxylate (140 mg, 72%) was used in the next step without further purification.

[0247] 1 H NMR (DMSO-d6) δ:12.84 (s, 1H), 8.96 (s, 1H), 8.11 (d, 1H), 7.86 (m, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.62 - 7.56 (m, 2H), 7.29 LC / MS:M+H=407.2.

[0248] Step 6: 3,5-Dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxylic acids 3,5-Dioxo-1 in dioxane (5 ml) and water (2 ml) 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7A solution of methyl 3,5-dioxo-1-carboxylate (165 mg, 406 μmol) and NaOH (114 mg, 2.84 mmol) was stirred at 40° C. for 1 day. The reaction mixture was diluted with water and acidified with 4 ml of 1 M HCl. A cloudy gel precipitated. The gel was centrifuged and the solid was washed twice with water / acetonitrile. 20 mg of the residue was dissolved in one drop of 28% ammonia in water (2 ml). The compound was purified by reversed-phase chromatography (Gemini NX-C18, 21*150 mm, water (50 mM NH4OH) / acetonitrile, gradient over 12 min, 25 ml / min) to give 3,5-dioxo-1-carboxylate. 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid was obtained.

[0249] 1 H NMR (DMSO-d6) δ:8.98 (s, 1H), 8.10 (d, 1H), 7.85 (m, 1H), 7.76 (d, 1H), 7.61 - 7.53 (m, 2H), 7.41 (d, 1H), 7.17 (m, 1H), 4.50 (m, 2H), 3.28 - 3.21 (m, 2H), 1.98 (s, 2H), 1.86 (s, 2H), 1.41 (s, 2H);LC / MS:M+H=393.1.

[0250] General Method A (used for the synthesis of example compounds 19-26): A solution of the corresponding acid (1 equiv.), amine (1.5 equiv.), HATU, and triethylamine in MeCN was stirred overnight at 50° C. The reaction mixture was diluted with water and methanol and purified by reverse-phase chromatography (50 mM aqueous NH4OH / acetonitrile). Pure fractions were pooled and concentrated to give the desired product.

[0251] Example 19: (E)-1 7 -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0252] [ka]

[0253] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 Prepared according to general procedure A starting from -carboxylic acid and 1-(oxetan-3-yl)piperazine.

[0254] 1 H NMR (DMSO-d6) δ:12.70 (s, 1H), 8.97 (s, 1H), 8.11 (d, 1H), 7.87 (m, 1H), 7.76 (d, 1H), 7.61 - 7.53 (m, 2H), 7.24 (m, 1H), 7.09 (d, 1H), 4.54 (m, 2H), 4.43 (m, 2H), 4.27 - 4.08 (m, 2H), 3.88 - 3.81 (m, 1H), 3.72 - 3.64 (m, 1H), 3.45 (m, 1H), 3.27 - 3.11 (m, 2H), 2.33 - 2.25 (m, 2H), 2.14 - 2.08 (m, 1H), 1.99 (br. s, 2H), 1.75 (br. s, 2H), 1.41 (br. s, 2H);LC / MS:M+H=517.3.

[0255] Example 20: (R,E)-1 7 -(2,4-dimethylpiperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0256] [ka]

[0257] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid and (R)-1,3-dimethylpiperazine according to general procedure A.

[0258] 1 H NMR (DMSO-d6) δ:12.69 (s, 1H), 8.96 (s, 1H), 8.11 (d, 1H), 7.88 - 7.82 (m, 1H), 7.75 (d, 1H), 7.60 - 7.51 (m, 2H), 7.23 (m, 1H), 7.13 - 6.95 (m, 1H);LC / MS:M+H=489.3.

[0259] Example 21: (S,E)-1 7 -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0260] [ka]

[0261] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7Prepared according to general procedure A starting from -carboxylic acid and (3S)-(-)-3-(dimethylamino)pyrrolidine.

[0262] 1 H NMR (DMSO-d6) δ 12.41 (s, 1H), 8.98 (s, 1H), 8.11 (d, 1H), 7.86 (m, 1H), 7.76 (d, 1H), 7.61 - 7.52 (m, 2H), 7.24 (m, 1H), 7.15 (m, 1H), 4.18 (s, 2H), 3.85 - 3.70 (m, 1H), 2.78 - 2.64 (m, 1H), 2.19 (s, 3H), 2.05 (s, 3H), 1.99 (s, 2H), 1.83 - 1.75 (m, 1H), 1.73 (s, 2H), 1.41 (s, 2H);LC / MS: M+H=489.3.

[0263] Example 22: (E)-1 7 -((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0264] [ka]

[0265] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid and (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane according to general procedure A.

[0266] 1 H NMR (DMSO-d6) δ 12.42 (s, 1H), 8.97 (s, 1H), 8.11 (d, 1H), 7.89 - 7.83 (m, 1H), 7.75 (d, 1H), 7.61 - 7.53 (m, 2H), 7.29 - 7.19 (m, 1H), 7.15 (d, 1H);LC / MS:M+H=487.2.

[0267] Example 23: (R,E)-1 7 -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0268] [ka]

[0269] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 Prepared according to general procedure A starting from -carboxylic acid and (3R)-(-)-3-(dimethylamino)pyrrolidine.

[0270] 1 H NMR (DMSO-d6) δ 8.97 (s, 1H), 8.11 (d, 1H), 7.88 (m, 1H), 7.75 (d, 1H), 7.61 - 7.53 (m, 2H), 7.24 (m, 1H), 7.15 (m, 1H), 4.17 (s, 2H), 3.84 - 3.70 (m, 1H), 2.19 (s, 3H), 2.05 (s, 3H), 1.73 (s, 2H), 1.41 (s, 2H);LC / MS:M+H=489.3.

[0271] Example 24: (S,E)-1 7 -(2,4-dimethylpiperazine-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0272] [ka]

[0273] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid and (S)-1,3-dimethyl-piperazine according to general procedure A.

[0274] 1 H NMR (DMSO-d6) δ 12.77 (s, 1H), 9.76 (s, 1H), 8.98 (d, 1H), 8.11 (d, 1H), 7.88 (m, 1H), 7.77 (d, 1H), 7.63 - 7.55 (m, 2H), 7.32 - 7.04 (m, 2H); LC / MS:M+H=489.3.

[0275] Example 25: (E)-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0276] [ka]

[0277] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid and (1R,4R)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane according to general procedure A.

[0278] 1 H NMR (DMSO-d6) δ 12.76 (s, 1H), 8.98 (s, 1H), 8.12 (d, 1H), 7.87 (m, 1H), 7.77 (d, 1H), 7.60 (m, 2H), 7.33 - 7.16 (m, 2H), 1.99 (s, 2H), 1.77 (s, 2H), 1.43 (s, 2H);LC / MS:M+H=487.3.

[0279] Example 26: (E)-1 7 -(4-methyl-1,4-diazepane-1-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0280] [ka]

[0281] (E)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxylic acid and N-methylhomopiperazine according to general procedure A.

[0282] 1 H NMR (DMSO-d6) δ 12.75 (s, 1H), 9.70 - 9.42 (m, 1H), 8.98 (s, 1H), 8.11 (d, 1H), 7.92 - 7.84 (m, 1H), 7.77 (d, 1H), 7.62 - 7.55 (m, 2H), 7.31 - 7.20 (m, 2H);LC / MS:M+H=489.3.

[0283] Example 27: (E)-N,N-dimethyl-1 5 -((4-methylpiperazin-1-yl)methyl)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0284] [ka]

[0285] Step 1: Preparation of methyl 5-bromo-2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate A suspension of methyl 5-bromo-2-fluoro-3-nitrobenzoate (556 mg, 2.0 mmol), tert-butyl (5-aminopentyl)carbamate (809 mg, 4.0 mmol), and K2CO3 (829 mg, 6.0 mmol) in MeCN (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was added to EtOAc (20 mL), washed with aqueous NaOH (3 × 20 mL, 1 M), and the organic layer was dried and concentrated using a phase separator to give a yellow oil (1.08 g). The crude product was purified by flash chromatography on silica gel (Biotage, 0–30% EtOAc in petroleum ether, 10 columns) to give methyl 5-bromo-2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate as a yellow oil (884.9 mg, 95%).

[0286] LC / MS: M+H=462.1; Rt=5.85 min.

[0287] Step 2: Preparation of methyl 2-amino-5-bromo-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-7-carboxylate NHCl (511 mg, 9.55 mmol) was added to a solution of methyl 5-bromo-2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-nitrobenzoate (400 mg, 869 μmol) in 10:1 EtOH / water (22 mL) at room temperature, followed by Fe powder (256 mg, 4.58 mmol). The mixture was heated to reflux (80 °C) for 2 h. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated, added to EtOAc (20 mL), and washed with aqueous NaOH (3 × 20 mL, 1 M). The combined aqueous layers were back-extracted with EtOAc (20 mL). The combined organic layers were dried and concentrated. Purification (Biotage 12 g, 1-5% MeOH (28% aq) with 1% NH in CHCl) gave a brown oil (364 mg). This brown oil was dissolved in water (2.0 mL), MeCN (2.0 mL), and MeOH (6.0 mL), and CNBr (108 mg, 1.02 mmol) was added. The reaction mixture was stirred overnight and concentrated under reduced pressure. The residue was dissolved in acetonitrile and water (approximately 2 mL total) and purified by reverse-phase chromatography on a C18 flash cartridge (Biotage 12 g, 5–60% MeCN in water with 0.1% TFA) to give methyl 2-amino-5-bromo-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-7-carboxylate as a white solid (133.3 mg, 27%). LC / MS: M+H=455.1; Rt=4.4 min.

[0288] Step 3: Preparation of methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate A flask was charged with Pd(OAc)2, XPhos, Cs2CO3, and potassium trifluoro((4-methylpiperazin-1-yl)methyl)borate under N2 gas, and a solution of 2-amino-5-bromo-1-(5-((tert-butoxycarbonyl)amino)pentyl)-1H-benzo[d]imidazole-7-carboxylate (133 mg, 234 μmol) in 10:1 THF / water (2.0 mL) was added at room temperature. The solution was heated at 80 °C for 48 h. The reaction mixture was poured into brine (25 mL) and extracted with CHCl2 (4 × 15 mL). The organic layer was dried and concentrated to give a yellow oil (155.5 mg). The residue was dissolved in DMSO / water and purified by reverse-phase chromatography (C18 column, 10-45% MeCN in water with 0.1% TFA) to give methyl 2-amino-1-(5-(tert-butoxycarbonyl)) as a white solid (94.7 mg, 33%).

[0289] LC / MS: M+H=489.3; Rt=3.6 min.

[0290] Step 4: Preparation of 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid 5M NaOH (50 μL, 250 μmol) was added to a solution of methyl 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (47 mg, 78 μmol) in dioxane / water 1:1 (6 ml). The reaction mixture was stirred at room temperature for 24 hours, and 5M NaOH (50 μL, 250 μmol) was added. Stirring in the solvent mixture was continued at room temperature for 24 hours. The reaction was purified by reverse-phase chromatography (C18 column, preparative HPLC, 5-20% MeCN in water with 0.1% ammonia) to give 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid (13.6 mg, 36%).

[0291] LC / MS: M+H=474.0; Rt=2.1 min.

[0292] Step 5: Preparation of tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate HATU (12.6 mg, 33 μmol) was added to a suspension of 2-amino-1-(5-((tert-butoxycarbonyl)amino)pentyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid (13.6 mg, 28 μmol) and dimethylamine (138 μl, 277 μmol, 2 M in THF) in THF (10 ml) at room temperature. The reaction was stirred for 2 h and then purified by reverse-phase chromatography (C18 column, preparative HPLC, 10–45% MeCN in water with 0.1% TFA) to give tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate as a clear oil (25.7 mg, 99%).

[0293] LC / MS: M+H=502.3; Rt=3.4 min.

[0294] Step 6: Preparation of tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate 3-(tert-Butoxycarbonyl)benzoic acid (12 mg, 55 μmol), HATU (21 mg, 55 μmol), and N,N-diisopropylethylamine (14 μl, 83 μmol) were dissolved in THF (5 ml) and stirred for 10 minutes. A solution of tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate (17 mg, 27 μmol) in THF (3 ml) was stirred for 10 minutes. The resulting reaction mixture was stirred overnight. The product was purified by reverse-phase chromatography (C18 column, preparative HPLC, 10-50% MeCN in water with 0.1% TFA) to give tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate as a white solid (11.3 mg, 50%).

[0295] LC / MS: M+H=706.4; Rt=4.5 min.

[0296] Step 7: Preparation of 3-((1-(5-aminopentyl)-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid 5 M HCl (1.0 ml) was added to a solution of tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (11.3 mg, 13.8 μmol) in dioxane (1.0 ml). The solution was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The residue was dissolved in MeOH and concentrated to dryness from TFA. The product was used without further purification.

[0297] Step 8: (E)-N,N-Dimethyl-1 5-((4-methylpiperazin-1-yl)methyl)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxamides HATU (7.9 mg, 21 μmol) was added to a suspension of 3-((1-(5-aminopentyl)-7-(dimethylcarbamoyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (20 mg, 13 μmol) and N,N-diisopropylethylamine (14 μl, 83 μmol) in THF (28 ml). The solution was heated at 40° C. and stirred overnight. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in DMF (25 ml), and N,N-diisopropylethylamine (0.5 ml) was added. The reaction mixture was stirred at 40° C. for 2 hours and then concentrated to dryness. The residue was dissolved in DMSO and a small amount of water and purified by reverse phase chromatography (C18 column, preparative HPLC, 10-40% MeCN in water containing 0.1% TFA) to give (E)-N,N-dimethyl-1 5 -((4-methylpiperazin-1-yl)methyl)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (0.9 mg, 10%) was obtained.

[0298] 1H NMR (methanol-d4) δ: 9.13 (s, 1H), 8.22 (d, 1H), 7.84 (d, 1H), 7.61 (m, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.17 (d, 1H), 4.46 - 4.33 (m, 1H), 4.20 - 4.07 (m, 1H), 3.77 (s, 2H), 3.46 - 3.37 (m, 2H), 3.21 (s, 3H), 2.97 (s, 3H), 2.89 (s, 3H), 2.17 - 2.07 (m, 2H), 1.94 - 1.82 (m, 2H), 1.61 - 1.51 (m, 2H);LC / MS: M+H=532.3.

[0299] Example 28: (E)-1 7 -(2-Methoxypyridin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0300] [ka]

[0301] Step 1: Preparation of tert-butyl (5-((2-bromo-6-nitrophenyl)amino)pentyl)carbamate K2CO3 (2.83 g, 20.5 mmol) was added to a solution of 1-bromo-2-fluoro-3-nitrobenzene (1.50 g, 6.82 mmol) and N-boc-1,5-diaminopentane (1.66 g, 8.2 mmol) in MeCN (30 mL). The reaction mixture was stirred at 80 °C overnight. The solvent was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was washed with 0.1 M NaOH, 0.1 M HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated. The product, tert-butyl (5-((2-bromo-6-nitrophenyl)amino)pentyl)carbamate (2.74 g, 99%), was used without further purification.

[0302] 1 H NMR (DMSO-d6) δ:7.83 (m, 1H), 7.82 (m, 1H), 6.82 - 6.77 (m, 1H), 6.74 (m, 1H), 5.95 (m, 1H), 3.04 (m, 2H), 2.86 (m, 2H), 1.49 (m, 2H), 1.39 - 1.29 (m, 11H), 1.21 (m, 2H);LC / MS:M+H-tert-Bu=347.0.

[0303] Step 2: Preparation of tert-butyl (5-((2-(2-methoxypyridin-3-yl)-6-nitrophenyl)amino)pentyl)carbamate A microwave vial was charged with Pepsi-iPr (13 mg, 20 μmol), 2-methoxy-3-pyridineboronic acid (151 mg, 988 μmol), and KCO (273 mg, 1.98 mmol) and flushed with N. A solution of tert-butyl (5-((2-bromo-6-nitrophenyl)amino)pentyl)carbamate (265 mg, 659 μmol) in toluene (3.0 mL) and MeOH (1.0 mL) was added to the vial, which was then purged with N. The mixture was heated at 120° C. with stirring in a microwave for 40 minutes. The reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried and concentrated to give a yellow oil (350 mg). Purification by flash chromatography on silica gel (Biotage 25 g, 0-30% EtOAc in petroleum ether) gave tert-butyl (5-((2-bromo-6-nitrophenyl)amino)pentyl)carbamate as a yellow oil (265 mg, 93%).

[0304] 1H NMR (DMSO-d6) δ:8.24 (m, 1H), 8.05 (m, 1H), 7.67 (m, 1H), 7.46 (m, 1H), 7.32 (m,1H), 7.09 (m, 1H), 6.82 (m, 1H), 6.70 (m, 1H), 3.84 (s, 3H), 2.78 (m, 2H), 2.55 - 2.51 (m, 2H), 1.35 (s, 9H), 1.30 - 1.13(m, 4H), 0.96 (p, J=7.6, 7.0 Hz, 2H);LC / MS:M+H=431.2.

[0305] Step 3: Preparation of tert-butyl (5-(2-amino-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate To a solution of tert-butyl (5-((2-bromo-6-nitrophenyl)amino)pentyl)carbamate (265 mg, 616 μmol) in MeOH (40 mL) under N2, 10% Pd / C (32 mg, 31 μmol) was added and the mixture was hydrogenated at room temperature for 35 minutes. The mixture was evacuated and filtered through Celite with MeOH (10 mL). The tan solution was concentrated to give a residue (192 mg). The residue was dissolved in water (3.0 mL) and MeOH (15.0 mL) and cyanogen bromide (78 mg, 739 μmol) was added. The reaction mixture was stirred at room temperature overnight. The solution was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel (Biotage 12 g, 1-7% MeOH in CH2Cl2 with 1% NH3 (28% in water)) to give tert-butyl (5-(2-amino-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate as a red oil (172.1 mg, 65%).

[0306] 1H NMR (DMSO-d6) δ:8.29 (m, 1H), 7.74 (m, 1H), 7.27 (d, 1H), 7.16 - 7.03 (m, 2H), 6.78 (d, 1H), 6.67 (m, 1H), 4.09 (m, 1H), 3.80 (s, LC / MS:M+H=426.2.

[0307] Step 4: Preparation of tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate A solution of tert-butyl (5-(2-amino-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-1-yl)pentyl)carbamate (177 mg, 404 μmol) and N,N-diisopropylethylamine (105 μL, 0.6 mmol) in MeCN (5 mL) was added to a solution of HATU (231 mg, 607 μmol), 3-(tert-butoxycarbonyl)benzoic acid (135 mg, 607 μmol), and N,N-diisopropylethylamine (105 μL, 0.6 mmol) in MeCN (5 mL) at room temperature. The reaction mixture was stirred for 5 hours and then concentrated to dryness. Purification by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) afforded tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate as a clear oil (215 mg, 84%).

[0308] 1H NMR (DMSO-d6) δ:12.97 (s, 1H), 8.76 (s, 1H), 8.42 (d, 1H), 8.33 (d, 1H), 8.02(d, 1H), 7.84 (m, 1H), 7.65 -7.54 (m, 2H), 7.28 (m, 1H), 7.17 (m, 1H), 7.02 (d, 1H), 6.64 (m, 1H),4.06 - 3.96 (m, 1H), 3.82 (s, 3H), 3.63 - 3.49 (m, 1H), 2.74 (m, 2H), 1.56 (s, 9H), 1.34 (s, 9H), 1.30 - 1.01 (m, 4H), 0.93 - 0.65 (m, 2H);LC / MS:M+H=630.3.

[0309] Step 5: Preparation of 3-((1-(5-aminopentyl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid 5 M HCl (3 ml, 15 mmol) was added to a solution of tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (107 mg, 170 μmol) in dioxane (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated to dryness and used in the next step without purification.

[0310] LC / MS: M+H=474.2; Rt=4.0 min.

[0311] Step 6: (E)-1 7 -(2-Methoxypyridin-3-yl)-1 2 ,1 3 -dihydro-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione HATU (97 mg, 255 μmol) was added to a solution of 3-((1-(5-aminopentyl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (100 mg, 170 μmol) and N,N-diisopropylethylamine (147 μl, 851 μmmol) in DMF (350 ml). The solution was stirred overnight at room temperature and then concentrated to dryness. The residue was dissolved in DMSO and purified using reverse-phase chromatography (30-50% MeCN in water with 0.1% TFA) to give (E)-1. 7 -(2-Methoxypyridin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (14.9 mg, 19%) was obtained.

[0312] 1 H NMR (DMSO-d6) δ:12.69 (s, 1H), 8.89 (s, 1H), 8.33 (d, 1H), 8.10 (d, 1H), 7.85 - 7.77 (m, 2H), 7.73 (d, 1H), 7.60 - 7.52 (m, 2H), 7.25 (m, 1H), 7.16 (m, 1H), 6.99 (d, 1H), 3.94 - 3.84 (m, 1H), 3.80 (s, 3H), 3.60 - 3.52 (m, 1H), 3.20 - 3.08 (m, 2H), 1.93 - 1.66 (m, 2H), 1.47 - 1.27 (m, 2H), 1.16 - 1.02 (m, 2H);LC / MS:M+H=456.2. Examples 29 and 30: (E)-11-methyl-1 7 -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione Example Compound 29:

[0313] [ka]

[0314] Example Compound 30:

[0315] [ka]

[0316] Preparation of tert-butyl 3-((1-(5-((tert-butoxycarbonyl)amino)pentyl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate HATU (70 mg, 184 μmol) was dissolved in DMF (10 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a solution of 1R,4R)-carboxylic acid (62 mg, 153 μmol) and N,N-diisopropylethylamine was added at room temperature. The reaction mixture was stirred for 5 min, and then (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (42 mg, 230 μmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solution was concentrated (to approximately 4 mL), diluted with water (approximately 2 mL), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-35% MeCN in water with 0.1% TFA). Elution was performed over 20 min, then at the highest elution strength over 5 min. Fractions containing the product were collected and lyophilized to give a white solid (38.5 mg, 41%). The diastereomers were separated on an IA column using 2% EtOH with 0.1% diethylamine in CHCl. The first eluting peak (epimer 1) and the second eluting peak (epimer 2) were pooled and concentrated, then redissolved in MeCN, concentrated to a solid, and dried under vacuum overnight.

[0317] Example 29, Diastereomer 1: 12.0 mg, white solid.

[0318] 1 H NMR (DMSO-d6) δ:12.75 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 8.11 (d, 1H), 7.88 - 7.70 (m, 2H), 7.59 (m, 2H), 7.25 (m, 1H), 7.15 (d, 1H), 4.85 - 1.20 (m, 23H); LC / MS:M+H=501.3.

[0319] Example 30, Diastereomer 2: 11.2 mg, white solid.

[0320] 1 H NMR (DMSO-d6) δ:12.76 (s, 1H), 8.78 (s, 1H), 8.10 (m, 2H), 7.88 - 7.69 (m, 2H), 7.59 (m, 2H), 7.24 (m, 1H), 7.18 - 7.06 (m, 1H), 4.80 - 1.20 (m, 23H);LC / MS:M+H=501.3.

[0321] Using X-ray crystallography, the absolute stereochemistry of Example 30 was determined to be (S), which makes Example 29 (R).

[0322] Examples 31 and 32: (E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0323] [ka]

[0324] Step 1: Preparation of methyl 2-((6-((tert-butoxycarbonyl)amino)hexan-2-yl)amino)-3-nitrobenzoate A solution of methyl 2-fluoro-3-nitrobenzoate (1.00 g, 5.02 mmol), tert-butyl N-(5-aminohexyl)carbamate (1.09 g, 5.02 mmol), and N,N-diisopropylethylamine (2.78 mL, 15.1 mmol) in DMF (10 mL) was heated at 80° C. for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase was dried (NaSO) and concentrated in vacuo. The crude residue was used in the next step without further purification.

[0325] 1 H NMR (DMSO-d6) δ:8.05 (d, 1H)m 8.03 (d, 1H), 6.83 (m, 1H), 6.74 (m, 1H), 3.86 (s, 3H), 3.15 (m, 1H), 2.87 (m, 2H), 1.45 (m, 2H), 1.05 d, 3H);LC / MS:M+H=396.16.

[0326] Step 2: Preparation of 2-((6-((tert-butoxycarbonyl)amino)hexan-2-yl)amino)-3-nitrobenzoic acid A solution of methyl 2-((6-((tert-butoxycarbonyl)amino)hexan-2-yl)amino)-3-nitrobenzoate (2.0 g, 4.05 mmol) and LiOH hydrate (849 mcg, 20.2 mmol) in THF (15 ml) and water (2.0 ml) was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with water (15 ml), cooled to 0° C., and acidified (pH-4) with 1N HCl. The precipitate was collected by filtration, washed with cold water, and dried in vacuo to give 2-((6-((tert-butoxycarbonyl)amino)hexan-2-yl)amino)-3-nitrobenzoic acid (1.50 g, 50% yield) as a white solid.

[0327] LC / MS: M+H=382.17, Rt=1.88 min.

[0328] Step 3: Preparation of tert-butyl (5-((2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate To a stirred solution of 2-((6-((tert-butoxycarbonyl)amino)hexan-2-yl)amino)-3-nitrobenzoic acid (1.50 g, 3.74 mmol) in DMF (10 ml) were added N,N-diisopropylethylamine (3.97 ml, 22.4 mmol) and HATU (2.84 g, 7.47 mmol) at 0° C. and stirred at room temperature for 3 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give tert-butyl (5-((2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate as a yellow solid (1.90 g, 88%).

[0329] 1 H NMR (DMSO-d6) δ:8.10 (d, 1H), 7.95 (s, 1H), 7.52 (d, 1H), 7.38 (d, 1H), 6.82 (m, 1H), 6.74 (m, 1H), 3.46 (m, 1H), 2.93 (s, 3H), 2.77 (s, 3H), 1.43 (m, 1H), 1.35 (s, 9H), 1.08 (d, 3H); LC / MS:M+H=409.22.

[0330] Step 4: Preparation of tert-butyl (5-((2-amino-6-(dimethylcarbamoyl)phenyl)amino)hexyl)carbamate To a stirred solution of tert-butyl (5-((2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate (1.90 g, 3.30 mmol) in methanol (30.0 mL) was added 10% Pd / C (211 mg, 1.98 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was filtered through Celite, washed with EtOAc, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 50% EtOAc / heptane) to give tert-butyl (5-((2-amino-6-(dimethylcarbamoyl)phenyl)amino)hexyl)carbamate (1.20 g, 87%) as a colorless liquid.

[0331] 1 H NMR (DMSO-d6) δ:6.77 (m, 1H), 6.68 (m, 2H), 4.70 (s, 1H), 3.66 (d, 1H), 3.06 (m, 1H), 2.94 (s, 3H), 2.89 (s, 3H), 0.88 (d, 3H);LC / MS:M+H=379.22.

[0332] Step 5: Preparation of tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To a stirred solution of tert-butyl (5-((2-amino-6-(dimethylcarbamoyl)phenyl)amino)hexyl)carbamate (1.0 g, 2.40 mmol) in methanol (10.0 mL), acetonitrile (5.00 mL), and water (5.00 mL), cyanogen bromide (280 mg, 2.64 mmol) was added and stirred at 55° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, quenched with ice-cold water, and extracted with EtOAc. The organic layer was washed with brine solution, dried over NaSO, and concentrated under reduced pressure to give tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (850 mg, 84%) as a brown solid.

[0333] 1 H NMR (DMSO-d6) δ:7.13 (d, 1H), 6.95 (m, 1H), 6.71 (m, 1H), 6.64 (d, 1H), 6.18 (s, 1H), 4.23 (m, 1H), 3.04 (s, 3H), 1.87-1.72 (m, 2H), 0.91 (m, 1H);LC / MS:M+H=404.25.

[0334] Step 6: Preparation of methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (850 mg, 2.02 mmol), 1-methyl-1H-imidazole (830 mg, 10.1 mmol), and (methoxycarbonyl)benzoic acid (546 mg, 3.03 mmol) in MeCN (10.0 mL) was added TCFH (1.42 g, 5.06 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine solution, dried over NaSO, and concentrated under reduced pressure to give a crude residue. The crude product was purified by column chromatography (silica gel, 70% EtOAc / heptane) to give methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (980 mg, 75%) as an off-white solid.

[0335] 1H NMR (DMSO-d6) δ:8.80 (s, 1H), 8.42 (d, 1H), 8.09 (d, 1H), 7.63 (m, 2H), 7.26 (m, 1H), 7.08 (m, 1H), 6.70 (m, 1H), 4.31 (m, 1H), 3.90 (s, 3H), 3.10 (s, 3H), 2.69 (s, 3H), 1.65 (m, 2H), 1.02 (m, 1H);LC / MS:M+H=566.23.

[0336] Step 7: Preparation of 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a stirred solution of methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (980 mg, 1.52 mmol) in THF (10.0 ml) and water (2.00 mL) was added potassium hydroxide (171 mg, 3.05 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The pH of the reaction mixture was adjusted to approximately 5 by adding 2 M HCl. The precipitate was collected by filtration to give 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (810 mg, 79%) as an off-white solid.

[0337] 1 H NMR (DMSO-d6) δ:8.78 (s, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.63 (m, 2H), 7.25 (m, 1H), 7.07 (m, 1H), 6.68 (m, 1H), 4.30 (m, 1H), 3.09 (s, 3H), 2.68 (s, 3H), 1.98 (m, 1H), 1.65 (m, 2H), 1.00 (m, 1H);LC / MS:M+H=552.34.

[0338] Step 8: Preparation of 3-((1-(6-aminohexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a stirred solution of 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (600 mg, 957 μmol) in CHCl (10.0 mL) was added 4 M HCl (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo to give 3-((1-(6-aminohexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (450 mg, 99%), which was used in the next step without further purification.

[0339] 1 H NMR (DMSO-d6) δ:879 (s, 1H), 8.40 (d, 1H), 8.09 (d, 1H), 7.79 (m, 2H), 7.65 (m, 2H), 7.27 (m, 1H), 7.06 (m, 1H), 3.10 (s, 3H), 2.00 (m, 1H), 1.50 (m, 2H); LC / MS:MH=450.22.

[0340] Step 9: N,N,11-trimethyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxamides To a stirred solution of 3-((1-(6-aminohexan-2-yl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (400 mg, 850 μmol) in MeCN (500 mL) and DMF (30.0 mL) was added TCFH (597 mg, 2.13 mmol). The resulting solution was added to a solution of 1-methyl-1H-imidazole (339 μL, 4.25 mmol) in MeCN (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified using preparative HPLC to give racemic N,N,11-trimethyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (43 mg, 12%). The enantiomers were separated using chiral chromatography.

[0341] Example 31, Enantiomer 1: 1 H NMR (DMSO-d6) δ:8.75 (m, 1H), 8.10 (d, 1H), 7.68 (m, 2H), 7.53 (m, 2H), 7.13 (bs, 1H), 6.91 (bs, 1H), 3.06 (s, 3H), 2.84 (s, 3H);LC / MS:M+H=434.19.

[0342] Chiralpak-IG (4.6 × 250 mm), 5 μ, 0.1% TEA in n-hexane:EtOH=(20:80) (v / v), flow rate: 1 ml / min, Rt=21.96 min.

[0343] Example 32, Enantiomer 2: 1H NMR (DMSO-d6) (T=353 K) δ:8.84 (bs, 1H), 8.07 (d, 1H,), 7.62 (d, 1H), 7.48 (m, 2H), 7.36 (m, 1H), 7.02 (m, 1H), 6.77 (d, 1H), 3.50 (m, 1H), 2.84 (s, 3H), 1.75 (m, 2H), 1.55 (m, 3H);LC / MS:M+H=434.45.

[0344] Chiralpak-IG (4.6 × 250), 5 μ, 0.1% TEA in n-hexane / EtOH = 20:80 (v / v), flow rate: 1 ml / min, Rt = 29.40 min.

[0345] (S,E)-11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 An independent synthesis starting from -carboxylic acid and dimethylamine confirmed the absolute stereochemistry of Example 32 to be (S).

[0346] Example 33: (E)-3-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)pyridine 1-oxide

[0347] [ka]

[0348] Step 1: Preparation of tert-butyl (5-((2-bromo-6-nitrophenyl)amino)hexyl)carbamate A mixture of 1-bromo-2-fluoro-3-nitrobenzene (1.0 g, 4.55 mmol), tert-butyl (5-aminohexyl)carbamate (1.03 g, 4.77 mmol), and K2CO3 (1.26 g, 9.09 mmol) in MeCN (30 mL) was stirred at room temperature for 2 days, filtered through Celite, and the filtrate was evaporated to dryness. tert-Butyl (5-((2-bromo-6-nitrophenyl)amino)hexyl)carbamate was used without further purification.

[0349] Step 2: Preparation of tert-butyl (5-(2-amino-7-bromo-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To SnCl2 (3.19 g, 16.8 mmol) was added a solution of tert-butyl (5-((2-bromo-6-nitrophenyl)amino)hexyl)carbamate (1.40 g, 3.36 mmol) in EtOH (35 mL) under Ar. The reaction mixture was heated to 80 °C in a sealed vial and stirred for 40 min. The mixture was cooled and evaporated to dryness. The residue was dissolved in EtOAc (50 mL), 2.5 M NaOH (50 mL) was added, and the mixture was stirred under argon for 5 min. Celite was added, and the mixture was filtered through a plug of Celite. The filtrate was evaporated to dryness. The residue was dissolved in MeOH (25 mL) and water (5 mL), and cyanogen bromide (427 mg, 4.04 mmol) was added. The reaction mixture was stirred overnight at room temperature under N2. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (Biotage 12 g, 50-100% EtOAc in petroleum ether). The crude product (712 mg) was used without further purification.

[0350] Step 3: Preparation of tert-butyl (5-(2-amino-7-(pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To Pd(PPh3)4 (13 mg, 11 μmol) in a vial was added a degassed solution of tert-butyl (5-(2-amino-7-bromo-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (45 mg, 109 μmol) and 3-(tributylstannyl)pyridine (54 mg, 148 μmol). The vial was sealed and heated at 120 °C for 36 h. The reaction mixture was purified using preparative HPLC (10-30% MeCN / HO with 0.1% TFA). The fractions were concentrated, dissolved in CHCl2, and washed with saturated NaHCO3 to give tert-butyl (5-(2-amino-7-(pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (17 mg, 38%).

[0351] 1 H NMR (DMSO-d6) δ:8.73 - 8.69 (m, 2H), 8.69 (m, 1H), 7.77 (m, 1H), 7.48 (d, 1H), 7.42 (m, 1H), 7.18 (m, 1H), 6.85 (d, 1H), 4.70 (s, 2H), 3.97 (m, 1H),2.98 (m, 6.3 Hz, 2H), 1.94 - 1.80 (m, 1H), 1.60 (d, 1H), 1.45 (s, 9H), 1.36 - 1.22(m, 5H), 1.01 (s, 1H), 0.90 - 0.75 (m, 1H).

[0352] Step 4: Preparation of tert-butyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate N,N-Diisopropylethylamine (59 μL, 342 μmol) was added to a solution of HATU (71 mg, 188 μmol) and 3-(tert-butoxycarbonyl)benzoic acid (42 mg, 188 μmol) in MeCN (0.5 mL). The solution was stirred for 5 minutes, and a solution of tert-butyl (5-(2-amino-7-(pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (70 mg, 171 μmol) in MeCN (2.0 mL) was added. The resulting solution was stirred for 2 hours. The reaction was purified by reverse-phase chromatography (C18 column, preparative HPLC, 5-20% MeCN in water with 0.1% NH3) to give tert-butyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate as a white solid (70 mg, 67%).

[0353] 1 H NMR (DMSO-d6) δ:12.86 (s, 1H), 8.90 (s, 1H), 8.73 (d, 2H), 8.42 (d, 1H), 8.13 (d, 1H), 7.77 (d, 1H), 7.51 (m, 2H), 7.38 (d, 1H), 7.30 (d, 1H), 7.06 (s, 1H), 3.91 (s, 1H), 2.96 (s, 2H), 2.50 (s, 1H), 1.62 (s, 9H), 1.33 (d, 9H);LC / MS:M+H=614.3.

[0354] Step 5: Preparation of 3-(1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazol-7-yl)pyridine 1-oxide mCPBA was added to a solution of tert-butyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (70 mg, 114 μmol) in CHCl (4.0 ml) under air at room temperature. The reaction mixture was stirred overnight. The reaction mixture was extracted with NaHCO (saturated aqueous solution), dried, and concentrated. 3-(1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazol-7-yl)pyridine 1-oxide (77 mg) was used without further purification.

[0355] 1 H NMR (DMSO-d6) δ:12.91 (s, 1H), 8.91 (s, 1H), 8.43 (d, 1H), 8.36 (d, 2H), 8.16 (d, 1H), 7.53 (m, 1H), 7.47 - 7.40 (m, 2H), 7.36 (d, 1H), 7.31 (, 1H), 7.08 - 7.01 (m, 1H), 3.99 (s, 1H), 3.00 (s, 2H), 2.62 - 2.29 (m, 1H), 2.07 (s, 1H), 1.64 (s, 9H), 1.42 (d, 11H), 1.14 (s, 1H), 0.98 (s, 1H).

[0356] Step 6: Preparation of 3-(1-(6-aminohexan-2-yl)-2-(3-carboxybenzamido)-1H-benzo[d]imidazol-7-yl)pyridine 1-oxide 3-(1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-2-(3-(tert-butoxycarbonyl)benzamido)-1H-benzo[d]imidazol-7-yl)pyridine 1-oxide (72 mg, 114 μmol) was dissolved in dioxane (2.0 ml) and 5 M aqueous HCl (2.0 ml) was added. The reaction mixture was stirred at room temperature for 70 hours. The reaction was concentrated under reduced pressure and the residue was dissolved in MeCN and evaporated to dryness. The product was used without further purification.

[0357] Step 7: 3-(11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 Preparation of (-yl)pyridine 1-oxide HATU (65 mg, 171 μmol) and N,N-diisopropylethylamine (98 μl, 569 μmol) were added to a solution of 3-(1-(6-aminohexan-2-yl)-2-(3-carboxybenzamido)-1H-benzo[d]imidazol-7-yl)pyridine 1-oxide in THF (250 ml). The reaction mixture was stirred at room temperature overnight, and HATU (40 mg, 171 μmol) and N,N-diisopropylethylamine (98 μl, 569 μmol) were added. The reaction mixture was refluxed overnight, cooled to room temperature, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase chromatography (C18 column, preparative HPLC, 5-20% MeCN in water with 0.1% NH3) to give 3-(11-methyl-3,5-dioxo-1-methylpyridine). 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)pyridine 1-oxide was obtained as a white powder (3.5 mg, 7%).

[0358] 1H NMR (DMSO-d6) δ:8.72 (s, 1H), 8.46 (d, 1H), 8.36 (d, 1H), 8.12 (d, 1H), 7.75 (d, 2H), 7.61 (m, 2H), 7.51 (d, 2H), 7.28 (m, 1H), 7.09 (d, 1H), 4.10 (s, 1H), 3.57 (s, 1H), 2.96 (s, 2H), 1.88 (d, 1H), 1.71 (s, 1H), 1.52 (s, 4H), 1.43 - 1.15 (m, 3H);LC / MS:M+H=456.2.

[0359] Example 34: (E)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0360] [ka]

[0361] N,11-dimethyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxamides HATU (12 mg, 32 μmol) was dissolved in DMF (1.0 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7To a solution of N,N-diisopropylethylamine (12 mg, 29 μmol), N,N-diisopropylethylamine (15 μl, 88 μmol), and 2 M methylamine in THF (44 μl, 88 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 40 min, diluted with water (1 ml), and purified by reverse-phase chromatography (18 column, 5-40% MeCN in water with 0.1% TFA) to give N,11-dimethyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide as a white solid (4.8 mg, 39%).

[0362] 1 H NMR (DMSO-d6) δ:12.77 (s, 1H), 8.81 (s, 1H), 8.75 - 8.68 (m, 1H), 8.11 (d, 1H), 7.83 (s, 1H), 7.75 (d, 1H), 7.64 - 7.54 (m, 2H), 7.22 (m, 1H), 7.16 (d, 1H), 4.83 (s, 1H), 3.05 (s, 2H), 2.81 (d, 3H), 1.98 - 1.35 (m, 9H);LC / MS:M+H=420.0.

[0363] Examples 35 and 36: (E)-11-methyl-1 7 -(2-oxo-1,2-dihydropyridin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0364] [ka]

[0365] Step 1: Preparation of 3-(2-fluoro-3-nitrophenyl)-2-methoxypyridine A solution of 1-bromo-2-fluoro-3-nitrobenzene (2.00 g, 9.09 mmol), (2-methoxypyridin-3-yl)boronic acid (4.17 g, 27.3 mmol), and tripotassium phosphate (5.79 g, 27.3 mmol) in 1,4-dioxane (10.0 mL) and water (1.00 mL) was purged with N for 10 minutes. Tetrakis(triphenylphosphane)palladium (1.05 g, 909 μmol) was added to the reaction mixture, and the reaction mixture was heated at 130 °C for 2 hours. The reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc, dried (NaSO), and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 0–15% EtOAc in hexanes) to give 3-(2-fluoro-3-nitrophenyl)-2-methoxypyridine (2.40 g, 79%) as a white solid.

[0366] 1 H NMR (DMSO-d6) δ:8.31 (m, 1H), 8.19 (m, 1H), 7.83 (m, 1H), 7.80 (m, 1H), 7.52 (m, 1H), 7.16 (m, 1H), 3.87 (s, 3H);LC / MS:M+H=249.05.

[0367] Step 2: Preparation of tert-butyl (5-((2-(2-methoxypyridin-3-yl)-6-nitrophenyl)amino)hexyl)carbamate A solution of 3-(2-fluoro-3-nitrophenyl)-2-methoxypyridine (2.00 g, 8.06 mmol), tert-butyl N-(5-aminohexyl)carbamate (1.74 g, 8.06 mmol), and N,N-diisopropylethylamine (4.46 mL, 24.2 mmol) in DMF (2.0 mL) was heated at 90° C. for 16 h, and the reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc, dried (NaSO), and concentrated in vacuo. The crude product was used without further purification.

[0368] LC / MS: M+H=445.08.

[0369] Step 3: Preparation of tert-butyl (5-((2-amino-6-(2-methoxypyridin-3-yl)phenyl)amino)hexyl)carbamate A solution of tert-butyl (5-((2-(2-methoxypyridin-3-yl)-6-nitrophenyl)amino)hexyl)carbamate (3.00 g, 4.32 mmol) and 10% Pd / C (palladium (2.00 g, 1.88 mmol)) in MeOH (60 ml) was stirred under H (1 atm) at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give tert-butyl (5-((2-amino-6-(2-methoxypyridin-3-yl)phenyl)amino)hexyl)carbamate (2.30 g) as an off-white solid, which was used without further purification.

[0370] 1 H NMR (DMSO-d6) δ:8.17 (m, 1H), 7.95 (s, 1H), 7.55 (m, 1H), 6.75 (m, 1H), 6.65 (m, 1H), 6.33 (m, 1H), 3.83 (s, 3H), 3.17 (m, 1H), 2.73 (m, 1H), 1.37 (m, 9H); LC / MS:M+H=415.33.

[0371] Step 4: Preparation of tert-butyl (5-(2-amino-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To a stirred solution of tert-butyl (5-((2-amino-6-(2-methoxypyridin-3-yl)phenyl)amino)hexyl)carbamate (2.30 g, 4.27 mmol) in methanol (10.0 ml), MeCN (5.0 ml), and water (5.0 ml) was added cyanogen bromide. The reaction mixture was stirred at 50° C. for 8 hours. After completion, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to give a crude residue. The crude product was used without further purification.

[0372] 1H NMR (DMSO-d6) δ:8.23 (m, 1H), 7.66 (m, 1H), 7.12 (m, 2H), 6.94 (m, 1H), 6.63 (d, 1H), 3.91 (s, 3H), 2.69 (m, 1H), 1.34 (s, 9H);LC / MS:M+H=440.18.

[0373] Step 5: Preparation of methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of tert-butyl (5-(2-amino-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate, (methoxycarbonyl)benzoic acid (822 mg, 4.56 mmol), and 1-methyl-1H-imidazole (1.52 mL, 19.0 mmol) in MeCN (60 mL) was added TCFH (2.13 g, 7.61 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc, dried (NaSO), and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 5% to 80% EtOAc in hexanes) to give methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (2.20 g, 88%) as a solid.

[0374] 1 H NMR (DMSO-d6) δ:8.78 (s, 1H), 8.41 (d, 1H), 8.33 (m, 1H), 8.08 (d, 1H), 7.79 (m, 1H), 7.64 (m, 2H), 7.26 (m, 1H), 7.18 (m, 1H), 6.97 (d, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 1.58 (d, 2H), 1.31 (s, 9H);LC / MS:M+H=602.11.

[0375] Step 6: Preparation of methyl 3-((1-(6-aminohexan-2-yl)-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (1.30 g, 1.86 mmol) and sodium iodide (557 mg, 3.72 mmol) in MeCN (50 ml) was added chlorotrimethylsilane (475 μL, 3.72 mmol) in portions at room temperature and the reaction mixture was heated at 55° C. for 16 h. After completion, the reaction mixture was quenched with saturated aqueous NaHCO solution. The aqueous layer was extracted with 10% MeOH in CH2Cl2, dried (Na2SO4), and concentrated in vacuo to give methyl 3-((1-(6-aminohexan-2-yl)-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (1.10 g, 92%) as a solid.

[0376] 1 H NMR (DMSO-d6) δ:8.80 (s, 1H), 8.41 (d, 1H), 8.08 (d, 1H), 7.58 (m, 4H), 7.25 (m, 1H), 6.96 (d, 1H), 6.35 (m, 1H), 4.35 (m, 1H), 3.89 (s, 3H), 1.44 (m, 1H), 1.15 (m, 1H); LC / MS:M+H=488.37.

[0377] Step 7: Preparation of 3-((1-(6-aminohexan-2-yl)-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid A solution of methyl 3-((1-(6-aminohexan-2-yl)-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (1.10 g, 1.80 mmol) and sodium hydroxide (217 mg, 3 equiv., 5.41 mmol) in methanol (15.0 mL) and water (2.00 mL) was heated at 65° C. for 8 hours. The reaction mixture was concentrated in vacuo. The crude residue was triturated with 1 N aqueous HCl. The precipitate was filtered, washed with cold water, and dried in vacuo to give 3-((1-(6-aminohexan-2-yl)-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (1.0 g, 83%) as an off-white solid.

[0378] 1 H NMR (DMSO-d6) δ:8.77 (m, 1H), 8.32 (m, 1H), 8.06 (m, 1H), 7.56 (m, 4H), 7.22 (m, 1H), 6.92 (d, 1H), 6.36 (m, 1H), 4.31 (m, 1H), 2.56 (m, 1H), 1.68 )m, 2H), 1.53 (m, 1H); LC / MS:M+H=474.29.

[0379] Step 8: 11-methyl-1 7 -(2-oxo-1,2-dihydropyridin-3-yl)-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione To a stirred solution of 3-((1-(6-aminohexan-2-yl)-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (200 mg, 359 μmol) and 1-methyl-1H-imidazole (146 μL, 1.80 mmol) in DMF (100 mL) was added TCFH (201 mg, 718 μmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with 5% MeOH in CHCl. ​​The residue was purified by preparative HPLC to give racemic 11-methyl-1H-imidazole. 7 -(2-oxo-1,2-dihydropyridin-3-yl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (35 mg, 21%) was obtained as a white solid. The optical isomers were separated by chiral chromatography.

[0380] Example 35, Enantiomer 1: 1 H NMR (DMSO-d6) δ:8.72 (s, 1H), 8.10 (m, 1H), 7.73 (m, 2H), 7.58 (m, 4H), 7.20 (m, 1H), 6.93 (m, 1H), 6.34 (m, 1H), 1.75 (m, 3H);LC / MS:M+H=456.36.

[0381] Chiralpak-IF (4.6×250) 5 μm, ethyl acetate / IPA=40:60 (v / v), flow rate: 1 ml / min, Rt=7.30.

[0382] Example 36, Enantiomer 2: 1 H NMR (DMSO-d6) δ:8.72 (s, 1H), 8.11 (m, 1H), 7.73 (m, 2H), 7.58 (m, 4H), 7.20 (m, 1H), 6.94 (m, 1H), 6.34 (m, 1H), 1.75 (m, 3H);LC / MS:M+H=456.38.

[0383] Chiralpak-IF (4.6×250) 5 μm, ethyl acetate / IPA=40:60 (v / v), flow rate: 1 ml / min, Rt=6.22.

[0384] Example 37: (E)-1 7 -(3,3-difluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0385] [ka]

[0386] HATU (11 mg, 30 μmol) was dissolved in DMF (1.0 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a solution of N,N-diisopropylethylamine (11 mg, 27 μmol), N,N-diisopropylethylamine (28 μl, 165 μmol), and 3,3-difluoropyrrolidine (12 mg, 83 μmol) was added at room temperature. The reaction mixture was stirred overnight at room temperature, diluted with water (1.0 mL), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-60% MeCN in water with 0.1% TFA) to give (E)-1. 7 -(3,3-difluoropyrrolidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione was obtained as a white solid (9.7 mg, 71%).

[0387] 1H NMR (DMSO-d6) δ:12.79 (s, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.83 (s, 1H), 7.75 (d, 1H), 7.59 (m, 2H), 7.34 - 7.22 (m, 1H), 7.17 (d, 1H), 4.69 - 1.14 (m, 18H); LC / MS:M+H=496.0.

[0388] Example 38: (E)-N-methyl-N-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 (-carbonyl)glycinic acid methyl ester

[0389] [ka]

[0390] HATU (11 mg, 29 μmol) was dissolved in DMF (1.0 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a solution of (E)-N-methyl-N-(11-methyl-3,5-dioxo-12,13-dihydro- ... 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 Methyl (-carbonyl)glycinate was obtained as a white solid (7.9 mg, 61%).

[0391] 1 H NMR (DMSO-d6) δ:12.75 (s, 1H), 8.78 (s, 1H), 8.11 (d, 1H), 7.75 (d, 2H), 7.66 - 7.52 (m, 2H), 7.33 - 7.16 (m, 1H), 7.12 - 6.92 (m, 1H), 4.82 - 2.65 (m, 11H), 2.07 - 1.13 (m, 9H);LC / MS:M+H=492.0.

[0392] Example 39: (E)-N-cyclobutyl-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0393] [ka]

[0394] N,N-Diisopropylethylamine (28 μl, 160 μmol) was dissolved in DMF (0.25 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a solution of (E)-N-cyclobutyl-N,11-dimethyl-3,5-dioxo-1-methyl-1H-pyridin-1-one (10 mg, 25 μmol) and HATU (10 mg, 27 μmol) was added at room temperature. After stirring the solution for 2 minutes, N-methylcyclobutanamine (6 mg, 49 μmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with water (1.0 mL), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-60% MeCN in water with 0.1% TFA) to give (E)-N-cyclobutyl-N,11-dimethyl-3,5-dioxo-1-methyl-1H-pyridin-1-one (10 mg, 25 μmol). 2 ,1 3 -dihydro-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (7.4 mg, 64%) was obtained.

[0395] 1 H NMR (DMSO-d6) δ:12.76 (s, 1H), 8.78 (s, 1H), 8.12 (d, 1H), 7.76 (d, 2H), 7.59 (m, 2H), 7.25 (m, 1H), 7.00 (m, 1H), 5.74 - 3.94 LC / MS:M+H=474.3.

[0396] Example 40: (E)-1 7 -(3,3-difluoroazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0397] [ka]

[0398] N,N-Diisopropylethylamine (21 μl, 123 μmol) was dissolved in DMF (0.25 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7To a solution of 1,3-difluoroazetidine (10 mg, 25 μmol) and HATU (10 mg, 27 μmol) was added at room temperature. The solution was stirred for 2 minutes, and then 3,3-difluoroazetidine (6 mg, 49 μmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with water (1.0 mL), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-60% MeCN in water with 0.1% TFA) to give (E)-1. 7 -(3,3-difluoroazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione was obtained as a white powder (8 mg, 67%).

[0399] 1 H NMR (DMSO-d6) δ:12.81 (s, 1H), 8.84 (s, 1H), 8.11 (d, 1H), 7.84 (s, 1H), 7.76 (d, 1H), 7.61 (m, 2H), 7.26 (d, 2H), 4.54 (m, 4H), 3.11 (s, 3H), 1.91 (s, 4H), 1.60 (s, 3H), 1.43 (s, 2H); LC / MS:M+H=482.2.

[0400] Example 41: (E)-N-(3-hydroxycyclobutyl)-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0401] [ka]

[0402] N,N-Diisopropylethylamine (21 μl, 123 μmol) was dissolved in DMF (0.25 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a solution of (E)-N-(3-hydroxycyclobutyl)-N,11-dimethyl-3,5-dioxo-12,13-dihydro-1-methylaminocyclobutan-1-ol (10 mg, 25 μmol) and HATU (10 mg, 27 μmol) was added at room temperature. After stirring the solution for 2 minutes, 3-(methylamino)cyclobutan-1-ol (6 mg, 49 μmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with water (1.0 mL), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-60% MeCN in water with 0.1% TFA) to give (E)-N-(3-hydroxycyclobutyl)-N,11-dimethyl-3,5-dioxo-12,13-dihydro-1-methylaminocyclobutan-1-ol (10 mg, 25 μmol). 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide was obtained as a white powder (8 mg, 65%).

[0403] 1 H NMR (DMSO-d6) δ:12.76 (s, 1H), 8.78 (s, 1H), 8.12 (d1H), 7.76 (d, 2H), 7.58 (m, 2H), 7.24 (m, 1H), 6.99 (m, 1H), 5.68 - 4.06 (m, LC / MS:M+H=490.3.

[0404] Example 42: (E)-11-methyl-1 7 -(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0405] [ka]

[0406] N,N-Diisopropylethylamine (21 μl, 123 μmol) was dissolved in DMF (0.25 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 A solution of (E)-11-methyl-1-(2-oxa-6-azaspiro[3.3]heptane oxalate (9 mg, 49 μmol) was added to the resulting solution at room temperature. The solution was stirred for 10 min before the addition of 2-oxa-6-azaspiro[3.3]heptane oxalate (9 mg, 49 μmol). The reaction mixture was stirred overnight at room temperature, diluted with water (1.0 mL), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-60% MeCN in water with 0.1% TFA) to give (E)-11-methyl-1-(2-oxa-6-azaspiro[3.3]heptane oxalate). 7 -(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione was obtained as a white powder (2 mg, 17%).

[0407] 1 H NMR (DMSO-d6) δ:12.78 (s, 1H), 8.83 (s, 1H), 8.11 (d, 1H), 7.84 (s, 1H), 7.75 (d, 1H), 7.59 (m, 2H), 7.32 - 7.04 (m, 2H), 4.68 (m, 5H), 4.35 - 4.04 (m, 4H), 3.10 (s, 2H), 1.91 (s, 3H), 1.50 (d, 6H);LC / MS:M+H=488.2.

[0408] Example 43: (E)-1 7-(azetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0409] [ka]

[0410] N,N-Diisopropylethylamine (9 μl, 49 μmol) was dissolved in DMF (0.25 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 A solution of 10 mg of 1-methyl-2-propanol (25 μmol) and HATU (10 mg, 27 μmol) was added at room temperature. The solution was stirred for 2 min before adding azetidine (3.3 μl, 49 μmol). The reaction mixture was stirred at room temperature for 1.5 h, diluted with water (1.0 ml), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-60% MeCN in water with 0.1% TFA) to give (E)-1. 7 -(azetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione was obtained as a white powder (7 mg, 67%).

[0411] 1H NMR (CDCl3) δ:12.04 (s, 1H), 9.05 (s, 1H), 8.28 (d, 1H), 7.95 (d, 1H), 7.61 (m, 1H), 7.39 (d, 1H), 7.21 (m, 2H), 6.91 (s, 1H), 5.15 (s, 1H), 4.30 (m, 2H), 4.06 (m, 2H), 3.72 (s, 1H), 3.33 (s, 1H), 2.53 - 2.31 (m, 3H), 2.10 (s, 3H), 1.75 (d, 3H), 1.58 (s, 2H);LC / MS:M+H=446.2.

[0412] Example 44: (S,E)-N,N,7-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0413] [ka]

[0414] Step 1: Preparation of (S)-(6-aminohexan-2-yl)carbamate TFA (2.0 ml, 27.1 mmol) was added to a solution of benzyl tert-butylhexane-1,5-diyl(S)-dicarbamate (250 mg, 713 μmol) in CHCl (2.0 ml), prepared from Z-(D)-lys-boc-OH as described in Mandal et al. Journal of Organic Chemistry (2014), 79(17), 8422-8427. The solution was stirred at room temperature for 1.5 hours. The reaction solution was diluted with CHCl (20 ml) and washed with 1 M NaOH (35 ml). The organic phase was dried and concentrated to give benzyl (S)-(6-aminohexan-2-yl)carbamate (169 mg, 95%).

[0415] 1 H NMR (DMSO-d6) δ:7.35 (m, 5H), 7.10 (d, 1H), 4.99 (s, 2H), 3.48 (m, 1H), 1.30 (m, 7H), 1.05 (d, 3H).

[0416] Step 2: Preparation of benzyl (S)-(6-((2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexan-2-yl)carbamate A solution of (S)-(6-aminohexan-2-yl)carbamate (168 mg, 671 μmol), 2-fluoro-N,N-dimethyl-3-nitrobenzamide (142 mg, 671 μmol), and KCO (185 mg, 1.34 mmol) in MeCN (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated. The crude product (275 mg) was used without further purification.

[0417] Step 3: Preparation of (S)-(6-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexan-2-yl)benzylcarbamate SnCl (589 mg, 3.11 mmol) and N,N-diisopropylethylamine (1.97 mL, 6.21 mmol) were added to a solution of (S)-(6-((2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexan-2-yl)benzylcarbamate (275 mg, 621 μmol) in EtOH (20.0 mL). The reaction mixture was stirred for 50 min and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and 1 M NaOH (30 mL) and filtered through Celite. The filtrate was washed with brine and 1 M NaOH, and the organic phase was dried and concentrated. The residue was dissolved in MeOH (10 mL) and water (2 mL), and cyanogen bromide (79 mg, 746 μmol) and N,N-diisopropylethylamine (214 μL, 1.24 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 21 hours, and the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with saturated NaHCO (aq) (50 mL) and brine (30 mL). The organic phase was dried and concentrated. Purification using flash chromatography (SiO, CHCl / CHCl-MeOH-NH (aq) 100:10:1) afforded benzyl (S)-(6-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexan-2-yl)carbamate as an oil (93 mg, 34%).

[0418] 1 H NMR (CDCl3) δ:7.45 (d, 1H), 7.38 (d, 4H), 7.36 - 7.31 (m, 1H), 7.12 (m 1H), 6.89 (d, 1H), 5.19 - 5.03 (m, 2H), 4.86 (s, 2H), 4.62 (s, 1H), 3.79 (s, 2H), 3.17 (s, 3H), 2.93 (s, 3H), 1.69 (d, 4H), 1.55 - 1.37 (m, 3H), 1.30 (m, 1H), 1.16 (d, 3H).

[0419] Step 4: Preparation of tert-butyl (S)-3-((1-(5-(((benzyloxy)carbonyl)amino)hexyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate N,N-Diisopropylethylamine (73 μL, 425 μmol) was added to a solution of 3-(tert-butoxycarbonyl)benzoic acid (52 mg, 234 μmol) and HATU (89 mg, 234 μmol) in MeCN (5.0 mL). After stirring the solution for 3 minutes, a solution of (S)-(6-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexan-2-yl)benzylcarbamate (93 mg, 213 μmol) in MeCN (4.0 mL) was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography (SiO, 40-100% EtOAc / petroleum ether) to afford tert-butyl (S)-3-((1-(5-(((benzyloxy)carbonyl)amino)hexyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (74 mg, 54%).

[0420] 1 H NMR (CDCl3) δ:12.52 (s, 1H), 8.98 (s, 1H), 8.46 (d, 1H), 8.11 (d, 1H), 7.50 (m, 1H), 7.41 - 7.29 (m, 6H), 7.24 (d, 1H), 7.11 (d, 1H), 5.05 (m, 3H), 4.34 (s, 2H), 3.69 (d, 1H), 3.19 (s, 3H), 2.95 (s, 3H), 1.75 (s, 3H), 1.59 (s, 13H), 1.14 (d, 3H).

[0421] Step 5: Preparation of (S)-3-((1-(5-aminohexyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid 10% Pd / C (12 mg, 11 μmol) was added to a solution of tert-butyl (S)-3-((1-(5-(((benzyloxy)carbonyl)amino)hexyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (74 mg, 115 μmol) in MeOH (15 ml) and 1 M HCl (2.0 ml). The reaction mixture was stirred at room temperature under an atmosphere of H for 40 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane / 5 M HCl 1:1 (10 ml), stirred at room temperature for 20 hours, and then concentrated to dryness under reduced pressure. It was used in the next step without further purification.

[0422] Step 6: (S,E)-N,N,7-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxamides A solution of (S)-3-((1-(5-aminohexyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (56 mg, 115 μmol) and N,N-diisopropylethylamine (119 μl, 0.69 mmol) in DMF (5 ml) and a solution of HATU (73 mg, 192 μmol) in DMF (5 ml) were added simultaneously via two separate syringes to a solution of HATU (14 mg, 38 μmol) and N,N-diisopropylethylamine (59 μl, 0.34 mmol) in DMF (5 ml) at room temperature at 250 μl / h over 20 h. The reaction mixture was concentrated to dryness under reduced pressure and purified using chromatography.

[0423] 1H NMR (DMSO-d6) δ:12.71 (s, 1H), 9.00 (s, 1H), 8.10 (d, 1H), 7.73 (d, 2H), 7.64 - 7.45 (m, 2H), 7.25 (m, 1H), 7.10 (s, 1H), 4.75 - 4.38 (m, 1H), 4.27 - 3.85 (m, 1H), 3.72 - 3.55 (m, 1H), 3.09 (s, 3H), 2.86 (s, 3H), 2.36 - 1.67 (m, 2H), 1.64 - 1.32 (m, 4H), 1.03 (d, 3H); LC / MS:M+H=434.2.

[0424] Example 45: (E)-N-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)acetamide

[0425] [ka]

[0426] Diphenylphosphoryl azide (17 μL, 81 μmol) was dissolved in toluene (1.0 mL) to give 11-methyl-3,5-dioxo-11H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7The resulting mixture was added to a solution of 1M HCl (30 mg, 74 μmol) and TEA (12 μL, 89 μmol). The reaction mixture was stirred for 30 minutes, and then NMP (1.0 mL) was added. Stirring was continued for 1.5 hours. 1M HCl (1.0 mL) was added, and the reaction mixture was heated at 60°C overnight. The reaction mixture was cooled, and 1M NaOH (2.0 mL) was added. The mixture was extracted with EtOAc (3 × 1 mL), and the combined organic layers were dried and concentrated. The residue was purified by reverse-phase chromatography (C18 column, preparative HPLC, 20-40% MeCN in water with 0.1% TFA). The purified intermediate was dissolved in THF (3.0 mL) and N,N-diisopropylethylamine (76 μL, 444 μmol), followed by the addition of acetyl chloride (16 μL, 222 μmol) at room temperature. The reaction mixture was stirred for 2.5 hours and then concentrated to dryness. The residue was purified by reverse phase chromatography (C18 column, preparative HPLC, 20-40% MeCN in water with 0.1% TFA) to give (E)-N-(11-methyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -yl)acetamide was obtained as a white solid (2.2 mg, 7%).

[0427] 1 H NMR (MeOH-d4) δ:8.98 (s, 1H), 8.21 (d, 1H), 7.82 (d, 1H), 7.61 (m, 1H), 7.46 (d, 1H), 7.25 (m, 1H), 7.03 (d, 1H);LC / MS:M+H=420.0.

[0428] Example 46: (R,E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -sulfonamides

[0429] [ka]

[0430] Step 1: Preparation of tert-butyl (R)-(5-((2-(N,N-dimethylsulfamoyl)-6-nitrophenyl)amino)hexyl)carbamate (R)-tert-Butyl (5-aminohexyl)carbamate (180 mg, 831 μmol) and K2CO3 (313 mg, 2.27 mmol) were added to a solution of 2-chloro-N,N-dimethyl-3-nitrobenzenesulfonamide (200 mg, 756 μmol) in MeCN (5.0 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was further diluted with DMF (2.0 mL) and heated at 60 °C for 48 h. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (silica gel, Biotage 12 g, 10–60% EtOAc in petroleum ether) to give tert-butyl (R)-(5-((2-(N,N-dimethylsulfamoyl)-6-nitrophenyl)amino)hexyl)carbamate as an oil (315 mg, 94%).

[0431] 1 H NMR (DMSO-d6) δ:12.71 (s, 1H), 9.00 (s, 1H), 8.10 (d, 1H), 7.73 (d, 2H), 7.64 - 7.45 (m, 2H), 7.25 (m, 1H), 7.10 (s, 1H), 4.75 - 4.38 (m, 1H), 4.27 - 3.85 (m, 1H), 3.72 - 3.55 (m, 1H), 3.09 (s, 3H), 2.86 (s, 3H), 2.36 - 1.67 (m, 2H), 1.64 - 1.32 (m, 4H), 1.03 (d, 3H); LC / MS:M+H=445.0.

[0432] Step 2: Preparation of tert-butyl (R)-(5-(2-amino-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate A solution of tert-butyl (R)-(5-((2-(N,N-dimethylsulfamoyl)-6-nitrophenyl)amino)hexyl)carbamate (315 mg, 709 μmol) in MeOH (25 ml) was hydrogenated over 10% Pd / C (38 mg, 35 μmol) at room temperature for 2 hours. The reaction mixture was filtered through Celite with MeOH and concentrated to give an oil. The residue was dissolved in MeOH (10 ml) and water (2.0 ml) and cyanogen bromide (90 mg, 850 μmol) was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, 0.5% MeOH (28% aq) with 1% NH in CHCl) to give tert-butyl (R)-(5-(2-amino-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (131 mg, 42%).

[0433] LC / MS: M+H=440.0; Rt=1.91 min.

[0434] Step 3: Preparation of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate A solution of HATU (124 mg, 325 μmol), N,N-diisopropylethylamine (77 μL, 443 μmol), and 3-(tert-butoxycarbonyl)benzoic acid (72 mg, 325 μmol) in CHCl (10 mL) was added to a solution of tert-butyl (R)-(5-(2-amino-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (130 mg, 296 μmol) and N,N-diisopropylethylamine (77 μL, 443 μmol) in CHCl (10 mL). The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 25 to 100% EtOAc in petroleum ether) to give (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)butyl benzoate (151.7 g, 80%).

[0435] LC / MS: M+H=644.2; Rt=3.71 min.

[0436] Step 4: Preparation of (R)-3-((1-(6-aminohexan-2-yl)-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid 5 M HCl (10 ml) was added to a solution of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (152 mg, 236 μmol) in dioxane (10 ml). The reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated to dryness under reduced pressure. The product was used without further purification.

[0437] LC / MS: M+H=488.0; Rt=1.93 min.

[0438] Step 5: (R)-N,N,11-trimethyl-3,5-dioxo-11 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of sulfonamides HATU (139 mg, 364 μmol) was added to a suspension of (R)-3-((1-(6-aminohexan-2-yl)-7-(N,N-dimethylsulfamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (127 mg, 243 μmol) and N,N-diisopropylethylamine in THF (486 ml). The reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was concentrated. The residue was dissolved in DMSO and purified by reverse-phase chromatography (C18 column, preparative HPLC, 30-60% MeCN in water with 0.1% formic acid) to give (R,E)-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -sulfonamide was obtained as a white solid (27 mg, 24%).

[0439] 1 H NMR (DMSO-d6) δ:13.04 (s, 1H), 8.74 (s, 1H), 8.11 (d, 1H), 7.88 - 7.71 (m, 3H), 7.67 - 7.56 (m, 2H), 7.36 (m, 1H), 5.61 - 5.43 (m, 1H), 3.75 - 3.56 (m, 1H);LC / MS:M+H=470.0.

[0440] Examples 47 and 48: (E)-N-isopropyl-N,11-dimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0441] [ka]

[0442] N,N-Diisopropylethylamine (13 μl, 74 μmol) was dissolved in DMF (0.25 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a solution of (E)-N-isopropyl-N,11-dimethyl-3,5-dioxo-12,13-dihydro-1-methylpropan-2-amine (10 mg, 25 μmol) and HATU (9 mg, 25 μmol) was added at room temperature. After stirring the solution for 2 minutes, N-methylpropan-2-amine (8 μl, 74 μmol) was added. The reaction mixture was stirred at room temperature for 48 hours, diluted with water (1.0 ml), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 15-45% MeCN in water with 0.1% TFA) to give (E)-N-isopropyl-N,11-dimethyl-3,5-dioxo-12,13-dihydro-1-methylpropan-2-amine (1.0 ml). 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide was obtained as a white powder (4 mg, 35%).

[0443] 1 H NMR (DMSO-d6) δ:8.71 (s, 1H), 8.15 (m, 1H), 7.70 (m, 1H), 7.62 (m, 1H), / .23 (m, 1H), 7.07 (m, 1H), 4.77 (m, 1H), 4.51 (m, 1H), 1.10 (m, 6H).

[0444] The enantiomers were separated on a Daicel IA 25 x 2 cm SFC column at 15 ml / min of 3% EtOH / CH2Cl2.

[0445] Example 47, Enantiomer 1: Rt=10.25; LC / MS: M+H=446.2.

[0446] Example 48, Enantiomer 2: Rt=16.35; LC / MS: M+H=446.2.

[0447] Examples 49 and 50: (E)-1 7 -(3-Methoxy-3-methylazetidine-1-carbonyl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0448] [ka]

[0449] N,N-Diisopropylethylamine (53 μl, 308 μmol) was dissolved in DMF (0.50 ml) and 11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 To a solution of 1,2-dihydroxybenzoyl ketone (25 mg, 62 μmol) and HATU (26 mg, 68 μmol) was added at room temperature. After stirring the solution for 2 minutes, 3-methoxy-3-methylazetidine (17 mg, 123 μmol) was added. The reaction mixture was stirred at room temperature for 45 minutes, diluted with water (1.0 mL), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 15-45% MeCN in water with 0.1% TFA) to give (E)-1. 7 -(3-Methoxy-3-methylazetidine-1-carbonyl)-11-methyl-12,13-dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione was obtained as a white powder (26 mg, 86%). The optical isomers were separated using chiral chromatography.

[0450] Example 49, Enantiomer 1: キラル Isolation Daicel IA SFC 2×25cm, 3% EtOH / CH2Cl2, 12ml / min: Rt=11.27.

[0451] 1 H NMR (CDCl3) δ:11.97 (s, 1H), 9.03 (s, 1H), 8.26 (d1H), 7.95 (d, 1H), 7.59 (m, 1H), 7.37 (d, 1H), 7.23 (m, 1H), 7.18 - 7.06 (m, 1H), 5.93 (s, 1H), 5.09 (s, 1H), 4.20 (m, 1H), 4.08 - 3.89 (m, 2H), 3.83 - 3.62 (m, 2H), 3.26 (d, 4H), 2.05 (s, 3H), 1.73 (d, 4H), 1.53 (d, 4H); LC / MS: M+H=499.0.

[0452] Example 50, Optically Abnormal Body 2: キラル Isolation Daicel IA SFC 2×25cm, 3% EtOH / CH2Cl2, 12ml / min: Rt=13.42.

[0453] 1 H NMR (CDCl3) δ:11.94 (s, 1H), 9.03 (s, 1H), 8.26 (d1H), 7.95 (d, 1H), 7.59 (m, 1H), 7.37 (d, 1H), 7.23 (m, 1H), 7.18 - 7.06 (m, 1H), 5.93 (s, 1H), 5.09 (s, 1H), 4.20 (m, 1H), 4.08 - 3.89 (m, 2H), 3.83 - 3.62 (m, 2H), 3.26 (d, 4H), 2.05 (s, 3H), 1.73 (d, 4H), 1.53 (d, 4H); LC / MS: M+H=499.0.

[0454] Example 51 and Example 52: (E)-N,N,10-Turicle-3,5-ジオキソ-1 2 ,1 3 -ジヒドロ-1 1H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0455] [ka]

[0456] Step 1: Preparation of methyl 2-((5-((tert-butoxycarbonyl)amino)-2-methylpentyl)amino)-3-nitrobenzoate N,N-Diisopropylethylamine (9.21 mL, 52.7 mmol) was added to a solution of methyl 2-fluoro-3-nitrobenzoate (3.50 g, 17.6 mmol) and tert-butyl N-(5-amino-4-methylpentyl)carbamate (5.23 g, 19.3 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred at 70 °C for 6 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The product was purified by flash chromatography (SiO, 30% EtOAc / heptane) to give methyl 2-((5-((tert-butoxycarbonyl)amino)-2-methylpentyl)amino)-3-nitrobenzoate (7 g).

[0457] LC / MS: MH=394.20.

[0458] Step 2: Preparation of 2-((5-((tert-butoxycarbonyl)amino)-2-methylpentyl)amino)-3-nitrobenzoic acid A solution of methyl 2-((5-((tert-butoxycarbonyl)amino)-2-methylpentyl)amino)-3-nitrobenzoate (7 g, 9.91 mmol) and LiOH (2.08 g, 49.6 mmol) in THF (50 ml) and water (50 ml) was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure. The crude residue was diluted with water (15 ml), cooled to 0° C., and acidified with 1 N HCl. The precipitate that formed was filtered, washed with cold water, and dried under vacuum to give 2-((5-((tert-butoxycarbonyl)amino)-2-methylpentyl)amino)-3-nitrobenzoic acid (3.78 g, 93%).

[0459] LC / MS: M H = 380.15.

[0460] Step 3: Preparation of tert-butyl (5-((2-(dimethylcarbamoyl)-6-nitrophenyl)amino)-4-methylpentyl)carbamate To a solution of 2-((5-((tert-butoxycarbonyl)amino)-2-methylpentyl)amino)-3-nitrobenzoic acid (7.16 g, 9.23 mmol) in DMF (30 ml) was added N,N-diisopropylethylamine (7.16 g, 554.4 mmol), HATU (14 g, 36.9 mmol), and 2 M dimethylamine (28 ml, 55.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure. The product was used without further purification.

[0461] 1 H NMR (DMSO-d6) δ:8.12 (d, 1H), 8.06 (s, 1H), 7.39 (d, 1H), 6.77 (m, 1H), 2.99 (s, 3H), 2.69 (s, 3H), 1.71 (m, 1H), 0.89 (d, 3H);LC / MS:M+H=409.22.

[0462] Step 4: Preparation of tert-butyl (5-((2-amino-6-(dimethylcarbamoyl)phenyl)amino)-4-methylpentyl)carbamate To a solution of tert-butyl (5-((2-(dimethylcarbamoyl)-6-nitrophenyl)amino)-4-methylpentyl)carbamate (4.50 g, 7.38 mmol) in MeOH (60 ml) was added nickel (2.17 g, 36.9 mmol). The reaction mixture was hydrogenated under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through Celite, washed with EtOAc, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 50% EtOAc / heptane) to give tert-butyl (5-((2-amino-6-(dimethylcarbamoyl)phenyl)amino)-4-methylpentyl)carbamate (4 g).

[0463] 1 H NMR (DMSO-d6) δ:6.79 (s, 1H), 6.64 (m, 2H), 6.34 (s, 1H), 2.94 (s, 3H), 2.69 (s, 3H), 1.36 (s, 9H);LC / MS:MH=377.25.

[0464] Step 5: Preparation of tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)carbamate To a solution of tert-butyl (5-((2-amino-6-(dimethylcarbamoyl)phenyl)amino)-4-methylpentyl)carbamate (4.00 g, 7.4 mmol) in MeOH (20 mL), MeCN (10 mL), and water (10 mL) was added cyanogen bromide (682 mg, 8.14 mmol). The reaction mixture was stirred at 55° C. for 4 h. The reaction mixture was concentrated under reduced pressure, quenched with ice-cold water, and extracted with EtOAc. The organic layer was washed with brine solution, dried over NaSO, and concentrated under reduced pressure to give the desired product, which was used without further purification.

[0465] LC / MS: M+H=404.38.

[0466] Step 6: Preparation of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)-2-methylpentyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a solution of tert-butyl (5-(2-amino-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)carbamate (3.20 g, 7.22 mmol) and 3-(methoxycarbonyl)benzoic acid (2.60 g, 14.4 mmol) in DMF (30 ml), N,N-diisopropylethylamine (2.80 g, 21.6 mmol) was added at 0° C., followed by HATU (5.49 g, 14.4 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO, 48% EtOAc / heptane) to give methyl 3-((1-(5-((tert-butoxycarbonyl)amino)-2-methylpentyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (3.0 g, 55%).

[0467] LC / MS: M+H=566.37.

[0468] Step 7: Preparation of 3-((1-(5-((tert-butoxycarbonyl)amino)-2-methylpentyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a solution of methyl 3-((1-(5-((tert-butoxycarbonyl)amino)-2-methylpentyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (3.00 g, 3.96 mmol) in THF (30 ml) and water (30 ml) was added LiOH (831 mg, 198.8 mmol). The reaction mixture was stirred at 50° C. for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous phase was acidified with 3 N HCl and extracted with EtOAc. The organic layer was concentrated under reduced pressure and the product was used without further purification.

[0469] 1 H NMR (DMSO-d6) δ:8.79 (s, 1H), 8.45 (d, 1H), 8.07 (d, 1H), 7.63 (m, 2H), 7.28 (m, 1H), 7.15 (d, 1H), 4.14 (m, 2H), 3.16 (s, 3H), 2.88 (s, 3H), 1.33 (s, 9H), 0.78 (m, 3H); LC / MS:M+H=552.35.

[0470] Step 8: Preparation of 3-((1-(5-amino-2-methylpentyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a solution of 3-((1-(5-((tert-butoxycarbonyl)amino)-2-methylpentyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (500 mg, 798 μmol) in CHCl (5.0 ml) was added 4 M HCl (1.99 ml, 8 mmol) at 0° C. The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the product was used without further purification.

[0471] 1H NMR (DMSO-d6) δ:8.79 (s, 1H), 8.45 (d, 1H), 8.09 (d, 1H), 7.63 (m, 2H), 7.28 (m, 1H), 7.15 (d, 1H), 4.10 (m, 2H), 3.11 (s, 3H), 2.88 (s, 3H), 2.69 (m, 2H), 0.88 (m, 3H); LC / MS:M+H=452.26.

[0472] Step 9: N,N,10-trimethyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxamides To a solution of 3-((1-(5-amino-2-methylpentyl)-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (300 mg, 551 μmol) in MeCN (200 ml) and DMF (30 ml) was added TCFH (233 mg, 831 μmol) and 1-methyl-1H-imidazole (185 μl, 2.33 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with water, and the precipitate was collected by filtration. The crude product was purified by preparative HPLC, followed by separation of the enantiomers by chiral chromatography to give Enantiomer 1 (20 mg) and Enantiomer 2 (24 mg).

[0473] Example 51, Enantiomer 1: 1 H NMR (DMSO-d6) δ:12.79 (s, 1H), 8.95 (s, 1H), 8.10 (d, 1H), 7.87 (m, 1H), 7.75 (d, 1H), 7.58 (m, 2H), 7.25 (m, 1H), 3.10 (s, 3H), 2.18 (m, 1H); LC / MS:M+H=434.45.

[0474] ChiralPak IG (4.6×250) 5μm, IPA / ethyl acetate=50:50(v / v), flow rate: 1ml / min, Rt=6.55min.

[0475] Example 52, Enantiomer 2: 1 H NMR (DMSO-d6) δ:12.79 (s, 1H), 8.95 (s, 1H), 8.10 (d, 1H), 7.87 (m, 1H), 7.75 (d, 1H), 7.58 (m, 2H), 7.25 (m, 1H), 3.10 (s, 3H), 2.18 (m, 1H); LC / MS:M+H=434.45.

[0476] ChiralPak IG (4.6 × 250) 5 μm, IPA / ethyl acetate = 50:50 (v / v), flow rate: 1 ml / min, Rt = 10.37 min.

[0477] Examples 53 and 54: (S,E)-1 6 -chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0478] [ka]

[0479] Step 1: Preparation of tert-butyl (S)-(5-((3-chloro-2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate 2,6-Dichloro-N,N-dimethyl-3-nitrobenzamide (281 mg, 1.07 mmol) was added to a solution of tert-butyl (S)-(5-aminohexyl)carbamate (231 mg, 1.07 mmol) in MeCN (5.0 mL) at room temperature. KCO (443 mg, 3.20 mmol) was added, and the suspension was heated to 40 °C. The reaction mixture was stirred for 6 days. The reaction mixture was cooled to room temperature, filtered, and concentrated to dryness. The residue was dissolved in MeCN and water and purified by reverse-phase chromatography on a C18 flash cartridge using 20–70% MeCN in water containing 0.1% TFA to give tert-butyl (S)-(5-((3-chloro-2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate (348 mg, 73%).

[0480] LC / MS: M+Na=465.0. Rt=2.93.

[0481] Step 2: Preparation of (S)-(5-(2-amino-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate tert-butyl To a solution of (S)-(5-((3-chloro-2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate (348 mg, 788 μmol) in MeOH (15 mL) was added 10% Pd / C (42 mg, 39 μmol), and the resulting mixture was hydrogenated at room temperature for 1.5 h. The reaction mixture was filtered through Celite with the aid of MeOH, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (1.0 mL) and MeOH (5.0 mL), and cyanogen bromide (100 mg, 945 μmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel in 1-7% MeOH in CHCl with 1% NH (28% in water) to give the product as a yellow oil (238.7 mg, 69%). This material was used without further purification.

[0482] LC / MS: M+H=438.0. Rt=1.97.

[0483] Step 3: Preparation of (S)-tert-butyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a solution of tert-butyl (S)-(5-(2-amino-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (239 mg, 545 μmol) and N,N-diisopropylethylamine (282 μl, 1.64 mmol) in MeCN (5 ml) was added a solution of HATU (249 mg, 654 μmol) in MeCN (5 ml). To the resulting solution was added 3-(tert-butoxycarbonyl)benzoic acid (145 mg, 654 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using 0–50% EtOAc in petroleum ether to give tert-butyl (S)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (141 mg, 40%).

[0484] LC / MS: M+H=642.3. Rt=3.57.

[0485] Step 4: Preparation of (S)-tert-butyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a solution of tert-butyl (S)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (142 mg, 220 μmol) in dioxane (10 ml) was added 5 M HCl (aq) (10 ml). The solution was stirred at room temperature overnight. The solution was concentrated and the product was used without further purification.

[0486] LC / MS: M+H=486.2. Rt=1.80.

[0487] Step 5: (S,E)-1 6 -chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxamides HATU (126 mg, 330 μmol) was added to a solution of tert-butyl (S)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (115 mg, 220 μmol) and N,N-diisopropylethylamine (190 μl, 1.10 mmol) in THF (440 ml). The reaction mixture was heated to 60° C. and stirred overnight. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DMSO and purified by reverse phase (C18 column, isocratic elution with 30% MeCN in water with 0.1% formic acid for 20 min). Fractions containing the first eluting product peak (P1) were collected separately and lyophilized to give a white solid (6.52 mg, 6.3%). Fractions containing the second eluting product peak (Example 54, P2) were collected separately and lyophilized to give a white solid (7.35 mg, 7.1%).

[0488] Example 53, Atropisomer / Stereoisomer 1: 1H NMR (DMSO-d6) δ:12.82 (s, 1H), 8.73 (s, 1H), 8.11 (d, 1H), 7.85 - 7.68 (m, 2H), 7.60 (m, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 4.49 - 4.19 (m, 1H), 3.10 (s, 3H), 2.88 (s,3H), 1.99 - 1.88 (m, 1H), 1.84 - 1.74 (m, 1H), 1.74 - 1.63 (m, 3H), 1.63 - 1.48 (m, 2H), 1.47 - 1.35 (m, 1H);LC / MS: M+H=468.0.

[0489] Example 54, Atropisomer / Stereoisomer 2: 1 H NMR (DMSO-d6) δ:12.75 (s, 1H), 8.71 (s,1H), 8.11 (d, 1H), 7.82 - 7.71 (m, 2H), 7.59 (t, 1H), 7.52 (d, 1H), 7.35 (d, 1H), 4.41 - 4.27 (m, 1H), 3.09 (s, 3H), 2.82 (s, 3H), 1.99 - 1.86 (m, 1H), 1.85 - 1.74 (m, 1H), 1.70 - 1.62 (m, 3H), 1.62 - 1.51 (m, 2H), 1.48 - 1.38 (m, 1H);LC / MS: M+H=468.0.

[0490] Examples 55 and 56: (R,E)-1 6 -chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0491] [ka]

[0492] Step 1: Preparation of 2,6-dichloro-N,N-dimethyl-3-nitrobenzamide A solution of 2,6-dichloro-3-nitrobenzoic acid (1.0 g, 4.24 mmol) in thionyl chloride (4.99 ml, 68.6 mmol) was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness by repeated evaporation with toluene. The residue was dissolved in THF (3.5 ml), cooled to 0° C., and dimethylamine (2 M in THF, 4.81 ml, 9.62 mmol) was added dropwise. The mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried and concentrated to dryness. The product was used without further purification.

[0493] 1 H NMR (chloroform, d3) δ: 7.83 (d, 1H), 7.49 (d, 1H), 3.19 (s, 3H), 2.90 (s, 3H); M+H=265.0.

[0494] Step 2: Preparation of tert-butyl (R)-(5-((3-chloro-2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate 2,6-Dichloro-N,N-dimethyl-3-nitrobenzamide (281 mg, 1.07 mmol) was added to a solution of tert-butyl (R)-(5-aminohexyl)carbamate (231 mg, 1.07 mmol) in MeCN (5.0 mL) at room temperature. KCO (443 mg, 3.20 mmol) was added, and the suspension was heated to 40 °C. The reaction mixture was stirred for 6 days. The reaction mixture was cooled to room temperature, filtered, and concentrated to dryness. The residue was dissolved in MeCN and water and purified by reverse-phase chromatography on a C18 flash cartridge using 20–70% MeCN in water containing 0.1% TFA to give tert-butyl (R)-(5-((3-chloro-2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate (356 mg, 75%).

[0495] LC / MS: M+Na=465.0. Rt=2.93.

[0496] Step 3: Preparation of tert-butyl (R)-(5-(2-amino-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To a solution of (R)-(5-((3-chloro-2-(dimethylcarbamoyl)-6-nitrophenyl)amino)hexyl)carbamate (354 mg, 799 μmol) in MeOH (15 mL) was added 10% Pd / C (43 mg, 40 μmol), and the resulting mixture was hydrogenated at room temperature for 1.5 h. The reaction mixture was filtered through Celite with the aid of MeOH, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (1.0 mL) and MeOH (5.0 mL), and cyanogen bromide (102 mg, 959 μmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel in 1-7% MeOH in CHCl with 1% NH (28% in water) to give the product as a yellow oil (247 mg, 71%). This material was used without further purification.

[0497] LC / MS: M+H=438.0. Rt=1.97.

[0498] Step 4: Preparation of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a solution of tert-butyl (R)-(5-(2-amino-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (247 mg, 563 μmol) and N,N-diisopropylethylamine (291 μl, 1.69 mmol) in MeCN (5 ml) was added a solution of HATU (257 mg, 676 μmol) in MeCN (5 ml). To the resulting solution was added 3-(tert-butoxycarbonyl)benzoic acid (150 mg, 676 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using 0–50% EtOAc in petroleum ether to give tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (257 mg, 71%).

[0499] LC / MS: M+H=642.3. Rt=3.57.

[0500] Step 5: Preparation of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a solution of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (257 mg, 400 μmol) in dioxane (10 ml) was added 5 M HCl (aq) (10 ml). The solution was stirred at room temperature overnight. The solution was concentrated and the product was used without further purification.

[0501] LC / MS: M+H=486.2. Rt=1.80.

[0502] Step 6: (R,E)-1 6-chloro-N,N,11-trimethyl-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Preparation of carboxamides HATU (228 mg, 600 μmol) was added to a solution of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-6-chloro-7-(dimethylcarbamoyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (209 mg, 400 μmol) and N,N-diisopropylethylamine (345 μl, 2.0 mmol) in THF (800 ml). The reaction mixture was heated to 60° C. and stirred overnight. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DMSO and purified by reverse phase (C18 column, isocratic elution with 30% MeCN in water with 0.1% formic acid for 20 min). The fractions containing the first eluting product peak (Example 55, P1) were collected separately and lyophilized to give a white solid (9.8 mg, 5.3%). The fractions containing the second eluting product peak (Example 56, P2) were collected separately and lyophilized to give a white solid (10.6 mg, 5.7%).

[0503] Example 55, Atropisomer 1: 1 H NMR (DMSO-d6) δ:12.83 (s, 1H), 8.73 (s, 1H), 8.11 (d, 1H), 7.76 (d, 2H), 7.59 (m, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 4.47 - 4.18 (m, 1H), 3.71 - 3.54 (m, 1H), 3.10 (s, 3H), 3.02 - 2.93 (m, 1H), 2.88 (s, 3H), 2.00 - 1.85 (m, 1H), 1.86 - 1.74 (m, 1H), 1.69 (s, 3H), 1.62 - 1.47 (m, 2H), 1.48 - 1.34 (m, 1H);LC / MS:M+H=468.0.

[0504] Example 56, Atropisomer 2: 1 H NMR (DMSO-d6) δ:12.82 (s, 1H), 8.71 (s, 1H), 8.11 (d, 1H), 7.85 - 7.69 (m, 2H), 7.59 (m, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 4.39 - 4.27 (m, 1H), 3.70 - 3.55 (m, 1H), 3.09 (s, 3H), 3.02 - 2.93 (m, 1H), 2.83 (s, 3H), 2.00 - 1.87 (m, 1H), 1.84 - 1.73 (m, 1H), 1.65 (s, 3H), 1.60 - 1.51 (m, 2H), 1.49 - 1.37 (m, 1H);LC / MS:M+H=468.0.

[0505] Example 57: (R,E)-1 7 -(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0506] [ka]

[0507] Step 1: Preparation of N'-acetyl-2-fluoro-3-nitrobenzohydrazide A solution of acetohydrazide (91 mg, 1.23 mmol) in MeCN (0.5 mL) containing a few drops of DMF was added to a solution of 2-fluoro-3-nitrobenzoyl chloride (250 mg, 1.23 mmol) in MeCN (10 mL). N,N-Diisopropylethylamine (212 μL, 1.23 mmol) was added to the resulting reaction mixture. The reaction mixture was stirred at room temperature for 1 h and then concentrated to dryness. The residue was diluted with EtOAc and NaHCO3 (aq). The phases were separated, and the aqueous layer was acidified to pH 2-3 with H2SO4 and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, and concentrated to give N'-acetyl-2-fluoro-3-nitrobenzohydrazide as a solid (237 mg, 80%).

[0508] 1 H NMR (DMSO-d6) δ:8.28 (m, 1H), 7.91 (m, 1H), 7.52 (m, 1H), 1.90 (m, 1H).

[0509] Step 2: Preparation of 2-(2-fluoro-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole POCl (116 μL, 1.24 mmol) was added to a solution of N'-acetyl-2-fluoro-3-nitrobenzohydrazide (100 mg, 415 μmol) in toluene (5.0 mL). The reaction mixture was heated at 120 °C for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NaHCO and brine. The organic phase was concentrated to dryness under reduced pressure to give 2-(2-fluoro-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole (83 mg, 90%), which was used without further purification.

[0510] 1 H NMR (DMSO-d6) δ:8.37 (m, 2H), 7.64 (m, 1H), 2.62 (m, 1H).

[0511] Step 3: Preparation of tert-butyl (R)-(5-((2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-nitrophenyl)amino)hexyl)carbamate A mixture of 2-(2-fluoro-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole (81 mg, 363 μmol), (R)-(5-aminohexyl)tert-butylcarbamate (78 mg, 363 μmol), and KCO (100 mg, 726 μmol) in MeCN (10 mL) was stirred at room temperature overnight. The reaction mixture was filtered, concentrated to dryness, and used in the next step without further purification.

[0512] 1 H NMR (CDCl3) δ:8.05 (m, 1H), 7.98 (m, 1H, 7.82 (m, 1H), 6.80 (m, 1H), 4.50 (m, 1H), 3.30 (m, 1H), 3.05 (m, 2H), 2.70 (s, 3H, 1.18 (d, 3H).

[0513] Step 4: Preparation of tert-butyl (R)-(5-((2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-6-nitrophenyl)amino)hexyl)carbamate Acetic acid (497 μl, 8.70 mmol) was added to a solution of tert-butyl (R)-(5-((2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-nitrophenyl)amino)hexyl)carbamate (152 mg, 362 μmol) in methylamine 40% in MeOH (3.70 ml) in a vial. The vial was sealed and the solution was heated in a microwave at 140 °C for 1 h. The volatiles were removed under reduced pressure and the residue was diluted with water and extracted with EtOAc and CHCl. ​​The combined organic phase was washed with brine and NaHCO. The organic phase was evaporated to dryness and purified using reverse phase chromatography (Gemini NX-C18, 25–55% MeCN / HO (TFA)) to give tert-butyl (R)-(5-((2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-6-nitrophenyl)amino)hexyl)carbamate (50 mg, 32 mg).

[0514] 1 H NMR (CDCl3) δ:8.39 (m, 1H), 7.63 (m, 1H), 7.06 (m, 1H), 3.55 (s, 3H), 3.04 (m, 2H), 2.76 (s, 3H), 2.40 (m, 1H), 1.54 - 1.00 (m, 17H), 0.96 (d, 3H).

[0515] Step 5: Preparation of tert-butyl (R)-(5-(2-amino-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate A solution of tert-butyl (R)-(5-((2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-6-nitrophenyl)amino)hexyl)carbamate (50 mg, 116 μmol) in MeOH (25 ml) was hydrogenated over 5% Pd / C (12 mg, 6 μmol) at room temperature for 40 minutes. The reaction mixture was filtered and placed into a solution of cyanogen bromide (15 mg, 139 μmol) in MeOH (5.0 ml). The resulting solution was stirred at room temperature for 1.5 hours and at 40° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, 0–10% MeOH in CHCl) to give tert-butyl (R)-(5-(2-amino-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (26 mg, 53%).

[0516] 1 H NMR (CDCl3) δ:7.55 (d, 1H), 7.20 (m, 1H), 6.90 (d, 1H), 4.91 (s, 1H), 4.60 (s, 3H), 3.94 (d, 1H), 3.50 (s, 3H), 3.41 (s, 3H), 3.05 (s, 3H), 2.57 (s, 3H).

[0517] Step 6: Preparation of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate A solution of tert-butyl (R)-(5-(2-amino-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (26 mg, 61 μmol) in DMF (1.0 mL) was added to a solution of HATU (25 mg, 67 μmol), N,N-diisopropylethylamine (21 μL, 122 μmol), and 3-(tert-butoxycarbonyl)benzoic acid (15 mg, 67 μmol) in DMF (0.25 mL) at room temperature. The reaction was stirred for 2 h, and additional HATU (6 mg, 16 μmol), N,N-diisopropylethylamine (15 μL, 87 μmol), and 3-(tert-butoxycarbonyl)benzoic acid (5 mg, 22 μmol) were added. The reaction mixture was stirred overnight, diluted with water, and purified by reverse-phase chromatography (C18 column, preparative HPLC, 35–65% MeCN in water with 0.1% TFA) to give tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (22 mg, 57%).

[0518] LC / MS: M+H=632.3; Rt=2.92 min.

[0519] Step 7: Preparation of (R)-3-((1-(6-aminohexan-2-yl)-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid 5M HCl (5.0 ml) was added to a solution of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (22 mg, 35 μmol) in dioxane (5.0 ml). The solution was stirred at room temperature for 48 hours and then concentrated to dryness under reduced pressure. The product was used without further purification.

[0520] Step 8: (R)-1 7 -(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione HATU (20 mg, 52 μmol) was added to a solution of (R)-3-((1-(6-aminohexan-2-yl)-7-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (17 mg, 35 μmol) and N,N-diisopropylethylamine (30 μL, 174 μmol) in THF (70 mL). The solution was stirred at 50 °C for 23 h and then concentrated to dryness under reduced pressure. The product was purified by reverse-phase chromatography (C18 column, preparative HPLC, using 10-40% MeCN in water with 0.1% TFA) to give (R,E)-1 7 -(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (5 mg, 31%) was obtained.

[0521] 1 H NMR (CDCl3) δ:9.00 (s, 1H), 8.30 (d, 1H), 7.96 (d, 1H), 7.63 (m, 1H), 7.59 - 7.52 (m, 1H), 7.39 (m, 1H), 7.14 (d, 1H), 6.93 (s, 1H), 5.55 (s, 2H), 4.04 - 3.65 (m, 1H), 3.55 (s, 3H), 3.28 (s, 1H), 2.72 (s, 3H), 2.03 (s, 2H), 1.65 - 1.37 (m, 3H), 1.30 (s, 3H);LC / MS:M+H=458.0.

[0522] Examples 58, 59, 60, and 61: (E)-11-methyl-1 7 -(2-oxopiperidin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0523] [ka]

[0524] Step 1: Preparation of 3-(2-fluoro-3-nitrophenyl)pyridin-2(1H)-one To a solution of 3-(2-fluoro-3-nitrophenyl)-2-methoxypyridine (7.00 g, 28.2 mmol) and sodium iodide (8.45 g, 2 equiv., 56.4 mmol) in MeCN (500 mL) was added chlorotrimethylsilane (7.16 mL, 2 equiv., 56.4 mmol) at room temperature, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with 10% MeOH / CHCl. ​​The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 3-(2-fluoro-3-nitrophenyl)pyridin-2(1H)-one (3.20 g, 46%) as a solid.

[0525] 1 H NMR (CDCl3) δ:8.12 (m, 1H), 7.85 (m, 1H), 7.64 (d, 1H), 7.53 (d, 1H), 7.46 (m, 1H), 6.33 (m, 1H);LC / MS:M+H=235.08.

[0526] Step 2: Preparation of tert-butyl (5-((2-nitro-6-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)amino)hexyl)carbamate To a solution of 3-(2-fluoro-3-nitrophenyl)pyridin-2(1H)-one (3.2 g, 13.7 mmol) and tert-butyl N-(5-aminohexyl)carbamate (2.96 g, 13.7 mmol) in thionyl chloride (4.99 mL, 68.6 mmol) in DMF (100 mL) was added N,N-diisopropylethylamine (8.83 g, 68.3 mmol). The reaction mixture was heated at 90° C. for 16 hours. The reaction mixture was poured into ice-cold water, and the precipitated product was collected by filtration, washed, dried, and used without further purification.

[0527] 1 H NMR (DMSO-d6) δ:8.00 (d, 1H), 7.31 (d, 1H), 7.10 (d, 1H), 6.84 (m, 1H), 6.71 (m, 1H), 6.28 (m, 1H), 3.14 (m, 1H), 2.78 (m, 2H), 1.35 (s, 9H), 0.87 (d, 3H); LC / MS:M+H=431.27.

[0528] Step 3: Preparation of tert-butyl (5-((2-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)amino)hexyl)carbamate To a solution of tert-butyl (5-((2-nitro-6-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)amino)hexyl)carbamate (3.2 g, 13.7 mmol) in methanol was added nickel (3.41 g, 58.1 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.

[0529] 1 H NMR (DMSO-d6) δ:7.46 (m, 2H), 6.78 (d, 1H), 6.65 (d, 1H), 6.37 (d, 1H), 6.31 (m, 1H), 4.09 (m, 2H), 1.37 (s, 9H), 0.070 (d, 3H);LC / MS:M+H=401.26.

[0530] Step 4: Preparation of tert-butyl (5-(2-amino-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To a solution of tert-butyl (5-((2-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)amino)hexyl)carbamate (2.50 g, 6.24 mmol) in methanol (20 mL) and MeCN (30 mL) was added cyanogen bromide (859 mg, 8.11 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated to dryness under reduced pressure. The crude product was dissolved in EtOAc and washed with NaHCO3 (aq). The phases were separated and the organic phase was dried (Na2SO4) and concentrated to dryness. The product (2.40 g, 90%) was used without further purification.

[0531] LC / MS: M+H=426.32.

[0532] Step 5: Preparation of tert-butyl (5-(2-amino-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate To a stirred solution of tert-butyl (5-(2-amino-7-(2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (3.50 g, 8.22 mmol) in ethanol (20 mL) in a steel vessel was added Pd / C (10.0 g, 94.0 mmol). The reaction mixture was hydrogenated at 70° C. under 100 psi (approximately 689 kPa) for 2 days. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.

[0533] LC / MS: M+H=430.51.

[0534] Step 6: Preparation of methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate To a stirred solution of tert-butyl (5-(2-amino-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (2.80 g, 6.52 mmol) and 3-(methoxycarbonyl)benzoic acid (1.76 g, 9.78 mmol) in MeCN (150 mL) was added HATU (4.96 g, 13.0 mmol), followed by N,N-diisopropylethylamine (5.67 mL, 32.76 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc and water. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, 100% EtOAc) to give the product (2.1 g, 34%).

[0535] LC / MS: M+H=592.3.

[0536] Step 7: Preparation of 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a stirred solution of methyl 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (2.80 g, 6.52 mmol) and 3-(methoxycarbonyl)benzoic acid (1.76 g, 9.78 mmol) in THF (20 ml) and water (10 ml) was added LiOH (709 mg, 16.9 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the crude product was diluted with 10 mL of ice-cold water. The aqueous solution was acidified with 50% citric acid solution at pH 6. The white precipitate was filtered off and dried to give a white solid product (430 mg, 42%).

[0537] 1H NMR (DMSO-d6) δ:8.78 (s, 1H), 8.38 (d, 1H), 8.06 (d, 1H), 7.61 (m, 1H), 7.50 (d, 1H), 7.15 (m, 1H), 7.03 (m, 1H), 6.69 (m, 1H), 1.73 (d, 3H), 1.32 (s, 9H); LC / MS:M+H=578.17.

[0538] Step 7: Preparation of 3-((1-(6-aminohexan-2-yl)-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid To a stirred solution of 3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (430 mg, 744 μmol) in CHCl (50 mL) was added 4 M HCl (9.30 mL). The solution was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and 370 mg of the crude product (diastereomeric mixture) was purified by reverse-phase preparative HPLC to give 80 mg of diastereomer 1 (91% purity) and 80 mg of diastereomer 2 (99% purity). These two peaks were analyzed separately.

[0539] Diastereomer 1: 1 H NMR (DMSO-d6) δ:8.78 (s, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.86 (s, 1H), 7.63 (m, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 2.17 (m, 2H); LC / MS: M+H=478.34, rt=1.31 min.

[0540] Diastereomer 2: 1H NMR (DMSO-d6) δ:8.78 (s, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.93 (s, 1H), 7.63 (m, 1H), 7.15 (m, 1H), 7.00 (m, 1H), 2.17 (m, 2H); LC / MS: M+H=478.37, rt=1.34 min.

[0541] Step 8: (E)-11-methyl-1 7 -(2-oxopiperidin-3-yl)-1 2 ,1 3 -dihydro-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione To a solution of 3-((1-(6-aminohexan-2-yl)-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (diastereomer 1) (80 mg, 165 μmol) in MeCN (75 ml) and DMF (25 ml) was added TCFH (70 mg, 250 μmol) and 1-methyl-1H-imidazole (97 mg, 1.17 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 1 ml of water and then concentrated under reduced pressure, and the residue was triturated with water, filtered, and dried. The crude product was purified by preparative HPLC to give racemic (E)-11-methyl-1H-imidazole. 7 -(2-oxopiperidin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione was obtained. The optical isomers were separated using chiral chromatography.

[0542] Example 58, Stereoisomer 1: 1H NMR (DMSO-d6) @ 353.1K δ:8.90 (bs, 1H), 8.10 (d, 1H), 7.74 (d, 1H), 7.59 (m, 2H), 7.47 (m, 2H), 7.13 (m, 1H), 7.04 (d, 1H), 4.04 (m, 1H), 3.35 (m, 2H), 2.23 (m, 1H), 1.96 (m, 4H), 1.73 (m, 3H); LC / MS: M+H=460.45.

[0543] ChiralPak IG (4.6×250) 5 μm, 0.1% TFA in MeOH / H2O = 98:2 (v / v), flow rate: 1 ml / min, Rt = 12.81 min.

[0544] Example 59, Stereoisomorph 2: 1 H NMR (DMSO-d6) @ 353.1 K δ:8.90 (bs, 1H), 8.10 (d, 1H), 7.74 (d, 1H), 7.59 (m, 2H), 7.47 (m, 2H), 7.13 (m, 1H), 7.04 (d, 1H), 4.04 (m, 1H), 3.35 (m, 2H), 2.23 (m, 1H), 1.96 (m, 4H), 1.73 (m, 3H); LC / MS: M+H=460.45.

[0545] ChiralPak IG (4.6×250) 5 μm, 0.1% TFA in MeOH / H2O = 98:2 (v / v), flow rate: 1 ml / min, Rt = 17.63 min.

[0546] To a solution of 3-((1-(6-aminohexan-2-yl)-7-(2-oxopiperidin-3-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (diastereomer 2) (80 mg, 165 μmol) in MeCN (75 ml) and DMF (25 ml) was added TCFH (70 mg, 250 μmol) and 1-methyl-1H-imidazole (97 mg, 1.17 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 1 ml of water and then concentrated under reduced pressure, and the residue was triturated with water, filtered, and dried. The crude product was purified by preparative HPLC to give racemic (E)-11-methyl-1H-imidazole. 7 -(2-oxopiperidin-3-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione was obtained. The optical isomers were separated using chiral chromatography.

[0547] Example 60, Stereoisomer 3: 1 H NMR (DMSO-d6) @ 353.1 K δ:8.88 (bs, 1H), 8.10 (d, 1H), 7.72 (d, 1H), 7.55 (m, 2H), 7.43 (m, 2H), 7.09 (m, 1H), 6.97 (d, 1H), 4.07 (m, 1H), 1.68 (d, 3H); LC / MS:M+H=460.48.

[0548] ChiralPak IG (4.6×250) 5μm, ethyl acetate / IPA=50:50(v / v), flow rate: 1ml / min, Rt=9.36min Example 61, Stereoisomer 4: 1H NMR (DMSO-d6) @ 353.1 K δ:8.88 (bs, 1H), 8.10 (d, 1H), 7.68 (d, 1H), 7.53 (m, 2H), 7.41 (m, 2H), 7.03 (m, 1H), 6.90 (d, 1H), 4.06 (m, 1H), 1.66 (d, 3H); LC / MS:M+H=460.48.

[0549] ChiralPak IG (4.6×250) 5μm, ethyl acetate / IPA=50:50(v / v), flow rate: 1ml / min, Rt=11.50min.

[0550] Examples 62 and 63: (E)-11-methyl-1 7 -(2-oxo-1,2-dihydropyridin-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0551] [ka]

[0552] Prepared in the same manner as examples 35 and 36 starting from (2-methoxypyridin-4-yl)boronic acid and 1-bromo-2-fluoro-3-nitrobenzene.

[0553] Example 62, Enantiomer 1: 1 H NMR (DMSO-d6) δ:8.72 (bs, 1H), 8.10 (d, 1H), 7.72 (m, 2H), 7.58 (m, 2H), 7.49 (d, 1H), 7.23 (m, 1H), 6.99 (d, 1H), 6.39 (m, 1H), 6.30 (m, 1H), 4.48 (m, 1H), 3.61 (m, 1H); LC / MS:M+H=456.41.

[0554] ChiralPak IG (4.6 × 250) 5 μm, IPA / ethyl acetate = 50:50 (v / v), flow rate: 1 ml / min, Rt = 6.47 min.

[0555] Example 63, Enantiomer 2: 1 H NMR (DMSO-d6) δ:8.71 (bs, 1H), 8.10 (d, 1H), 7.72 (m, 2H), 7.58 (m, 2H), 7.49 (d, 1H), 7.23 (m, 1H), 7.00 (d, 1H), 6.39 (m, 1H), 6.30 (m, 1H), 4.48 (m, 1H), 3.61 (m, 1H); LC / MS:M+H=456.38.

[0556] ChiralPak IG (4.6 × 250) 5 μm, IPA / ethyl acetate = 50:50 (v / v), flow rate: 1 ml / min, Rt = 10.70 min.

[0557] Example 64: (R,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -Carboxamide

[0558] [ka]

[0559] N,N-Diisopropylethylamine (11 μl, 64 μmol) was dissolved in DMF (0.75 ml) and (R)-11-methyl-3,5-dioxo-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7A solution of (R,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1-methyl-D6-HCl (17 mg, 32 μmol) and HATU (13 mg, 35 μmol) was added at room temperature. After stirring the solution for 2 minutes, methylamine-D6-HCl (6 mg, 64 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (1.0 ml), and purified by reverse-phase chromatography (C18 column, preparative HPLC, 14-44% MeCN in water with 0.1% TFA) to give (R,E)-11-methyl-N,N-bis(methyl-d3)-3,5-dioxo-1-methyl-D6-HCl (17 mg, 32 μmol). 2 ,1 3 -Dihydro-11H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 7 -carboxamide (5 mg, 36%) was obtained.

[0560] 1 H NMR (DMSO-d6) δ:12.75 (s, 1H), 8.78 (s, 1H), 8.12 (d, 1H), 7.91 - 7.68 (m, 2H), 7.67 - 7.52 (m, 2H), 7.25 (m, 1H), 7.06 (d, 1H), 4.51 (s, 1H), 3.57 (s, 1H), 3.13 - 2.89 (m, 1H), 2.11 - 1.25 (m, 8H);LC / MS:M+H=440.0.

[0561] Example 65: (R,E)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0562] [ka]

[0563] Step 1: Preparation of tert-butyl (2-((2-fluoro-3-nitrophenyl)amino)ethyl)carbamate AcOH (800 μL) was added to a solution of 2-fluoro-3-nitroaniline (500 mg, 3.2 mmol) and tert-butyl (2-oxoethyl)carbamate (765 mg, 4.80 mmol) in MeOH (8.0 mL) at room temperature, followed by NaCNBH (403 mg, 6.41 mmol). The reaction mixture was stirred at room temperature for 48 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with 1 M NaOH (3 × 10 mL). The organic layer was dried and concentrated. Purification by reverse-phase chromatography (C18 flash cartridge (Biotage 50 g), 10–60% MeCN in water with 0.1% TFA) gave tert-butyl (2-((2-fluoro-3-nitrophenyl)amino)ethyl)carbamate (464 mg, 48%).

[0564] LC / MS: M+H-tBu=244.0; Rt=2.75 min.

[0565] Step 2: Preparation of tert-butyl (2-((2-fluoro-3-nitrophenyl)amino)ethyl)carbamate Diphosgene (927 μL, 7.75 mmol) was slowly added to a solution of tert-butyl (2-((2-fluoro-3-nitrophenyl)amino)ethyl)carbamate (464 mg, 1.55 mmol) in CHCl (100 mL) at room temperature, followed by TEA (540 μL, 3.88 mmol). The resulting solution was stirred at room temperature for 5 hours before TFA (1.0 mL) was added. The reaction mixture was stirred overnight at room temperature. Additional TFA (1.0 mL) was added, and stirring was continued overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH and then purified by flash chromatography (silica gel (Biotage 12 g), 1-10% MeOH with 1% NH in CHCl) to give 1-(2-fluoro-3-nitrophenyl)imidazolidin-2-one as a solid (176 mg, 50%).

[0566] LC / MS: M+H=226.0; Rt=1.49 min.

[0567] Step 3: Preparation of 1-(2-fluoro-3-nitrophenyl)-3-methylimidazolidin-2-one To a solution of 1-(2-fluoro-3-nitrophenyl)imidazolidin-2-one (88 mg, 391 μmol) in DMF (4.0 mL) was added methyl iodide (243 μL, 3.91 mmol), followed by NaH (60% in mineral oil, 78 mg, 1.95 mmol) at room temperature. The reaction mixture was stirred for 3 hours. The reaction mixture was poured into 1 M HCl (60 mL) and extracted with CHCl (3 × 20 mL). The combined organic phases were dried and concentrated. The product (61 mg) was used without further purification.

[0568] LC / MS: M+H=240.0 Step 4: Preparation of tert-butyl (R)-(5-((2-(3-methyl-2-oxoimidazolidin-1-yl)-6-nitrophenyl)amino)hexyl)carbamate A mixture of 1-(2-fluoro-3-nitrophenyl)-3-methylimidazolidin-2-one (94 mg, 391 μmol), (R)-(5-aminohexyl)tert-butyl carbamate (89 mg, 411 μmol), and K2CO3 (162 mg, 1.17 mmol) in MeCN (5.0 mL) was stirred overnight at 80° C. The reaction mixture was filtered, concentrated to dryness, and purified by flash chromatography (silica gel (Biotage 15 g), 1-5% MeOH (aqueous 28%) with 0.1% ammonia in dichloromethane) to give (R)-(5-((2-(3-methyl-2-oxoimidazolidin-1-yl)-6-nitrophenyl)amino)hexyl)tert-butyl carbamate (95 mg, 56%).

[0569] LC / MS: M+H=436.0; Rt=2.88 min.

[0570] Step 5: Preparation of tert-butyl (R)-(5-(2-amino-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate A solution of tert-butyl (R)-(5-((2-nitro-6-(2-oxoimidazolidin-1-yl)phenyl)amino)hexyl)carbamate (95 mg, 218 μmol) in MeOH (30 ml) was hydrogenated over 10% Pd / C (12 mg, 11 μmol) at room temperature for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (10 ml) and water (2.0 ml) and cyanogen bromide (25 mg, 240 μmol) was added. The resulting solution was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc and washed with 1 M NaOH (3×10 ml). The organic phase was dried and concentrated. Purification by flash chromatography (silica gel, 0–10% MeOH in CHCl) gave tert-butyl (R)-(5-(2-amino-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (24 mg, 25%).

[0571] LC / MS: M+H=431.0; Rt=1.78 min.

[0572] Step 6: Preparation of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate A solution of HATU (25 mg, 66 μmol) and 3-(tert-butoxycarbonyl)benzoic acid (15 mg, 66 μmol) in MeCN (5.0 mL) was added to a solution of tert-butyl (R)-(5-(2-amino-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-1-yl)hexyl)carbamate (24 mg, 55 μmol) and N,N-diisopropylethylamine (28 μL, 164 μmol) in MeCN (5.0 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and purified by flash chromatography (silica gel (Biotage 10 g), 10 to 100% EtOAc in petroleum ether) to give tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (34.4 mg, 99%).

[0573] 1 H NMR (CDCl3) δ:8.91 (s, 1H), 8.35 (d, 1H) 8.12 (d, 1H), 7.42 (m, 1H), 7.26 (m, 2H), 7.05 (m, 1H), 5.20 (m, 1H);LC / MS:M+H=635.3.

[0574] Step 7: Preparation of (R)-3-((1-(6-aminohexan-2-yl)-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid 5 M HCl (20 ml) was added to a solution of tert-butyl (R)-3-((1-(6-((tert-butoxycarbonyl)amino)hexan-2-yl)-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate (34 mg, 54 μmol) in dioxane (20 ml). The solution was stirred at room temperature overnight. Five drops of HCl (conc.) were added and stirring was continued overnight. The reaction mixture was concentrated to dryness under reduced pressure and used without further purification.

[0575] LC / MS: M+H=479.0; Rt=1.79 min.

[0576] Step 8: (R,E)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 2 ,1 3 -dihydro-1 1 Preparation of H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione HATU (31 mg, 81 μmol) and N,N-diisopropylethylamine (47 μl, 271 μmol) were added to a solution of (R)-3-((1-(6-aminohexan-2-yl)-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-benzo[d]imidazol-2-yl)carbamoyl)benzoic acid (28 mg, 54 μmol) in THF (108 ml). The reaction mixture was stirred at room temperature for 4 days and then concentrated to dryness. The residue was dissolved in DMSO (3.0 ml) and purified by reverse-phase chromatography (C18 column, 20-50% MeCN in water with 0.1% formic acid) to give (R)-11-methyl-1 7 -(3-methyl-2-oxoimidazolidin-1-yl)-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione (3.8 mg, 15%) was obtained.

[0577] 1H NMR (methanol-d4) δ:8.94 (s, 1H), 8.26 - 8.15 (m, 1H), 7.82 (d, 1H), 7.60 (tm, 1H), 7.47 (d, 1H), 7.28 (m, 1H), 7.18 - 7.12 (m, 1H), 5.57 - 5.03 (m, 1H), 4.07 - 3.52 (m, 5H), 3.22 - 3.05 (m, 1H), 2.92 (d, 3H), 2.30 - 1.84 (m, 3H), 1.77 (s, 3H), 1.70 - 1.40 (m, 3H);LC / MS:M+H=461.0.

[0578] Example 66: (R,E)-11-methyl-1 7 -(1-methyl-1H-1,2,3-triazol-4-yl)-1 2 ,1 3 -dihydro-1 1 H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione

[0579] [ka]

[0580] Step 1: Preparation of ((2-fluoro-3-nitrophenyl)ethynyl)trimethylsilane TMS-acetylene (194 μL, 1.36 mmol) followed by N,N-diisopropylethylamine (470 μL, 2.73 mmol) was added to a degassed mixture of 1-bromo-2-fluoro-3-nitrobenzene (200 mg, 909 μmol), bis(triphenylphosphine)palladium(II) dichloride (32 mg, 45 μmol), and CuI (9 mg, 46 μmol) in THF (7.0 mL) under argon. The reaction mixture was stirred at room temperature for 3 days and then concentrated to dryness. The residue was dissolved in EtOAc and washed with 1 M HCl and brine. The organic phase was dried, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 0–10% EtOAc / petroleum ether) to give ((2-fluoro-3-nitrophenyl)ethynyl)trimethylsilane (140 mg, 65%).

[0581] Step 2: Preparation of tert-butyl (R)-(5-((2-ethynyl-6-nitrophenyl)amino)hexyl)carbamate A solution of ((2-fluoro-3-nitrophenyl)ethynyl)trimethylsilane (107 mg, 451 μmol) and (R)-(5-aminohexyl)tert-butylcarbamate (132 mg, 609 μmol) in MeCN (5.0 mL) was...

Claims

1. A compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof: 【Chemical 1】 [wherein, A is a 6-membered aromatic ring or a 5- to 6-membered aromatic heterocycle containing one or two atoms selected from the group consisting of N, S, and O; W １ , W ２ , W ３ is independently selected from CH and N; X is a linear C ２－８ alkylene which is optionally halogen; OH; C ３－６ cycloalkyl; C optionally substituted with one or more halogens or OH １－６ alkyl; and said linear C ２－８ alkylene which, together with the atoms of said linear C ２－８ alkylene forms a 3- or 4-membered cycloalkyl group, or is substituted with two groups bonded to the same carbon atom of said linear C ２－８ alkylene; and / or optionally, one or more carbon atoms of said alkylene are substituted with a group independently selected from O, NH, and S; is a linear C Y is NH or O; R １ and R ２ is H; C １－６ alkyl; C ２－６ alkenyl; C ２－６ alkynyl; OC １－６ alkyl; OC ２－６ alkenyl; OC ２－６ alkynyl; -R ａ ; C(O)R ａ ; C(O)OR ａ ; OCR ａ ; OC(O)(R ａ ); -C １－６ alkylene-R ａ ; -C(O)C １－６ alkylene-R ａ ; -C(O)OC １－６ alkylene-R ａ ; -OC １－６ alkylene-R ａ ; OC(O)C １－６ alkylene-R ａ ; and, -R ｂ is independently selected from, wherein said alkyl, alkenyl, or alkynyl is optionally substituted with one or more R ｂ groups; R ３ is H, halogen, OH, C １－６ alkyl, or OC １－６ alkyl, where the alkyl is optionally substituted with one or more halogens; wherein, R ａ is selected from C ３－８ cycloalkyl, or a 3- to 12-membered heterocyclic ring containing one, two, or three atoms selected from the group consisting of N, S, and O; said cycloalkyl or heterocyclic ring is optionally bridged with C １－４ alkylene and / or C １－４ alkyl; a 3- to 6-membered heterocyclic ring (containing one, two, or three atoms selected from the group consisting of N, S, and O); C ３－６ cycloalkyl; OC １－４ alkyl; O-(3- to 6-membered heterocyclic ring (containing one, two, or three atoms selected from the group consisting of N, S, and O)); OC ３－６ cycloalkyl; C(O)C １－４ alkyl; C(O)OC １－４ alkyl; OC(O)C １－４ alkyl; C(O)NH ２ ; and -C １－４ alkylene-OC １－４ alkyl and is substituted with one or more groups independently selected from; wherein the alkyl, alkylene, heterocyclic ring, or cycloalkyl in R ａ is optionally substituted with one or more groups independently selected from halogen; OH; O; SH; NH ２ ; NHC １－４ alkyl; or N(C １－４ alkyl) ２ ; and Each R ｂ is C(O)R ｃ ; C(O)OR ｃ ; OC(O)R ｃ ; SR ｃ ; SO ２ R ｃ ; NO ２ ; CN; NR ｃ R ｄ ; N(R ｃ )SO ２ C １－３ alkyl; N(R ｃ )C(O)R ｄ ; C(O)NR ｃ R ｄ ; SO ２ NR ｃ R ｄ ; halogen; SH; NH ２ ; and is independently selected from OH; said alkyl is optionally substituted with one or more groups independently selected from halogen, SH, NH ２ , and OH, and / or optionally, one or more carbon atoms in said alkyl are substituted with a group independently selected from O, NH, and S; and R ｃ and R ｄ are independently selected from H; C １－６ alkyl; C ２－６ alkenyl; C ２－６ alkynyl; -C １－４ alkylene - OC １－４ alkyl; and C ３－８ cycloalkyl; provided that said alkyl, alkylene, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more groups selected from halogen, SH, NH ２ , OH, and =O, and / or optionally, one or more carbon atoms in said alkyl are substituted with atoms independently selected from O, N, and S].

2. wherein X is a linear C ４－８ alkylene; the compound according to claim 1.

3. The compound according to claim 1, wherein one or two carbon atoms of the alkylene in X are substituted with a group independently selected from O, NH, and S.

4. The compound according to claim 1, wherein X is substituted with one, two, or three groups independently selected from halogen, OH, and C １－６ alkyl.

5. R １ The compound according to claim 1, wherein R is H.

6. R ２ The compound according to claim 1, wherein R is H.

7. R １ is H; and R ２ is -R ａ ; C(O)R ａ ; C(O)OR ａ ; OC(O)(R ａ ); -methylene-R ａ ; or, -R ｂ is The compound according to claim 1.

8. R １ is methyl; -R ａ ; C(O)R ａ ; C(O)OR ａ ; OC(O)(R ａ ); -methylene-R ａ ; or, -R ｂ and R ２ is H, The compound according to claim 1.

9. R １ and R ２ are each independently selected from methyl; -R ａ ; C(O)R ａ ; C(O)OR ａ ; OC(O)(R ａ ); -methylene-R ａ ; or, -R ｂ independently selected from The compound according to claim 1.

10. R ａ is a heterocyclic ring selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxopiperidinyl, homopiperazinyl, pyridinyl, oxodihydropyridinyl, pyrrolidinyl, azetidinyl, triazolyl, oxadiazolenyl, imidazoleyl, oxazolidinoneyl, or is a 9- to 11-membered spirocyclic heterocyclic ring containing one or two atoms selected from the group consisting of N and O, and the heterocyclic ring or spirocyclic heterocyclic ring is optionally bridged with C １－４ alkylene and / or methyl, ethyl, a 3- to 4-membered heterocyclic ring (containing one atom selected from the group consisting of N, S, and O); C ３－６ cycloalkyl; O-(a 3- to 6-membered heterocyclic ring (containing one, two, or three atoms selected from the group consisting of N, S, and O)); OC １－４ alkyl; C(O)C １－４ alkyl; C(O)OC １－４ alkyl; OC(O)C １－４ alkyl; C(O)NH ２ ; or is substituted with one group independently selected from -C １－４ alkylene-OC １－４ alkyl; wherein the alkyl, alkylene, heterocyclic ring, spirocyclic heterocyclic ring, or cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and OH The compound according to claim 1.

11. R ａ The compound according to claim 1, wherein R is selected from the group consisting of: 【Chemical Formula 2-1】 ​ [Chemical Formula 2-3]

12. R ｂ is C(O)R ｃ ; C(O)OR ｃ ; OC(O)R ｃ ; SR ｃ ; SO ２ R ｃ ; NO ２ ; CN; NR ｃ R ｄ ; N(R ｃ );SO ２ C １－３ alkyl; N(R ｃ ); C(O)R ｄ ; C(O)NR ｃ R ｄ ; F; Cl; SH; NH ２ ; or is independently selected from OH; said alkyl being optionally substituted with one or two groups independently selected from F, Cl, SH, NH ２ , and OH, the compound according to claim 1.

13. R ｃ and R ｄ are each independently selected from H, methyl, ethyl, propyl, and -C １－２ alkylene -OCH ３ The compound according to claim 1, wherein the compound is independently selected from the group consisting of

14. R ３ is H, F, Cl, Br, I, C １－４ alkyl, or OC １－４ alkyl, the compound according to claim 1.

15. The compound according to claim 1, wherein A is phenyl or thienyl.

16. W １ and W ２ each is CH, and W ３ is CH or N, the compound according to claim 1.

17. The compound according to claim 1, wherein each of one to six hydrogen atoms is substituted with a deuterium atom, and each deuterium has a deuterium abundance level of at least 1 mol%, 5 mol%, 10 mol%, 50 mol%, 90 mol%, or 98 mol%.

18. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of: 1 １ H-2,6-diaza-1(2,1)-benzod[1,3]imidazol-4(1,3)-benzeneacyclododeca-3,5-dione; 1 １ H-2,6-diaza-1(2,1)-benzodimidazo[4,3-d]benzeneacycloundecaphane-3,5-dione; 1 ５ -((4-Methylpiperazin-1-yl)methyl)-1 １ H-2,6-Diaza-1(2,1)-benzodimidazolo-4(1,3)-benzeneacycloundecaphane-3,5-dione; 1 ５ -Methyl-1 １ H-2,6-Diaza-1(2,1)-benzod[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; 1 １ H-9-oxa-2,6-diaza-1(2,1)-benzodimidazo[4,3-d]benzeneacycloundecaphane-3,5-dione; 11-Methyl-1 １ H-2,6-Diaza-1(2,1)-benzod[1,3]imidazol-4(1,3)-benzeneacycloundecaphane-3,5-dione; 11-Methyl-3,5-dioxo-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxylate; 11-Methyl-1 ７ -(4-Methylpiperazin-1-carbonyl)-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacylcycloundecaphane-3,5-dione; 4-(11-Methyl-3,5-dioxo-1 １ H-2,6-diaza-1(2,1)-benzodimidazo[4,3-d]benzocycloundecaphane-1 ７ -carbonyl)piperazine-1-carboxylic acid tert-butyl; 1 ７ -(4-Methylpiperazine-1-carbonyl)-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacyloundecaphane-3,5-dione; 1 ５ -(4-Methylpiperazine-1-carbonyl)-1 １ H-2,6-Diaza-1(2,1)-benzod]imidazo]a]cycloundecaphane-3,5-dione; 1 ５ -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; 4-(3,5-dioxo-1 １ H-2,6-diaza-1(2,1)-benz[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 ５ -carbonyl)piperazine-1-carboxylic acid tert-butyl; 4-(3,5-Dioxo-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-1 ７ -carbonyl)piperazine-1-carboxylic acid tert-butyl; 11-Methyl-1 ７ -(piperazine-1-carbonyl)-1 １ H-2,6-diaza-1(2,1)-benzod[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; 1 ５ -(piperazine-1-carbonyl)-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; 1 ７ -(piperazine-1-carbonyl)-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-3,5-Dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzod]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxylic acid; (E)-1 ７ - (4 - (oxetan - 3 - yl)piperazine - 1 - carbonyl)-1 ２ , 1 ３ - dihydro - 1 １ H - 2,6 - diaza - 1(2,1)-benzo[d]imidazola - 4(1,3)-benzeneacycloundecaphane - 3,5 - dione; (R,E)-1 ７ -(2,4-dimethylpiperazine-1-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo]a]cycloundecaphan-3,5-dione; (E)-1 ７ -((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo[4,3-d]benzocycloundecaphan-3,5-dione; (R,E)-1 ７ -(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -(2,4-Dimethylpiperazine-1-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzod][imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ７ -((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo[4,3-d]benzocycloundecaphan-3,5-dione; (E)-1 ７ -(4-Methyl-1,4-diazepane-1-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-N,N-Dimethyl-1 ５ -((4-methylpiperazin-1-yl)methyl)-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzodimidazo[4,3-d]benzenacycloundecaphane-1 ７ -carboxamide; (E)-1 ７ -(2-Methoxypyridin-3-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzodimidazo[4,3-d]benzenacycloundecaphane-3,5-dione; (R,E)-11-Methyl-1 ７ -((1R,4R)-5-Methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzod]imidazo[4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-11-Methyl-1 ７ -((1R,4R)-5-Methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzod]imidazo]4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-N,N,11-Trimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; ((E)-3-(11-Methyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -yl)pyridine 1-oxide; (E)-N,11-Dimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (E)-11-Methyl-1 ７ -(2-oxo-1,2-dihydropyridin-3-yl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo[4,3-b]benzeneacycloundecaphane-3,5-dione; (E)-1 ７ -(3,3-difluoropyrrolidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-N-Methyl-N-(11-methyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -carbonyl)glycine methyl ester; (E)-N-Cyclobutyl-N,11-dimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo]4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (E)-1 ７ -(3,3-difluoroazetidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzocycloundecaphan-3,5-dione; (E)-N-(3-Hydroxycyclobutyl)-N,11-dimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (E)-11-methyl-1 ７ -(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ７ -(azetidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-N,N,7-Trimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo-4(1,3)-benzeneacycloundecaphan-1 ７ -carboxamide; (E)-N-(11-Methyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -yl)acetamide; (R,E)-N,N,11-Trimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -sulfonamide; (E)-N-Isopropyl-N,11-dimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -carboxamide; (E)-1 ７ -(3-methoxy-3-methylazetidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzenacycloundecaphane-3,5-dione; (E)-N,N,10-Trimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (S,E)-1 ６ -Chloro-N,N,11-trimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo[4,3-d]benzocycloundecaphan-1 ７ -carboxamide; (R,E)-1 ６ -Chloro-N,N,11-trimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -carboxamide; (R,E)-1 ７ -(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo]4(1,3)-benzeneacycloundecafan-3,5-dione; (E)-11-Methyl-1 ７ -(2-oxopiperidin-3-yl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod[i]imidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (E)-11-Methyl-1 ７ -(2-Oxo-1,2-dihydropyridin-4-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzodimidazo[4,3-d]benzenacycloundecaphane-3,5-dione; (R,E)-11-Methyl-N,N-bis(methyl-d ３ )-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -carboxamide; (R,E)-11-Methyl-1 ７ -(3-Methyl-2-oxoimidazolidin-1-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazol-4(1,3)-benzeneacycloundecaphane-3,5-dione; (R,E)-11-Methyl-1 ７ -(1-Methyl-1H-1,2,3-triazol-4-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-11-Ethyl-N,N-dimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -carboxamide; (R,E)-1 ５ -(2-Hydroxypropan-2-yl)-N,N,11-trimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -carboxamide; ((E)-N-(2-Fluoroethyl)-N,11-dimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (E)-N-(2,2-Difluoroethyl)-N,11-dimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod[1,3]imidazol-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (S,E)-11-Methyl-1 ７ -(3-Methyl-2-oxoimidazolidin-1-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-11-Methyl-1 ７ -((R)-3-Methylmorpholine-4-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzod][imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-11-Methyl-1 ７ -((S)-3-Methylmorpholine-4-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-11-Methyl-1 ７ -(1-Oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ７ -(3-Methoxyazetidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo[4,3]-benzeneacycloundecafan-3,5-dione; (R,E)-11-Methyl-1 ７ -(1-Methyl-1H-1,2,4-triazol-3-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (R,E)-11-methyl-1 ７ -(1-methyl-1H-1,2,4-triazol-5-yl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphan-3,5-dione; (S,E)-11-Methyl-1 ７ -(1-Methyl-1H-1,2,3-triazol-4-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (E)-1 ７ -((S)-3-Fluoropyrrolidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzod[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-11-Methyl-1 ７ -(1-Methyl-1H-imidazol-2-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzenacycloundecaphane-3,5-dione; (E)-1 ７ -((R)-3-Fluoropyrrolidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzod[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (R,E)-1 ７ -(3-Hydroxy-3-methylazetidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -(3-Hydroxy-3-methylazetidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecafan-3,5-dione; (E)-1 ６ -(4-Methylpiperazine-1-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ６ -(4-(oxetan-3-yl)piperazine-1-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ５ -fluoro-1 ２ , 1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ６ -(piperazine-1-carbonyl)-1 ２ , 1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ６ -((4-Methylpiperazin-1-yl)methyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ５ -((4-Methylpiperazin-1-yl)methyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzod][imidazo[4,5-b]pyridine-4(2,6)-pyridineacycloundecaphane-3,5-dione; (E)-1 ５ -((4-Methylpiperazin-1-yl)methyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazo-4(2,6)-pyridineacylundecaphane-3,5-dione; (1 ２ E, 4 ２ Z)-1 ５ -((4-Methylpiperazin-1-yl)methyl)-1 ２ , 1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazo-4(4,2)-thiopheneacylcycloundecaphane-3,5-dione; (E)-4 ６ -fluoro-1 ５ -((4-methylpiperazin-1-yl)methyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -((R)-3-Hydroxy-3-methylpyrrolidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -(3-Cyclopropoxyazetidine-1-carbonyl)-11-methyl-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (1 ２ Z,4 ２ (E)-N,N,5-trimethyl-2,11-dioxo-4 ２ ,4 ３ -dihydro-4 １ H-3,10-diaza-1(4,2)-thiazo1a-4(2,1)-benzo[d]imidazolacycloundecaphane-4 ７ -carboxamide; (S,E)-11-Methyl-1 ７ -(3-(Trifluoromethoxy)azetidine-1-carbonyl)-1 ２ ,1 ３ -Dihydro-11H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzacycloundecafuran-3,5-dione; (S,E)-1 ７ -((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod[1,3]imidazol-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (S,E)-11-Methyl-1 ７ -(2-oxopyrrolidin-1-yl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo]a]cycloundecaphane-3,5-dione; (S,E)-11-Methyl-1 ７ -(2-Oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-11-Methyl-1 ７ -(2-Oxa-6-azaspiro[3.4]octane-6-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-11-Methyl-1 ７ -(5-Oxa-2-azaspiro[3.4]octane-2-carbonyl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzacycloundecaphan-3,5-dione; (S,E)-1 ７ -(7,7-difluoro-5-oxa-2-azaspiro[3.4]octane-2-carbonyl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-11-Methyl-N,N-bis(methyl-d ３ )-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo[4,3-d]benzeneacyloundecaphan-1 ７ -carboxamide; (S,E)-11-Methyl-1 ４ -(2-oxopyrrolidin-1-yl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione; (11S,E)-11-Methyl-17-(1-oxa-6-azaspiro[3.4]octane-6-carbonyl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ４ -(3-Cyclopropyl-2-oxoimidazolidin-1-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridine-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ５ -(2-Hydroxypropan-2-yl)-N,N,11-trimethyl-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod[1,3]imidazol-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (S,E)-N,N,11-Trimethyl-1 ５ -((4-Methylpiperazin-1-yl)methyl)-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-1 ７ -Carboxamide; (S,E)-N,N,11-Trimethyl-1 ５ -(morpholinomethyl)-3,5-dioxo-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,3-b]benzocycloundecaphane-1 ７ -carboxamide; (11S,E)-1 ４ -(3-Fluoro-2-oxopyrrolidin-1-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-N,N,11-Trimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-1 ４ -carboxamide; (S,E)-11-methyl-1 ７ -(1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazo]4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-11-Methyl-1 ４ -(3-Methyl-2-oxoimidazolidin-1-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,3)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphan-3,5-dione; (E)-N,N-dimethyl-3',5'-dioxospiro[cyclopropane-1,11'-2,6-diaza-1(2,1)-benzo[d]imidazol-4(1,3)-benzeneacylundecafane]-7'-carboxamide; (E)-11-Methyl-1 ７ -(5-Methyl-1,3,4-oxadiazol-2-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzod][imidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-1 ７ -(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)-11-methyl-1 ２ 1 ３ 1-dihydro-1 １ H-2,6-diaza-1(2,1)-benzodimidazo-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-11-Methyl-1 ７ -(1-Methyl-1H-imidazol-2-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-benzodimidazo[4,3-d]benzocycloundecaphan-3,5-dione; (E)-1 ７ - (1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (E)-1 ７ - (1 - (difluoromethyl)-1H-1,2,4-triazol-5-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod[1,3]imidazol-4(1,3)-benzeneacycloundecaphane-3,5-dione; (E)-1 ７ -(3-Cyclopropyl-2-oxoimidazolidin-1-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzodimidazo[4,1,3]benzeneacycloundecaphane-3,5-dione; (E)-11-Methyl-1 ７ -(3-(oxetan-3-yl)-2-oxoimidazolidin-1-yl)-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzod]imidazol-4(1,3)-benzeneacycloundecaphane-3,5-dione; (S,E)-N,N,11-Trimethyl-3,5-dioxo-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-diaza-1(2,1)-imidazo[4,5-c]pyridina-4(1,3)-benzeneacycloundecaphane-1 ７ -carboxamide; (11S,E)-1 ７ -(3-Fluoro-2-oxopyrrolidin-1-yl)-11-methyl-1 ２ ,1 ３ -dihydro-1 １ H-2,6-diaza-1(2,1)-benzo[d]imidazo[4,3-b]benzocycloundecaphan-3,5-dione; and (S,E)-11-Methyl-1 ７ -(3-Methyl-1,2,4-oxadiazol-5-yl)-1 ２ ,1 ３ -Dihydro-1 １ H-2,6-Diaza-1(2,1)-benzo[d]imidazola-4(1,3)-benzeneacycloundecaphane-3,5-dione.

19. A pharmaceutical composition comprising the compound according to claim 1 and at least one pharmaceutically acceptable excipient.

20. The compound according to any one of claims 1 to 18 for use in the treatment or prevention of a condition selected from cancer, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

21. The compound according to any one of claims 1 to 18 for use in the treatment or prevention of a disease or disorder that can be treated or prevented by inhibition of TAK1.

22. Use of the compound according to any one of claims 1 to 18 in the manufacture of a medicament for use in the treatment or prevention of a condition selected from cancer, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

23. The compound for use according to claim 20, wherein the inflammatory disease or autoimmune disease is systemic lupus erythematosus (SLE), Sjögren's syndrome, rheumatoid arthritis, osteoarthritis, gout, psoriatic arthritis, psoriasis, ankylosing spondylitis, diabetes, malaria, Crohn's disease, ulcerative colitis, inflammatory bowel disease, familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), deficiency of interleukin-1 receptor antagonist (DIRA), and hyper IgD syndrome (HIDS), myocardial infarction, reperfusion, ischemia, stroke, multiple sclerosis, or systemic sclerosis.

24. The compound for use according to claim 20, wherein the cancer is associated with a mutation in the KRAS gene.

25. The compound for use according to claim 20, wherein the cancer is carcinoma, sarcoma, myeloma, leukemia, or lymphoma.

26. The compound according to any one of claims 1 to 18 for use in the treatment or prevention of a condition selected from idiopathic pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease (COPD).

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