Aromatic amides and their conjugates as binders for TEAD

Abstract

The present invention provides novel conjugates of formula (I), conjugates comprising the compound of formula (I), pharmaceutical compositions comprising such compound, methods for using such compound in the treatment of a disease, and methods for preparing such conjugates, where (I) is as defined herein. [Formula 1] JPEG2026519523000268.jpg43169

Description

[Technical Field]

[0001] The present invention provides novel compounds and conjugates containing such compounds. The compounds may be conjugates to TEA domain transcription factors (TEADs). The conjugates may contain ligase-binding moieties. The present invention further provides pharmaceutical compositions containing such compounds and / or conjugates, as well as methods for using such pharmaceutical compositions in the treatment of diseases such as cancer and fibrosis. [Background technology]

[0002] Bifunctional decomposition agent Many diseases, including cancer, are caused by the excessive activation of proteins in signaling networks [1]. This excessive activation leads to abnormal growth, metabolism, or other pathological consequences. Conventional small molecule drugs can inhibit, antagonize, or block these overactivated proteins by binding to ortho- or allosteric sites on the proteins. In doing so, they can restore normal cellular homeostasis and mitigate the pathological consequences caused by these dysregulated proteins [2].

[0003] As an alternative to small molecule drugs that block protein function, bifunctional molecules that bind to both dysregulated proteins and E3 ligases can promote ligase-mediated ubiquitination of proteins, thus making the proteins targets for proteasomal degradation [3]. Instead of inhibiting the protein, intracellular protein levels are reduced by the bifunctional molecules [4]. The degradation agents can have good biochemical efficiency that persists even after the drug has been eliminated from the body [5] and have long-lasting effects [6].

[0004] Hippo signaling pathway Normal tissue growth, as well as its repair and reconstruction, requires careful control of transcriptional activity. This is achieved through the coordinated activity of several signaling pathways, including the Hippo pathway. The Hippo signaling network consists of Mst1 / 2 and Lats1 / 2 kinases, which, when activated, phosphorylate yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motifs (TAZ), resulting in their retention in the cytosol and proteasomal degradation. When the Hippo pathway is inactivated, YAP and TAZ remain unphosphorylated, allowing them to move to the nucleus where they can coactivate TEAD-mediated transcription [7].

[0005] By regulating TEAD-mediated transcription, the Hippo pathway plays a crucial role in regulating cell proliferation and apoptosis. The Hippo pathway also regulates stem cell regeneration and differentiation.[8] Finally, the Hippo pathway modulates several components of the immune system, including cytokine expression[9] and M1 / M2 macrophage polarization. Overexpression of TEAD-responsive genes has been shown to drive cancer cell proliferation, promote cancer stem cell regeneration and enhance the immunosuppressive tumor microenvironment by recruiting tumor-associated M2 macrophages

[10] and myeloid-derived suppressor cells (MDSCs) to tumors.

[11] Therefore, blocking TEAD-regulating gene expression in tumors has a triple-mode effect. Blockers have a direct antiproliferative effect on cancer cells, promote terminal differentiation of cancer stem cells, and reduce the immunosuppressive tumor microenvironment, resulting in a favorable opportunity for the immune system to recognize and eliminate the tumor.

[0006] The Hippo signaling pathway plays a role in regulating wound healing. Disruption of this pathway can lead to fibrosis.

[0007] TEAD transcription factor TEA domain transcription factors (TEADs) are a family of transcription factors that regulate gene transcription by binding to the upstream response elements of TEAD regulatory genes

[14] . Humans have four TEAD orthologues, designated TEAD1, TEAD2, TEAD3, and TEAD4. Co-regulators of TEAD transcription factors include yes-associated proteins (YAPs), transcription co-activators with PDZ-binding motifs (TAZs), and trace-like family members (VGLL1-4)

[15] . TEAD regulatory gene expression is the second-to-last step in the Hippo signaling pathway. Therefore, inhibiting or degrading TEADs has therapeutic effects in treating diseases such as cancer and fibrosis in which the Hippo pathway is abnormally activated.

[13]

[0008] YAP and TAZ interact with the C-terminal transactivating domain of TEAD via three surface interfaces. Interface 1 is an intermolecular β-sheet formed between YAP and the TEAD β-strand. At interface 2, YAP forms an α-helix that fits into a groove within the TEAD helix-turn-helix motif. At interface 3, YAP / TAZ adopts a loop-like structure that interacts with TEAD. In addition, TEAD contains an internal hydrophobic cavity occupied by palmitate as a result of self-palmitoylation. Only palmitoylated TEAD can bind to YAP with high affinity.

[16]

[0009] Several small molecules have been reported in the literature to prevent YAP binding to TEAD and thus block the transcription of TEAD regulatory genes. The most common target of these small molecules to date is the internal lipophilic binding pocket.

[16] A smaller number of inhibitors that bind to the external interface #2 or #3 have also been reported.

[16]

[0010] WO2023 / 031801 describes a bifunctional decomposition agent containing a TEAD binder, synthesized in 13 steps. [Overview of the project] [Problems that the invention aims to solve]

[0011] An object of the present invention is to provide novel compounds that can be used to treat diseases such as cancer and / or fibrosis. Another object of the present invention is to provide novel compounds that can bind to TEAD1, TEAD2, TEAD3, and / or TEAD4 and can be used to treat diseases such as cancer and / or fibrosis. Novel compounds can bind to TEAD1, TEAD2, TEAD3, and / or TEAD4 (TEADx) with high affinity. Another object of the present invention is to provide novel compounds that bind to both TEADx and E3 ligase to form a stable triple complex consisting of TEADx, E3 ligase, and the novel compound. A further object is to provide a conjugate containing a novel compound that binds to TEAD1, TEAD2, TEAD3, and / or TEAD4, which may be capable of at least partially degrading TEAD1, TEAD2, TEAD3, and / or TEAD4. [Means for solving the problem]

[0012] Therefore, according to a first aspect of the present invention, a compound comprising, essentially comprising, or being equivalent to formula (I), [ka] During the ceremony, X is selected from CH, CF, and N, or X is CR 1d And, A1 is phenyl, which is optionally substituted with fluorophenyl, and selected from the group consisting of 5-membered or 6-membered heteroaromatic rings containing at least one heteroatom selected from N, S, and O. A2 is phenyl, and the phenyl may optionally be a halogen, C1-C3 alkoxy, C1-C3 alkyl, CF3, etc.1-3 One or more substituents independently selected from the group consisting of haloalkyl, phenyl, and at least one heteroatom selected from the group consisting of N, S, and O, preferably a 5- or 6-membered heteroaromatic ring containing S, wherein the heteroaromatic ring is optionally selected from the group consisting of a 5- or 6-membered heteroaromatic ring substituted with one or more substituents independently selected from halogen, C1-C3 alkoxy, C1-C3 alkyl, preferably Cl. R 1 is hydrogen; halogen; C1-C6 haloalkoxy; O(CH2) n O(CH2) m R 1a ; NR 1b (CH2) n O(CH2) m ; optionally, C3-C6 cycloalkyl, COOH, (O-CH2) m -CONR 1b R 1c ; a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, or a C1-C6 alkoxy substituted with a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, preferably at least one N atom; and selected from the group consisting of 5- or 6-membered heteroaryloxy, R 1a is selected from the group consisting of hydrogen, C1-C2 alkyl, or a 4-membered heterocyclic ring containing NCOCH3, R 1b and R 1c are independently selected from the group consisting of hydrogen, C1-C6 alkyl, or R 1b and R 1c together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring, R 1d and R 1However, together with the carbon atoms to which they are bonded, they form a 5-membered or 6-membered aromatic ring, heteroaromatic ring, cyclic ring, or heterocycle. R 2 However, it is selected from the group consisting of hydrogen, C1-C3 alkyl, and halogen, R 3 However, hydrogen, hydroxy C1-C3 alkyl, (CH2) n OCH2CONR 9 R 9 , optionally selected from the group consisting of C1-C3 alkyl groups substituted with a 4-membered heterocycle containing NCOCH3, R 4 However, hydrogen, optionally substituted with OH, C1-C5 alkyl, or optionally substituted with OH, C1-C4 alkyl; optionally C1-C3 alkyl, NHR 9 CONR 9 R 9 NHCO(C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 Selected from the group consisting of 4-membered, 5-membered, 6-membered, or 7-membered saturated cyclic rings or heterocycles substituted with COOH, CHO, CO(C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O, Or NH-R 4 However, NH-R 4 It forms a 5-membered or 6-membered saturated heterocycle with respect to the bonded carbon, R 5 However, selected from hydrogen, OH, and fluoro, R 6 However, they are independently selected from the group consisting of hydrogen and C1-C3 alkyl, or R 6 R 6 However, together with the nitrogen atoms to which they are bonded, they form a five-membered or six-membered ring, and optionally, this five-membered or six-membered ring further contains oxygen. R 7 However, at least one NR 8 It is a 5-membered or 6-membered aromatic ring containing R 8However, hydrogen and CH2CONR 9 Selected from the group consisting of, R 9 However, independently selected from the group consisting of hydrogen and methyl, Each n is 1, 2, or 3 individually. Each m is either 0 or 1 in the compound. Alternatively, pharmaceutically acceptable salts, tautomers, or stereoisomers thereof are provided.

[0013] Those skilled in the art, R 1d and R 1 However, if they, together with the carbon atoms to which they are each bonded, form a five-membered or six-membered aromatic ring, heteroaromatic ring, cyclic ring, or heterocycle, it is understood that the resulting ring contains the carbon atoms to which X, R1 are bonded, and the atoms necessary to form the five-membered or six-membered aromatic ring, heteroaromatic ring, cyclic ring, or heterocycle.

[0014] In some embodiments, X is selected from CH, CF, and N. A1 is phenyl, which is optionally substituted with fluorophenyl, and selected from the group consisting of 5-membered or 6-membered heteroaromatic rings containing at least one heteroatom selected from N, S, and O. A2 is phenyl, and the phenyl may optionally be a halogen, C1-C3 alkoxy, C1-C3 alkyl, CF3, etc. 1-3 - A 5- or 6-membered heteroaromatic ring comprising phenyl and at least one heteroatom selected from the group consisting of N, S, and O, preferably S, which is substituted with one or more substituents independently selected from the group consisting of haloalkyls, wherein the heteroaromatic ring is optionally substituted with one or more substituents independently selected from halogens, C1-C3 alkoxys, and C1-C3 alkyls, preferably Cl, which are selected from the group consisting of 5- or 6-membered heteroaromatic rings. R 1 However, hydrogen; halogen; C1-C6 haloalkoxy; O(CH2)n O(CH2) m R 1a ;NR 1b (CH2) n O(CH2) m Optionally, C3-C6 cycloalkyl, COOH, (O-CH2) m -CONR 1b R 1c C1-C6 alkoxy substituted with a 5-membered or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, or a 5-membered or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O; a 5-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N atom; Furthermore, selected from the group consisting of 5-membered or 6-membered heteroaryloxys, R 1a However, it is selected from the group consisting of hydrogen, a C1-C2 alkyl group, or a four-membered heterocycle containing NCOCH3, R 1b and R 1c However, they are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R 1b and R 1c However, together with the nitrogen atom to which they are bonded, they form a 5-membered or 6-membered saturated heterocycle. R 2 However, it is selected from the group consisting of hydrogen, C1-C3 alkyl, and halogen, R 3 However, hydrogen, hydroxy C1-C3 alkyl, (CH2) n OCH2CONR 9 R 9 , optionally selected from the group consisting of C1-C3 alkyl groups substituted with a 4-membered heterocycle containing NCOCH3, R 4 However, hydrogen, optionally substituted with OH, C1-C5 alkyl, or optionally substituted with OH, C1-C4 alkyl; optionally C1-C3 alkyl, NHR 9 CONR 9 R 9NHCO(C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 Selected from the group consisting of 4-membered, 5-membered, 6-membered, or 7-membered saturated cyclic rings or heterocycles substituted with COOH, CHO, CO(C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O, Or NH-R 4 However, NH-R 4 It forms a 5-membered or 6-membered saturated heterocycle with respect to the bonded carbon, R 5 However, selected from hydrogen, OH, and fluoro, R 6 However, they are independently selected from the group consisting of hydrogen and C1-C3 alkyl, or R 6 R 6 However, together with the nitrogen atoms to which they are bonded, they form a five-membered or six-membered ring, and optionally, this five-membered or six-membered ring further contains oxygen. R 7 However, at least one NR 8 It is a 5-membered or 6-membered aromatic ring containing R 8 However, hydrogen and CH2CONR 9 Selected from the group consisting of, R 9 However, independently selected from the group consisting of hydrogen and methyl, Each n is 1, 2, or 3 individually. Each m is either 0 or 1 individually. or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0015] In some embodiments, X is selected from CH and N, A1 is phenyl, which is optionally substituted with fluorophenyl, and selected from the group consisting of 5-membered or 6-membered heteroaromatic rings containing at least one heteroatom selected from N, S, and O. A2 is phenyl, which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C3 alkoxy, and C1-C3 alkyl, and is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from the group consisting of N, S, and O, preferably S, which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C3 alkoxy, and C1-C3 alkyl, preferably Cl, and is selected from the group consisting of 5- or 6-membered heteroaromatic rings, R 1 is hydrogen; halogen; C1-C6 haloalkoxy; O(CH2) n O(CH2) m R 1a ; optionally, C3-C6 cycloalkyl, COOH, (O-CH2) m -CONR 1b R 1c and is a C1-C6 alkoxy substituted with a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from the group consisting of N, O, and S, preferably at least one N heteroatom, or a 5-membered aromatic heterocyclic ring containing at least one heteroatom selected from the group consisting of N, O, and S, preferably at least one N heteroatom; and is selected from the group consisting of 5- or 6-membered heteroaryloxy, R 1a is selected from the group consisting of hydrogen, C1-C2 alkyl, or a 4-membered heteroaliphatic ring containing NCOCH3, R 1b and R 1c are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C3 alkyl, or R 1b and R 1c together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring, R 2 is selected from the group consisting of hydrogen, C1-C3 alkyl, and halogen, R3 is selected from the group consisting of hydrogen, hydroxy C1-C3 alkyl, (CH2) n OCH2CONR 9 R 9 and, optionally, C1-C3 alkyl substituted with a 4-member heteroaliphatic ring containing NCOCH3, R 4 is selected from the group consisting of hydrogen, C1-C4 alkyl optionally substituted with OH (linear C1-C4 alkyl or, in some embodiments, branched when the alkyl is C3-C4 alkyl), optionally, C1-C3 alkyl, NHR 9 CONR 9 R 9 NHCO(C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 COOH, or OH, or a 4-member, 5-member, 6-member, or 7-member saturated cyclic or heterocyclic ring substituted with C1-C3 alkyl and OH, or CH2OH and =O, or or NH-R 4 is NH-R 4 forms a 5-member or 6-member saturated heterocyclic ring with respect to the carbon to which it is attached, R 5 is selected from the group consisting of hydrogen, OH, and fluoro, R 6 is independently selected from the group consisting of hydrogen, C1-C3 alkyl, or R 6 R 6 forms a 5-member or 6-member ring with the nitrogen to which they are attached, and optionally the 5-member or 6-member ring further contains oxygen, R 7 is a 5-member or 6-member aromatic ring containing at least one NR 8 R 8 is selected from the group consisting of hydrogen and CH2CONR 9 R 9 is independently selected from the group consisting of hydrogen and methyl, each n is, individually, 1, 2, or 3, ​Each m is either 0 or 1 individually. or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0016] The compounds described in Formula I can function as TEAD binders. This is shown in Example 202, which demonstrates an SPR assay for determining the binding affinity of exemplary compounds 1-46 to 84-110 to TEAD1-4.

[0017] According to this disclosure, the compound of formula I may further comprise a second compound having binding affinity to another target present in the mammalian body. Such a compound may be linked directly or via a suitable linker, optionally comprising the R of formula I. 1 , R 3 , or R 4 is either a bond site to a linker or a second compound, or contains a bond site.

[0018] In some embodiments, the halogen is selected from the group consisting of chloro and fluoro.

[0019] In some embodiments, X is CF, CH, or N. In some embodiments, X is CH or N. In some embodiments, X is CH.

[0020] In some embodiments, A1 is phenyl or a six-membered heteroaromatic compound. In some embodiments, A1 is phenyl or pyridine. In some embodiments, A1 is phenyl.

[0021] In some embodiments, A2 is a phenyl molecule substituted with at least one halogen. In some embodiments, A2 is a phenyl molecule substituted with one or two chlorine atoms and / or one or two fluorine atoms. In some embodiments, A2 is selected from the group consisting of phenyl molecules substituted with at least one halogen and five-membered heteroaromatic rings.

[0022] As will be apparent to those skilled in the art, according to formula I, A2 bonds to the rest of the molecule in an ortho, meta, or para configuration. Those skilled in the art will understand that this explains how A2 bonds to the ring containing X and the carbon to which A1 is bonded. In other words, A2 bonds to formula I such that the ring containing X and the carbon to which A1 is bonded are located ortho, meta, or para relative to each other.

[0023] In one embodiment, A2 binds to the remaining general portion of the molecular ortho. In one embodiment, A2 binds to the remaining general portion of the molecular meta. In one embodiment, A2 binds to the remaining general portion of the molecular para.

[0024] In some embodiments, R 1 However, hydrogen; halogen; C1-C6 haloalkoxy, O(CH2) n O(CH2) m R 1a ;NR 1b (CH2) n O(CH2) m Optionally, C3-C6 cycloalkyl, (O-CH2) m -CONR 1b R 1c , selected from the group consisting of a 6-membered heteroaromatic ring containing at least one N, or a 5-membered saturated heterocycle containing one heteroatom selected from N and O, C1-C6 alkoxy; a 5-membered aromatic heterocycle containing at least one N; and a 5-membered or 6-membered heteroaryloxy, R 1a However, it is selected from the group consisting of hydrogen, C1-C2 alkyl, and a four-membered heteroaliphatic ring containing NCOCH3, R 1b and R 1c However, they are independently selected from the group consisting of hydrogen and C1-C3 alkyl groups.

[0025] In some embodiments, R 1 However, hydrogen; halogen; C1-C6 haloalkoxy, O(CH2) n O(CH2) m R1a Optionally, C3-C6 cycloalkyl, (O-CH2) m -CONR 1b R 1c , selected from the group consisting of a 6-membered heteroaromatic ring containing at least one N, or a 5-membered saturated heterocycle containing one heteroatom selected from N and O, C1-C6 alkoxy; a 5-membered aromatic heterocycle containing at least one N; and a 5-membered or 6-membered heteroaryloxy, R 1a However, it is selected from the group consisting of hydrogen, C1-C2 alkyl, and a four-membered heteroaliphatic ring containing NCOCH3, R 1b and R 1c However, they are independently selected from the group consisting of hydrogen and C1-C3 alkyl groups.

[0026] In some embodiments, R1 is selected from the group consisting of the following: [ka]

[0027] In some embodiments, R 1 The group is selected from the following: [ka]

[0028] As will be obvious to those skilled in the art, [ka] This indicates the bonding position to R1 and can be seen as a bonding point to R1. As will be obvious to those skilled in the art, the bond can also be called a bonding point.

[0029] In some embodiments, R 2is selected from the group consisting of hydrogen and F.

[0030] In some embodiments, R 3 R is selected from the group consisting of C2 alkyl groups substituted with a four-membered heteroaliphatic ring containing hydrogen, (CH2)2OCH2CON(CH3)2, and NCOCH3. In some embodiments, R 3 It is hydrogen.

[0031] In some embodiments, R 4 However, C2-C4 alkyl substituted with hydrogen, C1-C4 alkyl, OH; 4-membered, 5-membered, 6-membered, or 7-membered saturated cyclic rings or heterocycles; C1-C3 alkyl, NHR 9 CONR 9 R 9 NHCO(C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 Selected from the group consisting of a 6-membered saturated cyclic ring or heterocycle substituted with COOH, or OH, or C1-C3 alkyl and OH, or CH2OH and =O, or NH-R 4 However, NH-R 4 It forms a 5-membered saturated heterocycle with respect to the bonded carbon. Alternatively, NH-R 4 However, NH-R 4 It forms a 6-membered saturated heterocycle with respect to the bonded carbon.

[0032] In some embodiments, R 4 However, hydrogen; C1-C4 alkyl; OH-substituted C2-C4 alkyl; 4-membered, 5-membered, 6-membered, or 7-membered saturated cyclic ring or heterocycle; C1-C3 alkyl, NHR 9 CONR 9 R 9 NHCO(C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 Selected from the group consisting of a 6-membered saturated cyclic ring or heterocycle substituted with COOH, OH, C1-C3 alkyl and OH, or CH2OH and =O, or NH-R4 However, NH-R 4 It forms a 5-membered saturated heterocycle with respect to the bonded carbon. Alternatively, NH-R 4 However, NH-R 4 It forms a 6-membered saturated heterocycle with respect to the bonded carbon.

[0033] In some embodiments, R 4 However, hydrogen, and CHO, COOH, CONHR 6 The group consists of , or 6-membered saturated rings substituted with NH2, selected from the group.

[0034] In some preferred embodiments, R 4 This is selected from the group consisting of 6-membered saturated rings substituted with hydrogen and NH2.

[0035] In some embodiments, R 5 It is hydrogen.

[0036] In some embodiments, A2 is bonded to formula I such that the ring having X and the carbon to which A1 is bonded are located ortho, meta, or para relative to each other.

[0037] In one embodiment, the compound of formula I is 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxoxazolidine-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidine-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide, (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-3-yloxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4s)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide, 5-(2-((1-acetylazetidine-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-3',6-difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-(methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H-pyrazole-1-yl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-N-(2-(2-(dimethylamino)-2-oxoethoxy)ethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, N-((1-acetylazetidine-3-yl)methyl)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)benzamide, 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)-3-fluorobenzamide, Selected from the group consisting of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-3'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide and / or 2'-Chloro-6-fluoro-5'-(2-((3-hydroxy-3-methylbutyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(morpholine-4-carbonyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(((1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl)amino)ethyl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-4',6-difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 3'-(2-amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide, (1r,4r)-4-((2-(6'-carbamoyl-4,6-dichloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and its stereoisomers, (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and its stereoisomers, 2'-Chloro-6-fluoro-5'-{1-fluoro-1-phenyl-2-[(propan-2-yl)amino]ethyl}-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-4'-methyl-[1,1'-biphenyl]-2-carboxamide, 5'-(2-((1-acetylpiperidine-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((R)-1-acetylpiperidine-3-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-((2-methoxyethyl)(methyl)amino)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate, 2'-Chloro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(propylamino)ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(isobutylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, (5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4,6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide hydrochloride, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-acetamidocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(methylcarbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, Selected from the group consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0038] In some embodiments, the compound is 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxoxazolidine-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidine-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide, (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-3-yloxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4S)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide, 5-(2-((1-acetylazetidine-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-3',6-difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-(methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H-pyrazole-1-yl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-N-(2-(2-(dimethylamino)-2-oxoethoxy)ethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, N-((1-acetylazetidine-3-yl)methyl)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)benzamide, 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)-3-fluorobenzamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-3'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-((3-hydroxy-3-methylbutyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(morpholine-4-carbonyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(((1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl)amino)ethyl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-4',6-difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 3'-(2-amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide, (1r,4r)-4-((2-(6'-carbamoyl-4,6-dichloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and its stereoisomers, (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and its stereoisomers, 2'-Chloro-6-fluoro-5'-{1-fluoro-1-phenyl-2-[(propan-2-yl)amino]ethyl}-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-4'-methyl-[1,1'-biphenyl]-2-carboxamide, 5'-(2-((1-acetylpiperidine-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((R)-1-acetylpiperidine-3-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-((2-methoxyethyl)(methyl)amino)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate, 2'-Chloro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(propylamino)ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(isobutylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, (5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4,6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide hydrochloride, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-acetamidocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(methylcarbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, Selected from the list consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0039] This disclosure provides a compound of formula I according to a first aspect of the present invention that targets TEAD. A conjugate comprising the compound of formula I and a ligase binder can recruit TEAD to E3 ubiquitin ligase for degradation. Thus, according to a second aspect of the present invention, formula II: A conjugate that is ABC(formula II), contains it, or is essentially derived from it, In the formula, A is a compound of formula I described in any one of the embodiments of the first embodiment, provided that R in formula I is 1 , R 3 , or R 4 A conjugate is provided in which one of them is a bond to B, or includes one. In other words, R in equation I 1 , R 3 , or R 4 The condition is that one of these is a bond site to B, or contains one. Alternatively, AB is a condensation product formed from the compound of formula I and linker B as described in the first embodiment. As will be apparent to those skilled in the art, the condensation product requires the removal of water in the reaction that forms the product. Thus, the condensation product AB is formed from a carboxylic acid (-COOH) and an amine (-NHR or -NH2) and may form an amide bond (-CONR- or -CONH-) and water (H2O). Therefore, when formula I is bonded to linker B via -COOH, the resulting conjugate will lack the OH previously present in the carboxylic acid of formula I, as will be apparent to those skilled in the art.

[0040] B is a linker. B may also be a linker that covalently bonds A to C.

[0041] C is a ligase binder. Conjugates according to formula II can function as TEAD binders. This is shown in Example 202, which demonstrates an SPR assay for determining the binding affinity of exemplary compounds 1-46 and 84-110, as well as exemplary conjugates 47-83 and 111-200, to TEAD 1-4.

[0042] Without being bound by any particular theory, the conjugate by formula II may induce the formation of a triple complex containing the conjugates of formula II, TEAD, and E3 ligase, or a triple complex containing the conjugates of formula II, TEAD, and cereblon.

[0043] The conjugate according to Formula II can function as a TEAD degrading agent. This is illustrated by some of the conjugates according to the second embodiment; see Example 204. This is evident from Figures 1 and / or 2, which show the amount of TEAD after incubation with the conjugate according to the second embodiment of the present invention.

[0044] As will be apparent to those skilled in the art, a linker is a group that covalently bonds the compound of formula I(A) to a ligase binder (C). Those skilled in the art will understand which linkers are suitable for the conjugate according to the second aspect of the present invention. For example, a linker may have 1 to 13, preferably less than 10, rotatable bonds. In addition, a linker may have 5 to 30, preferably less than 26, non-hydrogen atoms. In addition, a linker may have several hydrogen bond donors, preferably at most two. Those skilled in the art will be familiar with the meaning of rotatable bonds, as well as the meaning of non-hydrogen atoms and hydrogen bond donors. The linker according to the present invention may be a diamine linker, a spirocyclic or heterospirocyclic linker, a cyclic or heterocyclic linker, a linear or branched C1-C10 alkyl linker, an ether linker, or an amino acid linker, i.e., the linker may contain any or a combination of these groups.

[0045] The ligase binder is a group that can bind to ligases such as ubiquitin ligases, including cereblon E3 ubiquitin ligase. Other ligase binders suitable for the conjugate of formula II are also part of this disclosure.

[0046] As described above, those skilled in the art will understand which linker is suitable to be part of the conjugate according to formula II. In some embodiments, the linker B has formula -L1-X1-L2-X2-L3-(B), and the conjugate is formula: It has A-L1-X1-L2-X2-L3-C, and in the formula, L1 is selected from the group consisting of binding, -O-, -NR'-, -C(O)-, C1-C9 alkylene, C1-C9 heteroalkylene, *C(O)-C1-C6 alkylene, *C(O)-C1-C6 heteroalkylene, *C1-C6 alkylene-C(O), *C1-C6 heteroalkylene-C(O), and *L1a-C4-C7 cycloalkylene, where * indicates the binding of L1 to X1. L1a is selected from the group consisting of C(O), *NH-C(O), and *C1-C6 alkylene-NH-C(O), where * indicates the binding of L1a to X1. X1 and X2 are each independently selected from the group consisting of a 4-7 member heterocyclene containing 1-3 heteroatoms independently selected from the group consisting of a bond, C4-C7 cycloalkylene, N, O, and S, and a 5- or 6-member heteroarylene containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S. L2 is selected from the group consisting of bond, -O-, -NR'-, -C(O)-, C1-C6 alkylene, -NR'-C1-C9 alkylene-NR'-, *C1-C9 alkylene-NR'-, *NR'-C1-C9 alkylene, *C(O)NR'-C1-C5 alkylene, polyethylene glycol, -NR'-polyethylene glycol-NR'-, polyethylene glycol, *NR'-polyethylene glycol, and *polyethylene glycol-NR', where * indicates the bond of L2 to X2, or X1-L2-X2 forms a 7-13 member spiroheterocycline containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S. L3 is bonded, C1-C5 alkylene, C2- Selected from the group consisting of C5 alkenylene, C1-C6 alkylylene, C1C6 heteroalkylene, -C(O)-, -S(O)r, -O-, *C(O)-C1-C6 alkylene, *C(O)-C1-C5 alkylene-O, *C(O)-C1-C6 heteroalkylene, *C1-C5 alkylene-NH, and *NH-C1-C5 alkylene, where * indicates the bond of L3 to X2, and each R' is independently hydrogen or C1-C6 alkyl, preferably each R' is hydrogen.

[0047] In some embodiments, L1 is *L1a-C4-C1 cycloalkylene**, where L1a is selected from the group consisting of bond, C(O), *NH-C(O), and *C1-C5 alkylene-NH-C(O). * indicates bond to X1, and ** indicates bond to A. In some embodiments, L1 is *L1a-C6 cycloalkylene**, where L1a is selected from the group consisting of C(O), *NH-C(O), and *C1-C5 alkylene-NH-C(O) (e.g., *C2 alkylene-NHC(O))). * indicates bond to X1.

[0048] In some embodiments, the linker B has the formula -L1-X1-L2-X2-L3- or L1-X1-L2-X2-L3-X3-L4-(B), and the conjugate has the formula: Having A-L1-X1-L2-X2-L3-C or A-L1-X1-L2-X2-L3-X3-L4-C, X1 and X2 are each independently selected from the group consisting of bond, -O-, -CH2-, and -NH-. L1, L2, and L3, or L1, L2, L3, and L4, each individually, join, A heterospiror ring or spiro ring having 7 to 11 ring atoms, Ring or heteroring, A bicyclic or biheterocyclic ring, or two rings or heterocyclic rings bonded to each other via carbon, nitrogen, or oxygen, The linker is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, CO(C1-C6-alkyl), (C1-C3-alkyl)CO(C1-C3-alkyl), CO, CO(CH2)O, NHCO, NHCO(CH2)O, or the linker is the bond between A and C in formula II, and R 1a However, hydrogen, C1-C2 alkyl, or The group consists of aromatic or heteroaromatic rings having 5 to 6 ring atoms. Optionally, the heteroaromatic ring may contain one or two nitrogen atoms.

[0049] According to this embodiment, the linker is optionally replaced with F, Me, and OH. Those skilled in the art will understand which positions are suitable for such substitutions.

[0050] In some embodiments, L1, L2, and L3, or L1, L2, L3, and L4 are each individually linked to -CH2-, -C(=O)-, -O-, -NH-, -NH-C1-C3 alkyl, -NH-hydroxyC1-C3 alkyl, [ka] It is selected from the group consisting of the following.

[0051] As will be obvious to those skilled in the art, each [ka] is a bonding point to A, X1, X2, or C. Furthermore, the linker may be substituted with F, Me, OH at any preferred position of L1, L2, and / or L3, or L1, L2, L3, and / or L4. Those skilled in the art will understand that such substituents can be at any position of L1, L2, and / or L3, except at the bonding point, or they can be at L1, L2, L4, and / or L4.

[0052] In some embodiments, the linker is selected from the group consisting of the following: [ka] TIFF2026519523000009.tif236170TIFF2026519523000010.tif180170 In the formula, A is the compound of formula I, and C is the ligase binder.

[0053] In some embodiments, the linker is selected from the group consisting of the following: [ka] In the formula, A is the compound of formula I, and C is the ligase binder. In this embodiment, R of formula I 4 It is particularly preferable that this is a bond to B, or a portion of A that contains a bond to B. In other words, this linker group is R in formula I. 4 It is particularly suitable for bonding at this position.

[0054] In some embodiments, the linker is selected from the group consisting of the following: [ka] In the formula, A is the compound of formula I, and C is the ligase binder. In this embodiment, R of formula I 4 It is particularly preferable that this is a bond to B, or a portion of A that contains a bond to B. In other words, this linker group is R in formula I. 4 It is particularly suitable for bonding at this position.

[0055] In some embodiments, the linker is selected from the group consisting of the following: [ka] In the formula, A is the compound of formula I, and C is the ligase binder. In this embodiment, R of formula I 1 or R 3 It is particularly preferable that this is a bond to B, or a portion of A that contains a bond to B. In other words, this linker group is R of formula I. 1 or R 3 It is particularly suitable for bonding at this position.

[0056] In some embodiments, the linker is selected from the group consisting of the following: [ka] TIFF2026519523000015.tif254170TIFF2026519523000016.tif71170

[0057] As will be obvious to those skilled in the art, each [ka] is a bonding point to A or C. Furthermore, the linker may be substituted with F, Me, OH at any preferred position in L1, L2, L3 and / or L4, or at any position in L1, L2 and / or L3. Those skilled in the art will understand that such substituents can be at any position in L1, L2, L3 and / or L4, except at the bonding point, or at any position in L1, L2 and / or L3. In this embodiment, R 4 Formula I is preferably a bond to B, or a portion of A that contains a bond to B. In other words, this linker group is R of Formula I. 4 It is particularly suitable for bonding at the position of . According to this embodiment, the most preferred is R of formula I 4 However, it must be cyclohexyl-4-amine or cyclohexyl-4-formyl.

[0058] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0059] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0060] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0061] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0062] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0063] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0064] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0065] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0066] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0067] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0068] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0069] In some embodiments, the linker is selected from the group consisting of the following: [ka]

[0070] A conjugate according to a second aspect of the present invention includes a linker of a certain length. Such a length can be calculated as the shortest length between A and C in the conjugate. In some embodiments, the length of the linker is 2 to about 50 links between A and C, e.g., 3 to about 45 links, e.g., 3 to about 40 links, e.g., 3 to about 35 links, e.g., 3 to about 30 links, e.g., 4 to about 23 links, e.g., 4 to 23 links, or e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 links between A and C.

[0071] The ligase binders according to this disclosure may comprise two or three five-membered or six-membered cyclic or heterocyclic rings, at least one of which is aromatic. If the ligase binder comprises two rings, one of the rings may be phenyl or a phenyl substituted with an alkoxy such as methoxy. In some embodiments, the second ring is glutarimide or dihydrouracil.

[0072] If the ligase binder contains three rings, two of the rings may form a biringle, such as phthalimide. In some embodiments, the third ring is glutarimide or dihydrouracil.

[0073] The ligase binder may comprise a six-membered heterocyclic group containing one or two nitrogen atoms and / or two oxo substituents within the ring. In preferred embodiments, the ligase binder comprises a glutarimide or dihydrouracil group, or a similar group.

[0074] In some embodiments, the ligase binder is selected from the group consisting of the following: [ka]

[0075] In some embodiments, the ligase binder is selected from the group consisting of the following: [ka] During the ceremony, [ka] R is either a linking point to a linker or a linking to a linker such as linker B according to this disclosure, where R is H, F, Cl, methyl, or methoxy. In one embodiment, R is H. In one embodiment, R is F. In one embodiment, R is Cl. In one embodiment, R is methoxy. In one embodiment, R is methyl. Those skilled in the art will understand that R can be at any available position within the phenyl ring. In other words, if R is not H, R may substitute for H in the phenyl ring.

[0076] In some embodiments, the ligase binder is selected from the group consisting of the following: [ka] During the ceremony, [ka] This is either a coupling of a linking point to a linker, or a coupling to a linker such as linker B according to this disclosure.

[0077] In some embodiments, the ligase binder is selected from the group consisting of the following: [ka] During the ceremony, [ka] This is either a coupling of a linking point to a linker, or a coupling to a linker such as linker B according to this disclosure.

[0078] The conjugates according to this disclosure can be prepared as shown in the examples. In the embodiments, the conjugate comprises compound A of formula I as described in a first aspect of the present invention, and the conjugate is prepared by reacting the compound with an intermediate formed from a ligase binder C and a linker B as described in this disclosure. Thus, the intermediate may be represented by BC. In some embodiments, the intermediate is used to form the conjugate of formula II, 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-carboxylic acid, 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-carboxylic acid, 2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetic acid, 3-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethoxy}propanoic acid, 3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propanoic acid, 2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetic acid, 2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetic acid, 2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetic acid, 2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetic acid, 3-{2-[2-(2-{[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxyphenyl]formamide}ethoxy)ethoxy]ethoxy}propanoic acid, 2-{4-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperazine-1-yl}acetic acid, 2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxyacetic acid, 2-(2,6-dioxopiperidine-3-yl)-4-(piperazine-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione, 4-({2-[2-(2-aminoethoxy)ethoxy]ethyl}amino)-2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, 4-[4-(2-aminoethyl)piperidine-1-yl]-2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, 4-{[4,4'-bipiperidine]-1-yl}-2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, 2-(2,6-dioxopiperidine-3-yl)-4-[4-(piperidine-4-yloxy)piperidine-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione, 4-[4-(aminomethyl)piperidine-1-yl]-2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, 5-(3-aminoazetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, 5-[3-(aminomethyl)azetidine-1-yl]-2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, 2-(2,6-dioxopiperidine-3-yl)-4-{4-[(piperidine-4-yl)methyl]piperazine-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione, 2-(2,6-dioxopiperidine-3-yl)-4-[4-(piperidine-4-carbonyl)piperazine-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione, 2-(2,6-dioxopiperidine-3-yl)-5-{2-oxo-2-[4-(piperidine-4-yloxy)piperidine-1-yl]ethoxy}-2,3-dihydro-1H-isoindole-1,3-dione, and Selected from the group consisting of 5-{2-[4-(2-aminoethyl)piperidine-1-yl]-2-oxoethoxy}-2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione.

[0079] In one embodiment, the conjugate is 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetamide)cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(8-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]oxy}octanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethoxy}propanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-N-[(1r,4r)-4-[(2-{6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl}-2-phenylethyl)amino]cyclohexyl]piperidine-4-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propanamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxyphenyl]formamide}ethoxy)ethoxy]ethoxy}propanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5,6-difluoro-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]oxy}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}-2-oxoethyl)-1H-pyrazole-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)-2-oxoethyl]-1H-pyrazole-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}methyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-[2-({1-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propanoyl]azetidine-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-[2-({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetyl]azetidine-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-{2-[(1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-carbonyl}azetidine-3-yl)oxy]ethoxy}-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and 2'-Chloro-5-(2-{[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and 2-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylphenoxy)acetic acid, 4-Chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzoic acid, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxybenzoic acid, (1r,4r)-4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzoyl)piperidine-4-yl)oxy)cyclohexane-1-carboxylic acid, 1r,4r)-4-((1-(2-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylphenoxy)acetyl)piperidine-4-yl)oxy)cyclohexane-1-carboxylic acid, (1r,4r)-4-(4-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzoyl)piperazine-1-yl)cyclohexane-1-carboxylic acid--2,2,2-trifluoroacetic acid, (1r,4r)-4-(4-(2-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylphenoxy)acetyl)piperazine-1-yl)cyclohexane-1-carboxylic acid, 4-[[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]-4-piperidyl]oxy]cyclohexanecarboxylic acid, 1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxybenzoyl]piperidine-4-carboxylic acid, 2-[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxybenzoyl]-4-piperidyl]acetic acid, 1-[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]piperidine-4-carbonyl]piperidine-4-carboxylic acid, 2-[1-[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]piperidine-4-carbonyl]-4-piperidyl]acetic acid, 1-[1-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]piperidine-4-carbonyl]piperidine-4-carboxylic acid, 2-[4-[[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]-4-piperidyl]methyl]-1-piperidyl]acetic acid, 2-[3-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]-3,9-diazaspiro[5.5]undecane-9-yl]acetic acid, 2-[4-[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]-4-piperidyl]-1-piperidyl]acetic acid, 2-[4-[[1-[4-chloro-3-(2,4-dioxohexahydropyrimidine-1-yl)benzoyl]-4-piperidyl]methyl]-1-piperidyl]acetic acid, 2-[4-[[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]-4-piperidyl]oxy]-1-piperidyl]acetic acid, 2-[4-[2-[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzoyl]-4-piperidyl]ethyl]-1-piperidyl]acetic acid, 2-(4-{1-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperidine-4-yl}piperazine-1-yl)acetic acid, 2-[4-[[1-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]-4-piperidyl]methyl]-1-piperidyl]acetic acid, 2-[4-[1-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]-4-piperidyl]-1-piperidyl]acetic acid, 2-[3-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]-3,9-diazaspiro[5.5]undecane-9-yl]acetic acid, 2-[4-[2-[1-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]-4-piperidyl]ethyl]-1-piperidyl]acetic acid, 2-[4-[[4-[[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]amino]-1-piperidyl]methyl]-1-piperidyl]acetic acid, 2-[4-[4-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]piperazine-1-yl]-1-piperidyl]acetic acid, 2-[4-[[4-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]piperazine-1-yl]methyl]-1-piperidyl]acetic acid, 2-[4-[[1-[2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]acetyl]-4-piperidyl]oxy]-1-piperidyl]acetic acid, 2-[4-(2,4-dioxohexahydropyrimidine-1-yl)-3-methylphenoxy]acetic acid, 2-[4-(2,4-dioxohexahydropyrimidine-1-yl)-3-methylphenoxy]acetic acid, 2 2-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindorin-4-yl]-4-piperidyl]methyl]-1-piperidyl]acetic acid, 1-[2-Methoxy-5-[4-(4-piperidylmethyl)piperidine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione, N-(4-aminobutyl)-3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-benzamide, 1-[2-methoxy-5-(piperazine-1-carbonyl)phenyl]hexahydropyrimidine-2,4-dione, 1-[5-[4-(2-aminoethyl)piperidine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[5-[4-(2-aminoethoxy)piperidine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[5-(3,9-diazaspiro[5,5]undecane-3-carbonyl)-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[5-(2,9-diazaspiro[5,5]undecane-2-carbonyl)-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[2-methoxy-5-[4-(4-piperidyl)piperidine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methoxy-5-[4-(4-piperidyloxy)piperidine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-chloro-5-[4-(4-piperidylmethyl)piperidine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methoxy-5-[4-[2-(4-piperidyl)ethyl]piperidine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-Methoxy-5-(4-piperazine-1-ylpiperidine-1-carbonyl)phenyl]hexahydropyrimidine-2,4-dione, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-(4-piperidyl)benzamide, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-(4-piperidylmethyl)benzamide, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-[(3R)-3-piperidyl]benzamide, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-[(3S)-3-piperidyl]benzamide, 1-[5-[4-(4-aminopiperidine-1-carbonyl)piperidine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[5-[4-[4-(aminomethyl)piperidine-1-carbonyl]piperidine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[5-[4-[4-(2-aminoethyl)piperidine-1-carbonyl]piperidine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[5-[4-[4-(aminomethyl)benzoyl]piperazine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[5-[4-[[4-(aminomethyl)phenyl]methyl]-piperazine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 1-[2-Methoxy-5-(4-{[(1r,3r)-3-aminocyclobutyl]methyl}piperazine-1-carbonyl)phenyl]-1,3-diadinane-2,4-dione, 1-[2-methoxy-5-[4-[[1-(4-piperidylmethyl)-4-piperidyl]methyl]piperidine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-[1-(4-piperidylmethyl)-4-piperidyl]benzamide, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-[[1-(4-piperidylmethyl)-4-piperidyl]methyl]benzamide, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-[(3S)-1-(4-piperidylmethyl)-3-piperidyl]benzamide, 3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methoxy-N-[(3R)-1-(4-piperidylmethyl)-3-piperidyl]benzamide, 1-[2-methoxy-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione, 1-(2-methyl-5-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, 1-[5-[2-[4-(2-aminoethyl)-1-piperidyl]-2-oxo-ethoxy]-2-methylphenyl]hexahydropyrimidine-2,4-dione hydrochloride, 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidylmethyl)-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione hydrochloride, 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidyl)-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidyloxy)-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methyl-5-[2-oxo-2-[4-[2-(4-piperidyl)ethyl]-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]-N-(4-piperidyl)acetamide, 2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]-N-(4-piperidylmethyl)acetamide, 1-[2-methyl-5-[2-oxo-2-(4-piperazin-1-yl-1-piperidyl)ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[5-[2-(3,9-diazaspiro[5,5]undecane-3-yl)-2-oxo-ethoxy]-2-methylphenyl]hexahydropyrimidine-2,4-dione, 1-[5-[2-[4-(4-aminopiperidine-1-carbonyl)-1-piperidyl]-2-oxo-ethoxy]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione, 1-[5-[2-[4-[4-(aminomethyl)piperidine-1-carbonyl]-1-piperidyl]-2-oxo-ethoxy]-2-methylphenyl]hexahydropyrimidine-2,4-dione, 1-[5-[2-[4-[[4-(aminomethyl)phenyl]methyl]piperazin-1-yl]-2-oxo-ethoxy]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione, 1-[5-[4-[(3-aminocyclobutyl)methyl]piperazine-1-carbonyl]-2-methoxyphenyl]hexahydropyrimidine-2,4-dione, 2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]-N-[1-(4-piperidylmethyl)-4-piperidyl]acetamide, 2 2-[3-(2,4-dioxohexahydropyrimidine-1-yl)-4-methylphenoxy]-N-[[1-(4-piperidylmethyl)-4-piperidyl]methyl]acetamide, 1-[2-methyl-5-[2-oxo-2-[4-[[1-(4-piperidylmethyl)-4-piperidyl]methyl]-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methyl-5-[2-oxo-2-[4-[1-(4-piperidylmethyl)-4-piperidyl]-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidylmethyl)piperazine-1-yl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methyl-4-[2-oxo-2-[4-(4-piperidyloxy)-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methyl-4-[2-oxo-2-[4-(4-piperidylmethyl)-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 1-[2-methyl-4-[2-oxo-2-[4-(4-piperidyl)-1-piperidyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione, 2-(2,6-dioxo-3-piperidyl)-4-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3-dione, and The intermediate is selected from the group consisting of 3-(3-{4-[(piperidine-4-yl)methyl]piperidine-1-carbonyl}phenyl)piperidine-2,6-dione. The intermediate may be in the form of a salt, such as a trifluoroacetate.

[0080] This disclosure presents non-limiting examples of conjugates according to the present invention. In some embodiments, the conjugate is: 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetamide)cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(8-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]oxy}octanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethoxy}propanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-N-[(1r,4r)-4-[(2-{6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl}-2-phenylethyl)amino]cyclohexyl]piperidine-4-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propanamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxyphenyl]formamide}ethoxy)ethoxy]ethoxy}propanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5,6-difluoro-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]oxy}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}-2-oxoethyl)-1H-pyrazole-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)-2-oxoethyl]-1H-pyrazole-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}methyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-[2-({1-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propanoyl]azetidine-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-[2-({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetyl]azetidine-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-{2-[(1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-carbonyl}azetidine-3-yl)oxy]ethoxy}-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and Selected from the list consisting of 2'-chloro-5-(2-{[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide and / or 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-3-methoxybenzoyl]piperazine-1-carbonyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(2-{1-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(4-{[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxyphenyl]formamide}butyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{2-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{9-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]-3,9-diazaspiro[5;5]undecane-3-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{2-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methylphenoxy]acetyl}piperazine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinan-1-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-({1-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperidine-4-yl}oxy)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]-2,9-diazaspiro[5;5]undecane-9-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-(2-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-({4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-yl}methyl)cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzamide]piperidine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxyphenyl]formamide}methyl)piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3S)-3-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzamide]piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3R)-3-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzamide]piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{[(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{[(4-{4-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperazine-1-carbonyl}phenyl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-({[4-({4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-yl}methyl)phenyl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)piperidine-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)piperidine-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{[1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)piperidine-4-yl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)ethyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetamide}piperidine-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetamide}methyl)piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl-[4,4'-bipiperidine]-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl}piperidine-4-yl)oxy]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1'-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]-[4,4'-bipiperidine]-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{9-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]-3,9-diazaspiro[5;5]undecane-3-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(2-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}piperazine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}oxy)cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-4-yl}oxy)cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-{4-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-1-yl}cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}-N-[(1r,4r)-4-{[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxolan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methylphenoxy]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(9-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-3,9-diazaspiro[5;5]undecane-3-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)ethyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetamide}piperidine-1-yl)methyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)piperazine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)-N-[(1r,4r)-4-{[2'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxolan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl-[4,4'-bipiperidine]-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(dimethylcarbamoyl)methoxy]-3',6-difluoro-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,6-dioxopiperidine-3-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and Selected from the group consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl]piperidine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0081] In one embodiment, the conjugate is 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}-2-oxoethyl)-1H-pyrazole-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamyl do2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)-2-oxoethyl]-1H-pyrazole-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and Selected from the group consisting of 2'-chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide.

[0082] In a particularly preferred embodiment, the conjugate is 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindyl-4-yl]piperazine-1-carbonyl}piperidine, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and Selected from the group consisting of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0083] In one embodiment, the conjugate is 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and Selected from the group consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0084] The conjugate obtained by reacting the intermediate BC with the compound of formula I is within the scope of this disclosure.

[0085] In a third embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound described in any one embodiment of the first embodiment, or a conjugate described in any one embodiment of the second embodiment, and at least one pharmaceutically acceptable diluent, carrier, and / or excipient. Typically, the composition or conjugate of the present invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable diluent, carrier, and / or excipient, forms a pharmaceutical composition in a form suitable for oral or parenteral administration. Suitable pharmaceutically acceptable diluents, carriers, and / or excipients will be apparent to those skilled in the art.

[0086] In a fourth embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount for use as a pharmaceutical, of the compound described in any one embodiment of the first embodiment, or the conjugate described in any one embodiment of the second embodiment, or the pharmaceutical composition described in the third embodiment.

[0087] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of the compound described in any one embodiment of the first aspect, or the conjugate described in any one embodiment of the second aspect, for use in binding to TEAD, or the pharmaceutical composition described in the third aspect. TEAD may be any or all of TEAD1, 2, 3, and / or 4. The compound and / or conjugate may bind to TEAD1, TEAD2, TEAD3, and / or TEAD4 (TEADx) with high affinity, as described above. High affinity according to this disclosure may include affinity with a KD value of less than 500 μM, e.g., less than 400 μM, e.g., less than 300 μM, e.g., less than 200 μM, e.g., less than 100 μM, e.g., less than 50 μM, e.g., less than 40 μM, e.g., less than 30 μM, e.g., less than 20 μM, e.g., less than 15 μM, e.g., less than 10 μM, e.g., less than 7.5 μM, or preferably less than 5 μM, e.g., less than 4 μM, e.g., less than 3 μM.

[0088] Furthermore, a pharmaceutical composition is provided comprising a therapeutically effective amount of the compound described in any one embodiment of the first embodiment, or the conjugate described in any one embodiment of the second embodiment, for use in suppressing or deactivating the Hippo pathway and / or suppressing or blocking TEAD-mediated gene transcription, or for use in suppressing or blocking TEAD-mediated gene transcription, or for use in the pharmaceutical composition described in the third embodiment.

[0089] A fifth embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one embodiment of the first embodiment, or a conjugate according to any one embodiment of the second embodiment, or a pharmaceutical composition according to the third embodiment, for use in the treatment of a disease or disorder in which the Hippo pathway is hyperactivated. According to this embodiment, the Hippo pathway may be hyperactivated, for example, due to overexpression of YAP, or due to mutation or deletion of LATS2, or due to neurofibromatosis type 2 (NF2), or due to hypermethylation of the LATS2 promoter. Those skilled in the art will recognize that NF2-deficient tumors include schwannomas and meningiomas.

[0090] In a sixth embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of the compound, conjugate, or composition described in any one embodiment of the first embodiment, or the conjugate described in any one embodiment of the second embodiment, for use in the treatment of cancer by administration to a patient in need thereof. In some embodiments of the sixth embodiment, the cancer is selected from the group consisting of bone cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma.

[0091] In some embodiments of the sixth aspect, administration is combined with at least one compound selected from the group consisting of AKT inhibitors such as afrecertib, capivacertib, ipatasertib, mirancertib, perifosin, and uprosertib; CDK4 / 6 inhibitors such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors such as binimetinib, cobimetinib, and trametinib; FGFR inhibitors; mTOR inhibitors; MEK1 inhibitors; ALK inhibitors; HSP90 inhibitors; CDK8 inhibitors; PI3K-alpha inhibitors; ABL1 inhibitors; and XPO1 inhibitors. In some embodiments, the administration is combined with at least one compound selected from the group consisting of AKT inhibitors such as afrecertib, capivacertib, ipatasertib, mirancertib, perifosin, and uprosertib; CDK4 / 6 inhibitors such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors such as binimetinib, cobimetinib, and trametinib.

[0092] As described in the background of the present invention, the Hippo signaling pathway plays a role in regulating wound healing. When this pathway is disrupted, fibrosis may occur due to the overexpression of pro-fibrosis genes such as CTGF and ANKRD1, which are regulated by TEAD

[12] . Therefore, blocking TEAD-mediated gene transcription has potential applications in the treatment and prevention of fibrotic diseases

[13] . Accordingly, a seventh aspect provides a pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one embodiment of the first aspect, or a conjugate described in any one embodiment of the second aspect, or a pharmaceutical composition described in the third aspect, for use in the treatment of fibrosis by administration to a patient in need.

[0093] In some embodiments of the seventh aspect, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, scleroderma, or fibrosis associated with chronic diseases of major organs such as the liver (cirrhosis), heart, lungs, and / or kidneys. In some embodiments, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

[0094] In the eighth aspect, a method for treating cancer is provided, comprising administering a therapeutically effective amount of a compound according to any one embodiment of the first aspect, a conjugate according to any one embodiment of the second aspect, or a pharmaceutical composition according to the third aspect to a patient in need.

[0095] In some embodiments of the eighth aspect, the cancer is selected from the group consisting of bone cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma.

[0096] As will be apparent to those skilled in the art, cancer treatment may be beneficial when the treatment is combined with targeted cancer therapy. For example, the combination therapy according to this disclosure may be relevant when it is desired to overcome drug resistance caused by TEAD hyperactivation. Accordingly, in some embodiments, the administration is combined with at least one compound selected from the group consisting of AKT inhibitors such as afrecertib, capivacertib, ipatasertib, mirancertib, perifosin, and uprosertib; CDK4 / 6 inhibitors such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors such as binimetinib, cobimetinib, and trametinib; FGFR inhibitors; mTOR inhibitors; MEK1 inhibitors; ALK inhibitors; HSP90 inhibitors; CDK8 inhibitors; PI3K-alpha inhibitors; ABL1 inhibitors; and XPO1 inhibitors. In some embodiments, the administration is combined with at least one compound selected from the group consisting of AKT inhibitors such as afrecertib, capivacertib, ipatasertib, mirancertib, perifosin, and uprosertib; CDK4 / 6 inhibitors such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors such as binimetinib, cobimetinib, and trametinib.

[0097] A ninth aspect provides a method for treating fibrosis, comprising administering a therapeutically effective amount of a compound described in any one embodiment of the first aspect, a conjugate described in any one embodiment of the second aspect, or a pharmaceutical composition described in the third aspect to a patient in need.

[0098] In some embodiments, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, scleroderma, or fibrosis associated with a chronic disease in a major organ. The major organ may be the liver (cirrhosis), heart, lungs, and / or kidneys.

[0099] In some embodiments, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

[0100] In a tenth embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound according to any one embodiment of the first embodiment, or a conjugate according to any one embodiment of the second embodiment, for use in the manufacture of a medicament for use in the treatment of cancer, or a pharmaceutical composition according to the third embodiment. In some embodiments, the cancer is selected from the group consisting of bone cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma.

[0101] In an eleventh embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound according to any one embodiment of the first embodiment, or a conjugate according to any one embodiment of the second embodiment, for use in the manufacture of a medicament for use in the treatment of fibrosis, or the pharmaceutical composition according to the third embodiment. In some embodiments, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, scleroderma, or fibrosis associated with a chronic disease of a major organ. The major organ may be the liver (cirrhosis), heart, lungs, and / or kidneys. In a preferred embodiment, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

[0102] A conjugate according to a second aspect of the present invention can be prepared according to the embodiments described below. Accordingly, a twelfth aspect provides a method for preparing a conjugate according to formula II. This method includes the following:

[0103] The method involves reacting a ligase binder C with a linker B, wherein the ligase binder and the linker are as described in a second aspect of this disclosure. Such a reaction forms an intermediate BC. Furthermore, this method includes the following:

[0104] The intermediate is reacted with the compound of formula I described in the first embodiment to form the conjugate of formula II described in the second embodiment. As will be apparent to those skilled in the art, this method is carried out under conditions that enable the formation of the intermediate and the conjugate, conditions that are known to those skilled in the art.

[0105] Racemic and diastereomer mixtures, as well as single stereoisomers, of the disclosed and claimed compounds are within the scope of the present invention. Depending on the selection of starting materials and procedures, the conjugate may exist in one form of one of the possible stereoisomers, or as a mixture thereof, depending on the number of chiral carbon atoms, for example, as a pure optical isomer or as a stereoisomer mixture such as a racemic and diastereomer mixture. The present invention means to include all such possible stereoisomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)-stereoisomers and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or may be divided using the prior art. If the conjugate contains a double bond, the substituent may be in an E or Z configuration. If the conjugate contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomer forms are also intended to be included.

[0106] The compounds of the present invention may form salts within the scope of the present invention. Salts of the compounds of formula (I) suitable for pharmaceutical use are, for example, those in which the counterions are pharmaceutically acceptable.

[0107] Suitable salts according to the present invention include those formed from organic acids, inorganic acids, or bases. In particular, suitable acid addition salts according to the present invention include those formed from inorganic acids, strong organic carboxylic acids, or optionally, halogen-substituted organic alkyl or aryl sulfonic acids.

[0108] 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, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, salicylic 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, or glutamic acid, and lysine or arginine.

[0109] Examples of pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, such as those of potassium and sodium, alkaline earth metal salts, such as those of calcium and magnesium, and salts having organic bases, such as 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 dimethylpropylamine, or mono, di, or trihydroxy lower alkylamines, such as mono, di, or triethanolamine.

[0110] The corresponding internal salts of the compounds of the present invention can be further formed.

[0111] The compounds of the present invention may also be labeled with isotopes. Therefore, compounds having one or more atoms that are structurally identical to those disclosed above but have different atomic masses or mass numbers than those commonly found in nature are within the scope of the present invention. Examples of isotopes that may be incorporated into the compounds of the present invention include, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O,31 P, 32 P, 35 S, 18 F, and 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl.

[0112] Compounds of the present invention containing any of the above isotopes and / or other isotopes, as well as pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, are within the scope of the present invention.

[0113] Compounds labeled with the isotopes of the present invention may be useful in the field of drug discovery and development, for example, in drug and / or substrate tissue distribution, and in target occupation assays. Furthermore, at a specific position of the molecule in question, 2 Compounds labeled with heavier isotopes, such as 1H, may offer certain therapeutic benefits due to a decrease in metabolic rate, which can result in an increased in vivo half-life or a reduction in the required dose.

[0114] The isotope-labeled compounds of the present invention may be prepared by methods known in the field of organic chemistry, for example, by performing known synthetic procedures and by substituting the isotope-labeling reagents available for the corresponding non-isotope-labeling reagents.

[0115] As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine. As used herein, the term "halo" means fluorine, chlorine, bromine, or iodine.

[0116] As used herein, the term "C1-C2 alkyl" means a saturated hydrocarbon group having one or two carbon atoms. Examples of "C1-C2 alkyl" groups are methyl and ethyl.

[0117] As used herein, the term "C1-C3 alkyl" refers to both linear and branched saturated hydrocarbon groups having 1 to 3 carbon atoms. Non-limiting examples of C1-C3 alkyl groups include methyl, ethyl, n-propyl, and isopropyl groups.

[0118] As used herein, the term "C2-C3 alkyl" refers to both linear and branched saturated hydrocarbon groups having two to three carbon atoms. Non-limiting examples of C2-C3 alkyl groups include ethyl, n-propyl, and isopropyl groups.

[0119] As used herein, the term "C2-C6 alkyl" refers to both linear and branched saturated hydrocarbon groups having 2 to 6 carbon atoms. Non-limiting examples of C2-C6 alkyl groups include ethyl, n-propyl, isopropyl, n-butane, s-butane, t-butane, n-pentane, isopentane, and hexane.

[0120] As used herein, the term "C1-C2 haloalkyl" means a saturated hydrocarbon group having one or two carbon atoms and one to all hydrogen atoms substituted with different or the same type of halogen. Examples of C1-C2 haloalkyl groups include methyl, which is substituted with 1 to 3 halogen atoms, and ethyl, which is substituted with 1 to 5 halogen atoms.

[0121] As used herein, the term "C2-C3 haloalkyl" refers to both linear and branched saturated hydrocarbon groups having two or three carbon atoms and one to all hydrogen atoms substituted with different or the same type of halogen. Examples of C2-C3 haloalkyl groups include ethyl substituted with one to five halogen atoms, and n-propyl or isopropyl substituted with one to seven halogen atoms.

[0122] As used herein, the term "halomethyl" means a methyl group substituted with one to three halogen atoms. Examples of halomethyl groups include, but are not limited to, difluoromethyl, trifluoromethyl, dichloromethyl, and trichloromethyl.

[0123] As used herein, the term CHO means aldehyde. As used herein, the term =O means double-bonded oxygen.

[0124] As used herein, the term "C1-C3 alkoxy" means an O-C1-C3 alkyl group, and "C1-C3 alkyl" is used as described above. Examples of C1-C3 alkoxy groups include methoxy, ethoxy, isopropoxy, and n-propoxy.

[0125] As used herein, the term "C1-C3 haloalkoxy" refers to saturated alkoxy groups, both linear and branched, having 1 to 3 carbon atoms and 1 to all hydrogen atoms substituted by different or the same type of halogen atoms. Examples of C1-C3 haloalkoxy groups include methoxy substituted with 1 to 3 halogen atoms, ethoxy substituted with 1 to 5 halogen atoms, and n-propoxy or isopropoxy substituted with 1 to 7 halogen atoms.

[0126] As used herein, the term “monocyclic heteroaryl” means a monocyclic aromatic group of carbon atoms in which one to three of the carbon atoms are independently replaced by one or more heteroatoms selected from nitrogen, oxygen, or sulfur.

[0127] Examples of monocyclic heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

[0128] As used herein, the terms heteroaliphatic ring and heterocyclic ring are used interchangeably and mean a non-aromatic ring having at least one heteroatom selected from N, O, and S.

[0129] As used herein, the term "C3-C6 cycloalkyl" means a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Examples of C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0130] As used herein, the terms “heterocyclyl,” “heterocycle,” and “heterocycle” refer to a cyclic group of carbon atoms in which one to three carbon atoms are independently replaced by one or more heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups and heterocycles include oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetedinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and dioxanyl.

[0131] As used herein, the term TEAD means a TEA domain transcription factor and includes all four TEAD orthologues, referred to as TEAD1, TEAD2, TEAD3, and TEAD4.

[0132] As used herein, the term “excipients” includes adjuvants and diluents. Those skilled in the art will understand that any adjuvants and diluents disclosed herein are suitable in the pharmaceutical composition and that they have the knowledge to make an appropriate selection thereof. Those skilled in the art will also understand that the pharmaceutical composition may be adapted to suit a desired dosage.

[0133] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” also include plural references unless the context clearly indicates otherwise.

[0134] The term “therapeutic dose” of the conjugate in this disclosure means the amount of the conjugate that induces a biological or medical response to the subject, such as reduction, inhibition or degradation of enzyme or protein activity, or improvement of symptoms, alleviation of a condition, delay or slowing of disease progression, or prevention of disease.

[0135] As used herein, the terms “to treat,” “to treat,” or “to cure” any disease or disorder mean to reduce or improve the disease or disorder (i.e., to delay or halt the onset of the disease or at least one of its clinical symptoms), or to reduce or improve at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be identifiable to the patient.

[0136] Those skilled in the art know that numerical values ​​related to measurements are subject to measurement errors that limit their precision. For this reason, general conventions of scientific and technical literature apply. The last decimal place of a numerical value indicates its accuracy. Unless other tolerances are given, the maximum margin is determined by applying rounding rules to the last decimal place; for example, in a measurement of 3.5 cm, the tolerance is 3.45 to 3.54. Those skilled in the art proceed by the same standard when interpreting ranges of values ​​in patent specifications.

[0137] References 1.Sever R,Brugge JS.Signal transduction in cancer.Cold Spring Harb Perspect Med.2015;5(4). 2.Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T, et al.Small molecules in targeted cancer therapy:advances, challenges, and future perspectives.Signal Transduct Target Ther.2021;6(1):201. 3.Chirnomas D,Hornberger KR,Crews CM.Protein degraders enter the clinic-a new approach to cancer therapy.Nat Rev Clin Oncol.2023;20(4):265-78. 4.Martin-Acosta P,Xiao X.PROTACs to address the challenges facing small molecule inhibitors.Eur J Med Chem.2021;210:112993. 5.Swinney DC.Biochemical mechanisms of drug action:what does it take for success? Nat Rev Drug Discov.2004;3(9):801-8. 6.Ambrosini M,Fuca G,Duca M,Damian S,De Santis F,Corti F,et al.Targeted protein degraders from an oncologist point of view:The Holy Grail of cancer therapy? Crit Rev Oncol Hematol.2022;169:103532. 7.Wu Z,Guan KL.Hippo Signaling in Embryogenesis and Development.Trends Biochem Sci.2021;46(1):51-63. 8.Cao X,Wang C,Liu J,Zhao B.Regulation and functions of the Hippo pathway in stemness and differentiation.Acta Biochim Biophys Sin(Shanghai).2020;52(7):736-48. 9.Matthaios D,Tolia M,Mauri D,Kamposioras K,Karamouzis M.YAP / Hippo Pathway and Cancer Immunity:It Takes Two to Tango.Biomedicines.2021;9(12). 10.Guo X,Zhao Y,Yan H,Yang Y,Shen S,Dai X,et al.Single tumor-initiating cells evade immune clearance by recruiting type II macrophages.Genes Dev.2017;31(3):247-59. 11.Yang W,Yang S,Zhang F,Cheng F,Wang X,Rao J.Influence of the Hippo-YAP signalling pathway on tumor associated macrophages(TAMs)and its implications on cancer immunosuppressive microenvironment.Ann Transl Med.2020;8(6):399. 12.Dey A,Varelas X,Guan KL.Targeting the Hippo pathway in cancer,fibrosis,wound healing and regenerative medicine.Nat Rev Drug Discov.2020;19(7):480-94. 13.Kim CL,Choi SH,Mo JS.Role of the Hippo Pathway in Fibrosis and Cancer.Cells.2019;8(5). 14.Piccolo S,Dupont S,Cordenonsi M.The biology of YAP / TAZ:hippo signaling and beyond.Physiol Rev.2014;94(4):1287-312. 15.Yamaguchi N.Multiple Roles of Vestigial-Like Family Members in Tumor Development.Front Oncol.2020;10:1266. 16. Pobbati AV, Kumar R, Rubin BP, Hong W. Therapeutic targeting of TEAD transcription factors in cancer.Trends Biochem Sci.2023;48(5):450-62. [Brief explanation of the drawing]

[0138] [Figure 1] Western blots of panTEAD from representative examples after 4 hours of incubation with exemplary compounds are shown. [Figure 2] The bar graph highlights the relative expression of panTEAD normalized to DMSO and HSP90 levels after 4 hours of incubation with exemplary compounds. [Figure 3] This demonstrates the inhibition of cell proliferation by exemplary conjugate compounds 165, 166, 167, 178, and 188 in cell lines NCI-H226, NCI-H2052, NCI-H2452, and NCI-H28. [Figure 4] This study demonstrates the inhibition of cell proliferation in cell lines NCI-H226, NCI-H2052, NCI-H2452, and NCI-H28 by the reference TEAD palmitoylation inhibitors IK-930, VT-103, and GNE-7883. [Examples]

[0139] The following are some non-limiting embodiments of the present invention.

[0140] Preparation of compounds The compounds of the present invention can be prepared as free bases or pharmaceutically acceptable salts thereof by the methods described below. Through the following description of such methods, it will be understood that, where appropriate, suitable protecting groups are 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 described, for example, in TW Greene, PGM Wutz, 4th Edition, Wiley-Interscience, New York, 2006. Alternatively, it will be understood that microwaves may be used to heat the reaction mixture.

[0141] General method All reactions were carried out in oven-dried glassware. Unless otherwise specified, all reagents were used as received, at the highest commercial quality, without further purification. The progress of the reactions was monitored by thin-layer chromatography (Merck silica gel 60 F-254, pre-coated plate on alumina) using UV light (254 nm) as a visualization factor. An oil bath or heating block was used as a heat source to heat the reactants. Unless otherwise specified, yields refer to isolated homogeneous material. LC-MS data were collected using a Shimadzu LC-MS-2020 or Agilent 1260 Infinity lab LC / MSD by using a Kinetex C18 column (4.6 × 30 mm), 2.6 μm, 100A; mobile phase: A: 0.1% HCO2H or 0.1% TFA in H2O; mobile phase B: MeCN (100%). HPLC was performed using a UHPLC (or) HPLC Arc system, employing a Kinetex EVO C18 column (4.6 × 150 mm, 5 μm) or a YMC Triart ExRS C18 4.6 × 150 mm, 5 μm; mobile phase A: 0.1% HCO2H in H2O / 0.01 M NH4OAc in H2O / 0.1% TFA in H2O; mobile phase B: MeCN (100%). The crude reaction mixture was purified by silica gel column chromatography (E. Merck silica gel, 100-200 mesh) and / or preparative reverse-phase HPLC performed using a Kinetex EVO C18 column (20 × 21.2 mm), 5 μm, with mobile phase A: 0.1% HCO2H in H2O / 0.01 M NH4OAc in H2O / 0.1% TFA in H2O; mobile phase B: MeCN (100%). 1 The 1H NMR spectrum was recorded at 400 MHz using a JEOL NMR or Varian spectrometer. 1 The chemical shift for 1H NMR is the residual solvent signal (at 7.26 ppm). 1 At H, CDCl3; 2.45 ppm 1 H, DMSO-d6; 3.31 ppm 1H is associated with tetramethylsilane (=0) via methanol-d4), and is abbreviated as s (single line), d (double line), t (triple line), q (quadruple line), m (multiple lines), br (broad line).

[0142] Abbreviations: The following abbreviations are used in the examples.

number

[0143] Example 1. Synthesis of 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: (3-bromo-4-chlorophenyl)(phenyl)methanone (2) To a stirred solution of 3-bromo-4-chlorobenzoic acid (1) (5.0 g, 21.37 mmol) in a 50 mL round-bottom flask, SOCl2 (8.0 mL) was added at room temperature, and the mixture was stirred at 80 °C for 4 hours. After the reaction was complete (monitored by TLC), excess SOCl2 was removed under vacuum. The resulting crude product was dissolved in 60 mL of benzene, and AlCl3 (7.3 g, 64.11 mmol) was added in small amounts. The reaction mixture was heated at 90 °C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum and diluted with ice-cold H2O. The resulting solid was filtered and washed with saturated NaHCO3 aqueous solution to obtain the title compound (2) (4 g, 63%) as an off-white solid. LC-MS: No ionization, t R =3.01.LC-MS purity:98.31%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.04(s,1H),7.84-7.70(m,5H),7.60-7.57(m,2H).

[0144] Step 2: 2-(3-bromo-4-chlorophenyl)-2-phenyloxirane(4) To a stirred solution of Me3SI(3) (1.37 g, 6.75 mmol) in DMSO / THF (1:1, 12 mL), NaH (270 mg, 6.75 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. Then, (3-bromo-4-chlorophenyl)(phenyl)methanone(2) (1.0 g, 3.37 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 18 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with siRNA. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (4) (850 mg, crude, 81%) as a yellow liquid. LC-MS: m / z 308.9 [MH] + ;t R =1.95min LC-MS purity: 70%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.61(s,1H),7.35(s,6H),7.26-7.22(m,1H),3.32(s,1H),3.20(s,1H).

[0145] Step 3: 2-(3-bromo-4-chlorophenyl)-2-phenylacetaldehyde (5) To a stirred solution of 2-(3-bromo-4-chlorophenyl)-2-phenyloxirane (4) (850 mg, 2.74 mmol) in Et2O (6 mL), BF3·Et2O (779 mg, 5.49 mmol) was added at 0°C, and the reaction mixture was stirred at the same temperature for 10 minutes. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (2 × 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as a yellow liquid (600 mg, crude, 100%). The crude compound was used in the next step without further purification.

[0146] Step 4: 2-(3-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-2-phenylethane-1-amine(7) To a stirred solution of 2-(3-bromo-4-chlorophenyl)-2-phenylacetaldehyde (5) (1.0 g, 3.23 mmol) in MeOH / DCM (1:1, 8 mL), (4-methoxyphenyl)methaneamine (6) (1.3 g, 9.69 mmol), followed by AcOH (0.01 mL) at room temperature, the reaction mixture was stirred at the same temperature for 4 hours. Then, NaCNBH3 (608 mg, 9.69 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (40 mL) and extracted with siRNA (2 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 35% siRNA in hexane (12 g silica gel column) to obtain the title compound (7) (0.82 g, 58%) as a brown, gum-like liquid. LC-MS: m / z 430.1 and 432.2 [M+H and M+3H] + ;t R =2.19.LC-MS purity:74.82%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.66(d,J=1.6Hz,1H),7.52-7.50(d,J=8.4Hz,1H),7.31-7.24(m,5H),7.20-7.15(m,3H),6.84- 6.82(d,J=8.4Hz,2H),4.19-4.17(t,J=8.0Hz,1H),3.71(s,3H),3.63(s,2H),3.10-2.99(m,2H).

[0147] Step 5: 2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-methoxybenzyl)-2-phenylethane-1-amine(9) To a stirred solution of 2-(3-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-2-phenylethane-1-amine (7) (800 mg, 1.85 mmol) in 1,4-dioxane (8 mL), KOAc (546 mg, 5.57 mmol) and bis(pinacolate)diborone (8) (613 mg, 2.41 mmol) were added, and the reaction mixture was degassed with argon for 5 minutes. Then, Pd(dppf)Cl2·DCM (151 mg, 0.18 mmol) was added, and the reaction mixture was again degassed with argon for 5 minutes. The reaction mixture was then heated at 100 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (70 mL) and extracted with  (2 × 150 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (9) as a brown liquid (1.0 g, crude, 110%). LC-MS: m / z 478.0 [M+H] + ;t R =1.52min.LC-MS purity:35.62%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.77-7.15(m,7H),6.84-6.82(m,1H),4.21-4.14(m,1H),4.09-3.95(m,1H),3.72(s,2H),3.6 8(s,1H),3.65(s,3H),3.08-3.04(m,1H),1.90(s,1H),1.26(s,4H),1.19(s,8H),1.10(s,3H).

[0148] Step 6: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile(11) To a stirred and cooled solution of 2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-methoxybenzyl)-2-phenylethane-1-amine (9) (600 mg, 1.25 mmol) and 2-bromo-3-fluorobenzonitrile (10) (301 mg, 1.50 mmol) in toluene / H2O (5:1, 10 mL), K3PO4 (799 mg, 3.76 mmol), N-xanthophos (69 mg, 0.12 mmol), and Pd2(dba)3 (57 mg, 0.06 mmol) were added at room temperature, and the reaction mixture was degassed with argon for 5 minutes. The reaction mixture was then heated at 100 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (2 × 150 mL). The organic layer was washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 50% toluene in hexane (2 × 4 g silica gel column) to obtain the title compound (11) as a brown liquid (250 mg, 41%). LC-MS: m / z 471.1 [M + H] + ;t R =2.24min.LC-MS purity:69.7%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.85-7.72(m,2H),7.53-7.11(m,7H),6.76(bs,1H),4.22(bs,1H),4.01-3.90(m ,2H),3.67(s,3H),3.06(bs,1H),2.75(bs,3H),1.97(s,1H),1.22-1.05(m,3H).

[0149] Step 7: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide(13) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (11) (250 mg, 0.53 mmol) in EtOH / H2O (5:1, 8 mL), Parkins catalyst (12) (68 mg, 0.15 mmol) was added at room temperature, and the reaction mixture was then heated at 80 °C for 5 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with  (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 7% MeOH in DCM (4 g silica gel column) to obtain the title compound (13) as a brown solid (160 mg, 60%). LC-MS: m / z 489.2[M+H] + ;t R =2.14min.LC-MS purity:68.4%.

[0150] Step 8: 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 1) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide (13) (50 mg, 0.08 mmol) in MeCN / H2O (1 mL), cerium ammonium nitrate (179 mg, 0.32 mmol) was added at 0°C, and the reaction mixture was then stirred at room temperature for 16 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, concentrated under vacuum, and purified by preparative HPLC [column: ZORBAX BONUS-RP (150 × 4.6 mm; 5 μm); mobile phase A: 0.1% TFA in H₂O, mobile phase B: MeCN; flow rate: 1.0 ml / min; gradient time (min) / %B: 0 / 5, 2 / 5, 6 / 60, 9 / 100, 13 / 100, 14 / 5, 15 / 5] to obtain the crude compound. The pure preparative fraction was lyophilized to obtain the trifluoroacetate (5 mg, 4.7%) of the title compound (Example 1) as an off-white solid. LC-MS: m / z 369.1 [M+H] + ;t R =1.92min.LC-MS purity:98.52%,t R =5.50min.HPLC purity:96.35%. 1 ¹H NMR (400 MHz, DMSO-d6 and D2O) = δ ppm 7.59–7.28 (m, 12H), 4.31–4.27 (m, 1H), 3.56–3.51 (m, 2H).

[0151] Example 2. Synthesis of 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone(3) To a stirred solution of (3-bromo-4-chlorophenyl)(phenyl)methanone (1) (1.0 g, 3.38 mmol) in 1,4-dioxane (20.0 mL), bis(pinacolate)diborone (2) (1.288 g, 5.07 mmol) and KOAc (0.995 g, 10.1 mmol) were added, and the reaction mixture was degassed under nitrogen for 10 minutes. To this solution, PdCl2(dppf)·DCM complex (0.276 g, 0.338 mmol) was added, and the reaction mixture was stirred at 100°C for 16 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, and the precipitated solid was filtered through a Buchner funnel with Celite and washed with SiO2 (2 × 100 mL). The combined organic layers were washed with H2O (200 mL) and brine (200 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 8% toluene in hexane (40 g silica gel column) to obtain the title compound (3) as an off-white solid (700 mg, 60.86%). LC-MS: m / z 343.1 [M+H] + ;t R =3.20min.LC-MS purity:44.93%.

[0152] Step 2: 5'-Benzoyl-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carbonitrile (5) 2-bromo-3-fluorobenzonitrile (4) (0.400 g, 1.999 mmol) and (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (3) (0.685 g, 1.999 mmol) were stirred in DME / H2O (4:1, 15 mL), to which K2CO3 (0.829 g, 5.999 mmol) was added. The reaction mixture was degassed under nitrogen for 5 minutes, Pd(PPh3)4 (0.231 g, 0.199 mmol) was added, and the reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, the precipitated solid was filtered through Celite, and the filtrate was washed with ELISA (100 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 10% Â in hexane (24 g silica gel column) to obtain the title compound (5) as a white solid (250 mg, 37.09%). LC-MS: m / z 336.25 [M+H] + ;t R =1.81min.LC-MS purity:89.52%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.92-7.91(m,4H),7.82-7.69(m,5H),7.60-7.56(m,2H).

[0153] Step 3: 2'-Chloro-6-fluoro-5'-(2-phenyloxylan-2-yl)-[1,1'-biphenyl]-2-carbonitrile(7) To a stirred solution of Me3SI(6) (0.790 g, 3.871 mmol) in DMSO (10.0 mL), NaH (0.15 g, 3.871 mmol, 60% dispersion in mineral oil) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Then, 5'-benzoyl-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carbonitrile(5) (0.650 g, 1.935 mmol, dissolved in 5.00 mL of THF) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, H2O (50 mL) was added, and the mixture was extracted with siRNA (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 8% toluene in hexane (4g silica gel column) to obtain the title compound (7) as an off-white solid (550 mg, 81.24%). LC-MS: m / z 350.10 [M+H] + ;t R =1.86min.LC-MS purity:93.03%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.90-7.33(m,11H),3.39-3.35(m,1H),3.29-3.25(m,1H).

[0154] Step 4: 2'-Chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (8) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-phenyloxylan-2-yl)-[1,1'-biphenyl]-2-carbonitrile (7) (100 mg, 0.28 mmol) in THF (2 mL), BF3·Et2O (81 mg, 0.57 mmol) was added at 0°C, and the reaction mixture was then stirred at the same temperature for 10 minutes. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with Et2O (2 × 30 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound (8) (100 mg, crude, 100%) as a yellow liquid, which was used in the next step without further purification. LC-MS: m / z 347.9 [MH] + ;t R =2.71min.LC-MS purity:69.39%.

[0155] Step 5: tert-butyl(4R)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate(10) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (8) (100 mg, 0.28 mmol) in MeOH / DCM (2 mL), tert-butyl(4R)-4-aminoazepane-1-carboxylate (9) (61 mg, 0.28 mmol), followed by AcOH (2 drops), was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then NaCNBH3 (35 mg, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 60 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 2% MeOH in DCM (4g silica gel column) to obtain the title compound (10) as a yellow liquid (55mg, 35%). LC-MS: m / z 548.3 [M+H] + ;tR =2.29min.LC-MS purity:98.10%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.90-7.87(m,1H),7.77-7.69(m,2H),7.58-7.54(m,2H),7.47-7.43(t,J=8.4Hz,1H),7.33-7.26(m,4H),7.20-7.16(t,J= 7.2Hz,1H),4.18-4.15(t,J=5.6Hz,1H),3.70-3.80(bs,1H),3.16(bs,7H),1.90(s,1H),1.80-1.65(m,4H),1.39(m,15H).

[0156] Step 6: tert-butyl(4R)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate(11) To a stirred solution of tert-butyl(4R)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate (10) (53 mg, 0.096 mmol) in EtOH / H2O (2.4 mL, 1:1), Parkins catalyst (12 mg, 0.029 mmol) was added at room temperature, and the reaction mixture was then heated at 80 °C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with H2O (10 mL), and extracted with ELISA (2 × 40 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude compound was purified by washing with pentane to obtain the title compound (11) (50 mg, 91%) as an off-white solid. LC-MS: m / z 566.3[M+H] + ;t R =2.19min.LC-MS purity:91.37%.HPLC purity:93.55%,t R = 7.30 min. 1H NMR(400MHz,DMSO-d6)=δ ppm 8.10(bs,1H),7.90(s,1H),7.74-7.71(m,1H),7.62-7.49(m,2H),7.44-7.18(m,10H), 4.10-4.08(d,J=8.8Hz,1H),3.75-3.71(m,1H),3.31-3.10(m,7H),1.90-1.23(m,20H).

[0157] Step 7: 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 2) To a stirred solution of tert-butyl(4R)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate (11) (50 mg, 0.088 mmol) in DCM (1 mL), TFA (30 mg, 0.264 mmol) was added at 0°C. The reaction mixture was then warmed to room temperature and stirred for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was purified by preparative HPLC [column: X-Select CSH C18 (250 mm × 19 mm; 5.0 μm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 12 mL / min; gradient time (min) / %B: 0 / 25, 2 / 25, 10 / 55] to obtain the trifluoroacetate (23 mg, 46%) of the title compound (Example 2) as a white solid. LC-MS: m / z 466.2 [M+H] + ;t R =1.77min.LC-MS purity:99.95%,HPLC purity:97.01%,t R = 6.66 min, 1H NMR(400MHz,DMSO-d6)=δ ppm 8.770-8.570(m,4H),7.811-7.796(m,1H),7.557-7.467(m,2H),7.447-7.350(m,7H),7.295-7.278(m,2H),4.411-4.380( m,1H),3.345-3.272(m,2H),3.128(m,1H),3.002(m,2H),2.203-2.145(m,2H),1.916-1.884(m,2H),1.695-1.583(m,2H).

[0158] Example 3. Synthesis of 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: (4S)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate tert-butyl(3) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (1) (100 mg, 0.28 mmol) in MeOH / DCM (2 mL), (S)-4-aminoazepane-1-carboxylate tert-butyl (2) (61 mg, 0.28 mmol), followed by AcOH (2 drops), was added at room temperature, and the reaction mixture was stirred at the same temperature for 4 hours. Then, NaCN(BH3) (35 mg, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 60 mL). The organic layer was washed with H2O (200 mL) and brine (200 mL), dried over Na2SO4, and concentrated under vacuum. The crude compound was purified by combiflash chromatography using 2% MeOH in DCM (4g silica gel column) to obtain the title compound (3) as an off-white solid (75 mg, 48%). LC-MS: m / z 548.3 [M+H] + ;t R =2.31min.LC-MS purity:98.45%.

[0159] Step 2: tert-butyl(4S)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate(5) To a stirred solution of tert-butyl(4S)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate (3) (73 mg, 0.133 mmol) in EtOH / H2O (2.4 mL), Parkins catalyst (17 mg, 0.039 mmol) was added at room temperature, and the reaction mixture was heated to 80 °C and stirred for 18 hours. TLC showed 20% of the starting material, and Parkins catalyst (17 mg, 0.039 mmol) was added again at room temperature, and the reaction mixture was stirred at 80 °C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (2 × 40 mL). The organic layer was washed with H2O (200 mL) and brine (200 mL), dried over Na2SO4, and concentrated under vacuum to obtain the crude title compound (4) (70 mg, crude product, 101%) as an off-white solid. LC-MS: m / z 566.3 [M+H] + ;t R =2.20min.LC-MS purity:79.92%.

[0160] Step 3: 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide To a stirred solution of tert-butyl(4S)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate(5) (70 mg, 0.123 mmol) in DCM (1 mL), TFA (42 mg, 0.370 mmol) was added at 0°C, and the reaction mixture was allowed to reach room temperature and stirred at the same temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was purified by preparative HPLC [column: Luna omega C18 (250 mm × 21.2 mm; 5.0 μm); mobile phase: 0.1% TFA in H2O(A) / MeCN(B); flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 25, 3 / 25, 10 / 50]. The pure preparative fraction was freeze-dried to obtain the trifluoroacetate (28 mg, 40%) of the title compound (Example 3) as an off-white solid. LC-MS: m / z 466.2 [M+H] + ;t R =1.73min.LC-MS purity:99.48%.HPLC purity:98.54%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.757(brs,2H),8.527(brs,1H),7.804-7.792(m,1H),7.577-7.525(m,1H),7.496-7.350(m,8H),7.294-7.262(m,2H),4.408-4 .390(m,1H),3.792-3.691(m,2H),3.131(m,1H),3.004(m,2H),2.203-2.077(m,2H),1.912-1.883(m,2H),1.670-1.581(m,2H).

[0161] Example 4. Synthesis of 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 5'-Benzoyl-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrili(3) To a stirred solution of 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (2) (2.2 g, 8.05 mmol) in toluene / H2O (9:1, 50 mL), (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (1, prepared according to the same reaction procedure as Int.3 of Example 2) (4.2 g, 12.08 mmol), K3PO4 (5.1 g, 24.015 mmol), and xanthophos (466 mg, 0.80 mmol) were added at room temperature. The resulting reaction mixture was degassed with N2 for 10 minutes, then Pd2(dba)3 (368 mg, 0.405 mmol) was added to the reaction mixture at room temperature, and it was again degassed with N2 for 5 minutes. The reaction mixture was then stirred at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with HCl (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by combiflash chromatography (12 g silica gel column) using 15% HCl in hexane to obtain the title compound (3) as a colorless liquid (3.20 g, 97%). 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.94-7.91(m,2H),7.89-7.78(m,4H),7.72-7.68(m,1H),7.63-7.56(m,2 H),7.50-7.44(m,1H),4.38-4.31(m,2H),3.73-3.69(m,2H),3.31(s,3H).

[0162] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxylan-2-yl)-[1,1'-biphenyl]-2-carbonitrile(5): To a stirred solution of Me3SI(4) (3.4 g, 17.0 mmol) in THF (18 mL) and DMSO (18 mL), NaH (683 mg, 60% in mineral oil, 17.0 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxylan-2-yl)-[1,1'-biphenyl]-2-carbonitrile(3) (3.5 g, 8.53 mmol) was added to the reaction mixture at 0°C, and the reaction mixture was then stirred at room temperature for 18 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (200 mL) and extracted with RINKAN (2 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (5) as a yellow liquid (3.0 g, crude, 82%). 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.50-7.29(m,8H),7.22-7.19(m,1H),7.10-7.00(m,1H),4.27-4.20(m ,2H),3.81-3.77(m,2H),3.44(s,3H),3.35-3.33(m,1H),3.26(m,1H).

[0163] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile(6) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxylan-2-yl)-[1,1'-biphenyl]-2-carbonitrile (5) (200 mg, 0.471 mmol) in Et2O (2 ml), BF3·OEt2 (133 mg, 0.943 mmol) was added at 0°C, and the reaction mixture was stirred at the same temperature for 10 minutes. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL), extracted with Et2O (2 × 50 mL), the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (6) as a yellow liquid (200 mg, crude, 100%). LC-MS: m / z 422.0 [MH] + ;t R=2.68,LC-MS purity:57.9%.

[0164] Step 4: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile(8) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (6) (200 mg, 0.47 mmol) in MeOH / DCM (3 mL), (4-methoxyphenyl)methaneamine (7) (194 mg, 1.41 mmol), followed by AcOH (3 drops), was added at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. Then, NaCNBH3 (88 mg, 1.41 mmol) was added, and the reaction mixture was stirred at room temperature for 21 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 2% MeOH in DCM (4g silica gel column) to obtain the title compound (8) as an off-white solid (70 mg, 25%). LC-MS: m / z 545.2 [M+H] + ;t R =2.21min.LC-MS purity:90.85%.

[0165] Step 5: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide(10) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile (8) (50 mg, 0.09 mmol) in EtOH / H2O (5:1, 1 mL), Parkins catalyst (9) (15 mg, 0.03 mmol) was added at room temperature, and the reaction mixture was then heated at 80 °C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with  (2 × 50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (10) as a yellow liquid (50 mg, crude). LC-MS: m / z 563.2 [M + H] + ;t R =2.12min.LC-MS purity:74.31%.

[0166] Step 6: 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 4) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide (10) (50 mg, 0.08 mmol) in MeCN / H2O (2 mL), cerium ammonium nitrate (292 mg, 0.53 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 aqueous solution (15 mL) and  (2 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC [column: X-SELECT CSH; mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min, gradient, time (min) / %B: 0 / 30, 10 / 50]. The pure preparative fraction was lyophilized to obtain the trifluoroacetate of the title compound (Example 4) as an off-white solid (5 mg, 8%). LC-MS: m / z 443.1 [M+H] + ;t R =1.93min.LC-MS purity:99.88%,t R =8.09min,HPLC purity:99.78%. 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.52-7.44(m,2H),7.39-7.26(m,8H),4.28-4.21(m,3H),3.71-3.69(m,2H),3.60-3.52(bs,2H),3.32(s,3H).

[0167] Example 5. Synthesis of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile(3) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (1, prepared according to the same reaction procedure as Int. 6 of Example 4) (100 mg, 0.23 mmol) in MeOH / DCM (2 ml), [(4-methoxyphenyl)methyl](methyl)amine (2) (53 mg, 0.35 mmol), followed by AcOH (2 drops) was added at room temperature, and the reaction mixture was stirred at the same temperature for 4 hours. Then, NaCNBH3 (43 mg, 0.69 mmol) was added, and the reaction mixture was stirred at the same temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 60 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography using 40% toluene in hexane (4g silica gel column) to obtain the title compound (3) as a yellow liquid (30 mg, 38%). LC-MS: m / z 559.2 [M+H] + ;(t R =2.21min).LC-MS purity:84.99%.

[0168] Step 2: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide(5) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile (3) (50 mg, 0.089 mmol) in EtOH / H2O (2.4 mL), Parkins catalyst (4) (11 mg, 0.026 mmol) was added at room temperature. The reaction mixture was then heated to 80 °C and stirred for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with RINKAN (2 × 60 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (5) as a yellow liquid (30 mg, crude, 58%). LC-MS: m / z 577.3 [M + H] + ;(t R (2.159 min). LC-MS purity: 85.702%. The crude product was used in the next step without further purification.

[0169] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 5) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide (5, crude) (30 mg, 0.05 mmol) in DCM (2 ml), DDQ (35 mg, 0.15 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with  (2 × 80 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by preparative HPLC [column: Kinetex C18 (250 mm × 21.2 mm, 5.0 μm), mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 mL / min; gradient time (min) / %B: 0 / 5, 2 / 5, 10 / 50]. The pure fraction was lyophilized to obtain the trifluoroacetate (3 mg, 10%) of the title compound (Example 5) as a white solid. LC-MS: m / z 457.2 [M+H] + ;(t R =1.988min).LC-MS purity:98.502%.HPLC purity:98.89%,(t R (6.949 min, at 210 nm). 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.497-7.422(m,3H),7.382-7.304(m,5H),7.290-7.263(m,2H),4.392-4.352( m,1H),4.283-4.215(m,2H),3.707-3.647(m,4H),3.316(s,3H),2.563(s,3H).

[0170] Example 6. Synthesis of 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: tert-butyl(4S)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate(3) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (1, prepared according to Int. 6 of Example 4) (150 mg, 0.35 mmol) in MeOH / DCM (3 ml), tert-butyl(S)-4-aminoazepane-1-carboxylate (2) (83 mg, 0.38 mmol), followed by AcOH (2 drops), was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then NaCNBH3 (44 mg, 0.71 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with ELISA. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography using 40%–80% siRNA in hexane (4g silica gel column) to obtain the title compound (3) (56 mg, 25%) as an off-white solid. LC-MS: m / z 622.4 [M+H] + ;t R =2.21min.LC-MS purity:90.32%.

[0171] Step 2: tert-butyl(4S)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate(5) To a stirred solution of tert-butyl(4S)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate (3) (55 mg, 0.088 mmol) in EtOH / H2O (2.4 ml), Parkins catalyst (4) (11 mg, 0.026 mmol) was added at room temperature. The reaction mixture was then heated to 80 °C and stirred for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (5) (50 mg, 88%) as a yellow liquid. LC-MS: m / z 640.4 [MH] + ;t R =2.2min.LC-MS purity:76%.

[0172] Step 3: 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 6) To a stirred solution of tert-butyl(4S)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azepan-1-carboxylate (50 mg, 0.078 mmol) in DCM (1 ml), TFA (26 mg, 0.23 mmol) was added at 0°C, and the reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC [column: Kinetex C18 (250 mm × 21.2 mm, 5.0 μm), mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 20, 2 / 20, 10 / 40]. The pure fraction was freeze-dried to obtain the trifluoroacetate of the title compound (Example 6) as a white solid (11 mg, 22%). LC-MS: m / z 540.3 [M+H] + ;(t R=1.34min).LC-MS purity:99.70%.HPLC purity:96.76%(t R =6.43 min, 31.56% and t R (6.51 min, 68.32%, at 210 nm). 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.518-7.442(m,3H),7.420-7.363(m,5H),7.311-7.270(m,2H),4.412-4.345(m,1H),4.257-4.248(m,2H),3.775-3.650(m,3H),3.320- 3.251(m,5H),3.149-3.137(m,1H),3.032-2.974(m,2H),2.249-2.162(m,2H),2.106(s,2H),1.945-1.906(m,2H),1.690-1.635(m,2H).

[0173] Example 7. Synthesis of 2'-chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile(3) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (1, prepared according to the same reaction procedure as Int.6 of Example 4) (150 mg, 0.35 mmol) in MeOH / DCM (3 ml), cyclobutylamine (50 mg, 0.70 mmol), followed by AcOH (2 drops), was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours, then NaCNBH3 (44 mg, 0.71 mmol) was added, and the reaction mixture was stirred at the same temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4g silica gel column) using 4% MeOH in DCM to obtain the title compound (3) (52 mg) as an off-white solid. LC-MS (ESI): m / z 479.2 [M+H] + ;t R =2.158min;LC-MS purity:54.85%.

[0174] Step 2: 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 7) To a stirred solution of 2'-chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile (3) (52 mg, 0.108 mmol) in EtOH / H2O (2.4 ml), Parkins catalyst (4) (13 mg, 0.032 mmol) was added at room temperature, and the reaction mixture was then heated to 80°C and stirred for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was purified by preparative HPLC [column: Kinetex C18 (250 mm × 21.2 mm, 5.0 μm), mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 20, 2 / 20, 10 / 50] to obtain the trifluoroacetate of the title compound (Example 7) as a white solid (8 mg, 13%). LC-MS: m / z 497.2 [M+H] + ;(t R =2.058min).LC-MS purity:99.77%.HPLC purity:95.66%(t R (7.2 min, at 210 nm). 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.478-7.384(m,2H),7.361-7.265(m,7H),4.275-4.241(m,3H),3.711(m,3H),3.455-3.4 23(m,2H),3.312(s,3H),2.143-2.113(m,2H),2.019-1.996(m,2H),1.730-1.708(m,2H).

[0175] Example 8. Synthesis of 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile(3) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (1, prepared according to the same reaction procedure as Int. 6 of Example 4) (140 mg, 0.33 mmol) in MeOH / DCM (3 ml), (1r,4r)-4-amino-1-methylcyclohexane-1-ol (85 mg, 0.66 mmol), followed by AcOH (2 drops) was added at room temperature. The reaction mixture was stirred for 4 hours, then NaCNBH3 (41 mg, 0.66 mmol) was added, and the reaction mixture was stirred at the same temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4g silica gel column) using 2% MeOH in DCM to obtain the title compound (3) as an off-white solid (50 mg, 28%). LC-MS (ESI): m / z 537.2 [M-Boc+H] + ;t R =2.122min;LC-MS purity:78.56%.

[0176] Step 2: 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 8) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile (3) (50 mg, 0.09 mmol) in EtOH / H2O (2.4 ml), Parkins catalyst (4) (11 mg, 0.02 mmol) was added at room temperature. The reaction mixture was then heated to 80 °C and stirred for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by preparative HPLC [column: Kinetex C18 (250 mm × 21.2 mm, 5.0 μm), mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 25, 2 / 25, 10 / 50] to obtain the trifluoroacetate of the title compound (Example 8) as a white solid (50 mg, 28%). LC-MS: m / z 555.20 [M+H] + ;(t R =1.995min).LC-MS purity:99.48%.HPLC purity:95.73%(t R (6.183 min, at 210 nm). 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.516-7.437(m,3H),7.411-7.350(m,5H),7.320-7.2671(m,2H),4.410-4.333(m,1H),4.255-4.219(m,2H),3.761 (m,4H),3.319(s,3H),3.061-3.046(m,1H),1.934(m,1H),1.607-1.583(m,2H),1.434-1.342(m,4H),1.115(s,3H).

[0177] Example 9. Synthesis of 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxylan-2-yl)-[1,1'-biphenyl]-2-carbonitrile (1, prepared according to the same procedure as Int. 5 of Example 4) (150 mg, 0.353 mmol) in Et2O (2 mL), BF3·Et2O (100 mg, 0.707 mmol) was added at 0°C, and the reaction mixture was stirred at the same temperature for 10 minutes. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with Et2O (2 × 30 mL). The organic layer was washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound (2) as crude (150 mg, crude, 100%). The crude was used in the next step without further purification.

[0178] Step 2: 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile(3) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (crude product, 2) (150 mg, 0.35 mmol) in MeOH / DCM (3 mL), isopropylamine (62 mg, 1.06 mmol), followed by AcOH (2 drops), was added at room temperature, and the reaction mixture was stirred for 4 hours. Then, NaCNBH3 (44 mg, 0.70 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with siRNA (2 × 60 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude compound was purified by combiflash chromatography using 2% MeOH in DCM (4g silica gel column) to obtain the title compound (3) as an off-white solid (52mg, 31%). LC-MS: m / z 467.2 [M+H] + ;t R =2.09min.LC-MS purity:95.76%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.84-7.82(d,J=8.8Hz,1H),7.64-7.21(m,10H),4.38-4.20(m,3H),3.72-3.70(t,J=4.0Hz,2H),3.27(s,3H),1.23-1.01(m,7H).

[0179] Step 3: 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 9) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile (3) (50 mg, 0.107 mmol) in EtOH / H2O (2.4 mL), Parkins catalyst (4) (13.5 mg, 0.032 mmol) was added at room temperature, and the reaction mixture was then heated at 80°C for 18 hours. TLC showed 20% of the starting material, and again, Parkins catalyst (13.5 mg, 0.032 mmol) was added at room temperature, and the reaction mixture was stirred at 80°C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with RINKAN (2 × 40 mL). The combined organic layers were washed with brine solution (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude compound was purified by preparative HPLC [column: X-Select CSH (250 mm × 21.2 mm; 5.0 μm), mobile phase: 0.1% TFA in H2O(A) / MeCN(B); gradient, time (min) / %B: 0 / 55, 10 / 85; flow rate: 15 mL / min] to obtain the trifluoroacetate of the title compound (Example 9) as an off-white solid (25 mg, 40%). LC-MS: m / z 485.2 [M+H] + ,t R =1.99min, LC-MS purity: 99.17%, HPLC purity: 99.45%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.27-8.12(m,2H),7.61-7.58(m,1H),7.47-7.26(m,10H),7.15-7.10(m,1H),4.37-4.33(t,J =7.6Hz,1H),4.29-4.21(m,2H),3.75-3.68(m,5H),3.31(s,3H),1.22-1.19(t,J=4.8Hz,6H).

[0180] Example 10. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: tert-butyl((1r,4r)-4-((2-(3-bromo-4-chlorophenyl)-2-phenylethyl)amino)cyclohexyl)carbamate(3) To a stirred solution of 2-(3-bromo-4-chlorophenyl)-2-phenylacetaldehyde (1, prepared according to Int. 5 of Example 1) (600 mg, 1.96 mmol) in methanol / DCM (1:1, 6 mL), tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (2) (631 mg, 2.94 mmol), followed by AcOH (3 drops), was added at room temperature. After stirring the reaction mixture for 4 hours, NaCNBH3 (369 mg, 5.88 mmol) was added, and the reaction mixture was left overnight. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 40%–80% ethyl acetate in hexane to obtain the title compound (3) as an off-white solid (400 mg, 40%). LC-MS: m / z 507.2[M+H] + ;t R =2.21min.LC-MS purity:86.87%.

[0181] Step 2: tert-butyl(2-(3-bromo-4-chlorophenyl)-2-phenylethyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(4) To a stirred solution of tert-butyl((1r,4r)-4-((2-(3-bromo-4-chlorophenyl)-2-phenylethyl)amino)cyclohexyl)carbamate (3) (400 mg, 0.78 mmol) in THF / H2O (3:1, 8 mL), NaHCO3 (132 mg, 1.56 mmol), followed by di-tert-butyl dicarbonate (257 mg, 1.18 mmol), was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 30% ethyl acetate in hexane to obtain the title compound (4) (300 mg, 62%) as an off-white solid. LC-MS showed two peaks with the desired mass. LC-MS: m / z 495.20[M-2tBu+H] + ;t R =2.20 min. LC-MS purity: 46.32%, and LC-MS: m / z 495.00 [M-2tBu+H] + ;t R =2.23min.LC-MS purity 52.41%.

[0182] Step 3: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-phenylethyl)carbamate(6) To a stirred solution of tert-butyl(2-(3-bromo-4-chlorophenyl)-2-phenylethyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (4) (250 mg, 0.41 mmol) in 1,4-dioxane (5 mL), KOAc (121 mg, 1.23 mmol) and bis(pinacolate)diborane (5) (135 mg, 0.53 mmol) were added, and the reaction mixture was degassed with argon for 5 minutes. Then, Pd(dppf)Cl2-DCM (33 mg, 0.041 mmol) was added, and the reaction mixture was again degassed with argon for 5 minutes. The reaction mixture was then stirred in a sealed tube at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (6) as a brown liquid (220 mg, crude, 81%). LC-MS: m / z 555.3 [M-Boc+H] + ;t R =3.58min.LC-MS purity=49.83%.

[0183] Step 4: ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate (8) To a stirred solution of ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-phenylethyl)carbamate tert-butyl (6) (220 mg, 0.335 mmol) and 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (7) (110 mg, 0.403 mmol) in toluene / H2O (10:1, 4.4 mL), K3PO4 (222 mg, 1.005 mmol), N-xanthophos (18.5 mg, 0.033 mmol), and Pd2(dba)3 (15.3 mg, 0.016 mmol) were added at room temperature, and the reaction mixture was degassed with argon for 5 minutes. The reaction mixture was then stirred at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (12 g silica gel column) using 60% ethyl acetate in hexane to obtain the title compound (8) as an off-white solid (180 mg, 74%). LC-MS: m / z 566.15 [M-Boc-tBu+H] + ;t R =2.04min.LC-MS purity=98.33%,HPLC purity:99.35% t R =8.118min, 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.84-7.80(m,1H),7.59-7.19(m,8H),6.67-6.62(m,1H),4.37-4.30(s,2H),3.73-3.69(q, J=7.2Hz,3H),3.32-3.31(d,J=3.6Hz,3H),3.05(bs,1H),1.71-1.33(m,18H),1.03(m,7H).

[0184] Step 5: ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate (10) To a stirred solution of ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate tert-butyl (8) (180 mg, 0.249 mmol) in EtOH / H2O (5:1, 12 mL), Parkins catalyst (9) (32 mg, 0.074 mmol) was added at room temperature. The reaction mixture was then heated to 80 °C and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4g silica gel column) using 4% MeOH in DCM to obtain the title compound (10) as an off-white solid (140 mg, 76%). LC-MS (ESI): m / z 640.40 [M-Boc+H] + ,t R =1.85min.LC-MS purity:95.77%;HPLC purity:97.97% [t R = 10.47 min (22.64%) and 10.50 min (75.33%). 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.62-7.12(m,11H),7.59-7.19(m,8H),6.67-6.63(m,1H),4.27-4.20(s,2H),3.73- 3.68(q,J=8.6Hz,2H),3.31(s,3H),3.05(bs,1H),1.68-1.62(bs,3H),1.33(m,22H).

[0185] Step 6: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 10) To a stirred solution of ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate tert-butyl(10) (140 mg, 0.189 mmol) in DCM (2 mL), TFA (107 mg, 0.945 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was ground with pentane to obtain the crude compound (130 mg), which was purified by preparative HPLC [column: Luna Omega C18 (250 mm × 21.2 mm, 5.0 μm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min, gradient time (min) / %B: 0 / 25, 3 / 25 10 / 60] to obtain the trifluoroacetate of the title compound (Example 10) as a white solid (83 mg, 63%). LC-MS: m / z 541.40 [M+H] + ;(t R =1.34min).LC-MS purity:98.69%.HPLC purity:99.88%(t R =6.43min 31.56% and t R (6.51 min, 68.32%, at 210 nm). 1H NMR(400MHz,DMSO-d6)=δ ppm 8.57-8.40(m,1H),8.12-7.92(m,3H),7.64-7.61(m,1H),7.49-7.43(m ,3H),7.40-7.34(m,4H),7.31-7.27(m,2H),7.17-7.16(m,1H),4.39(t, J=6.8Hz,1H),4.29-4.22(m,2H),3.86-3.64(m,4H),3.30(s,3H),3.03 -2.92(m,2H),2.09-2.08(m,2H),1.97-1.95(m,2H),1.49-1.24(m,4H).

[0186] The chiral separation in Example 10 was performed using chiral HPLC (see Examples 11 and 12).

[0187] Examples 11 and 12 Stereoisomers of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Examples 11 and 12) Chiral HPLC was used to separate Example 10 and obtain two pairs of stereoisomers for Example 11 and Example 12. Column: Chiral Pak IC (250 × 4.6 mm; 5 μm); Mobile phase A: 0.1% DEA in hexane, Mobile phase B: EtOH; Method: Isocratic elution A:B 60:40; Flow rate: 1.0 mL / min; Column temperature: 25°C; Diluent: IPA / DCM (90:10). Example 11(t R =16.80 minutes) and Example 12 (t R (=19.06 min). The relative / absolute stereochemistry of Examples 11 and 12 has not been determined.

[0188] Example 13. Synthesis of 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide [ka] Step 1: tert-butyl((1r,4r)-4-acetamidocyclohexyl)carbamate (3) To a stirred solution of tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (1) (400 mg, 1.86 mmol) in DCM (5 mL), Et3N (944 mg, 9.33 mmol) and acetyl chloride (2) (439 mg, 5.59 mmol) were added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with RINKAN (2 × 150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography (4 g silica gel column) using 2% MeOH in DCM to obtain the title compound (3) as an off-white solid (300 mg, 60%). LC-MS: m / z 548.3 [M-tBu+H] + ;t R =2.09min.LC-MS purity:88.92%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.72-7.70(d,J=7.6Hz,1H),6.73-6.71(d,J=8Hz,1H),3.41-3.37(m,1H ),3.17-3.16(m,1H),1.75-1.73(m,7H),1.40(s,9H),1.22-1.12(m,4H).

[0189] Step 2: N-((1r,4r)-4-aminocyclohexyl)acetamide(4) To a stirred solution of tert-butyl((1r,4r)-4-acetamidocyclohexyl)carbamate (3) (300 mg, 1.86 mmol) in DCM (3 mL), TFA (667 mg, 5.85 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was basicized with saturated NaHCO3 aqueous solution (15 mL) and extracted with 10% MeOH / DCM (2 × 60 mL). The combined organic layers were washed with H2O (50 mL) and brine (500 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound (4) as an off-white solid (250 mg, crude product, 120%). LC-MS: m / z 157.2 [M + H] + ;t R =0.37min.LC-MS purity:93.98%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.69-7.67(d,J=7.6Hz,1H),1.76-1.70(m,9H),1.17-1.04(m,6H).

[0190] Step 3: N-((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)acetamide(6) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (5, prepared according to Int. 6 of Example 4) (150 mg, 0.35 mmol) in MeOH / DCM (3 mL), N-((1r,4r)-4-aminocyclohexyl)acetamide (4) (82 mg, 0.53 mmol), followed by AcOH (2 drops) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. Then, NaCNBH3 (66 mg, 1.05 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 20 hours. After completion (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 60 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 7% MeOH in DCM (4 g silica gel column) to obtain the title compound (6) as an off-white solid (7 mg, 3.5%). LC-MS: m / z 564.3 [M+H] + ;t R =2.06min.LC-MS purity:97.26%.

[0191] Step 4: 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide (Example 13) To a stirred solution of N-((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)acetamide (6) (7 mg, 0.012 mmol) in EtOH / H2O (5:1, 1.2 mL), Parkins catalyst (7) (1.5 mg, 0.003 mmol) was added at room temperature, and the reaction mixture was then heated to 80 °C for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC [column: Kinetex C18 (250 mm × 21.2 mm; 5.0 μm), mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min; gradient time (min) / %B: 0 / 10, 10 / 60] to obtain the trifluoroacetate of the title compound (Example 13) as an off-white solid (1.5 mg, 18%). LC-MS: m / z 582.3 [M+H] + ;t R =2.00min.LC-MS purity:99.48%,HPLC purity:96.18%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.38-8.10(m,2H),7.76-7.74(m,1H),7.62-7.59(m,1H),7.48-7.27(m,10H),7.18-7.11(m,1H),4.36-4.21(m,3H),3.76- 3.55(s,4H),3.32(s,3H),3.05-3.02(bs,1H),2.08-2.04(m,2H),1.83-1.75(m,5H),1.40-1.39(m,2H),1.23-1.05(m,6H).

[0192] Example 14. Synthesis of 2'-chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: Ethyl 2-(4-formyl-1H-pyrazole-1-yl)acetate (3) To a stirred solution of 1H-pyrazole-4-carbaldehyde (1) (2 g, 20.8 mmol) in DMF (15 mL), KOtBu (2.8 g, 24.9 mmol) was gradually added at 0°C and the mixture was stirred for 10 minutes. Ethyl-2-bromoacetate (2) (3.5 g, 22.8 mmol) was added dropwise to the reaction mixture at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with HCl (2 × 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography (12 g silica gel column) using 30% HCl in hexane to obtain the title compound (3) as a yellow liquid (1.4 g, 40%). 1 H NMR(400MHz,DMSO-d6)=δ ppm 9.83(s,1H),8.48(s,1H),8.02(s,1H),5.18(s,2H),4.17(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H).

[0193] Step 2: Benzyl N-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]carbamate (6) To a stirred solution of tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (4) (5 g, 23.36 mmol) in DCM (50 mL), DIPEA (12.2 mL, 70.08 mmol) and benzyl chloroformate (5) (3.98 g, 23.36 mmol) were added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with DCM (2 × 150 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 2% MeOH in DCM (2 × 4 g silica gel column) to obtain the title compound (6) as an off-white solid (6.5 g, 80%). LC-MS: m / z 249.2[M-Boc+H] + ;t R =2.58min,LC-MS purity:96%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.38-7.28(m,5H),7.19(d,J=8.0Hz,1H),6.72(d,J=8.0Hz,1H),4.98(s,2H),3.18-3.12(m,2H),1.76(bs,4H),1.40(s,9H),1.23-1.12(m,4H).

[0194] Step 3: Benzyl((1r,4r)-4-aminocyclohexyl)carbamate(7) To a stirred solution of benzyl N-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]carbamate (6) (6.5 g, 18.67 mmol) in DCM (60 mL), TFA (7.8 ml, 93.3 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The resulting crude product was ground with pentane to obtain the trifluoroacetate of the title compound (7) as an off-white solid (5 g, 98%). LC-MS: m / z 249.2 [M+H] + ;t R =1.77min,LC-MS purity:98.38%. 1H NMR(400MHz,DMSO-d6)=δ ppm 7.38-7.28(m,5H),7.15(d,J=7.6Hz,1H),4.98(s,2H),3.21-3.16(m,1H),2.47-2.41(m,1H),1.72(bs,4H),1.21-0.98(m,4H).

[0195] Step 4: Ethyl 2-(4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate(8) To a stirred solution of ethyl 2-(4-formyl-1H-pyrazole-1-yl)acetate (3) (1.4 g, 7.69 mmol) in MeOH / DCM (20 mL), benzyl ((1r,4r)-4-aminocyclohexyl)carbamate (7) (1.9 g, 7.69 mmol), followed by AcOH (0.23 mL, 3.84 mmol), was added at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. Then, NaCNBH3 (1.4 g, 3.84 mmol) was added to the reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by combi-flash chromatography using 20% ​​MeOH in DCM (on a 40g silica gel column) to obtain the title compound (8) as a colorless, gum-like solid (1.3g, 42%). LC-MS: m / z 415.2 [M+H] + ;t R =1.38,LC-MS purity:93.9%. 1H NMR(400MHz,DMSO-d6)=δ ppm 7.76(s,1H),7.51(s,1H),7.29-7.19(m,5H),5.01(s,2H),4.90(s,2H),4.07-4.01(m,2H),3.95(s,1H),3.25 -3.06(m,2H),2.85-2.79(m,1H),1.99-1.97(m,2H),1.81-1.77(m,2H),1.27-1.22(m,2H),1.13-1.05(m,5H).

[0196] Step 5: Ethyl 2-[4-({[(tert-butoxy)carbonyl][(1r,4r)-4-{[(benzyloxy)carbonyl]amino}cyclohexyl]amino}methyl)-1H-pyrazole-1-yl]acetate (9) To a stirred solution of ethyl 2-(4-((((1r,4r)-4-(((benzyloxy)carbonyl)aminocyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate (8) (1.3 g, 3.13 mmol) in THF / H2O (3:1, 20 mL), NaHCO3 (0.788 g, 9.39 mmol), followed by (Boc)2O (1.3 g, 6.27 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with SiO (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 80% toluene in hexane (4g silica gel column) to obtain the title compound (9) as a colorless gum-like liquid (1.2g, 75%). LC-MS: m / z 459 [M-tBu+H] + ;t R =2.74min,LC-MS purity:88.22%. 1H NMR(400MHz,DMSO-d6)=δ ppm 7.59(s,1H),7.38-7.28(m,5H),7.19(d,J=7.2Hz,1H),5.00(d,J=8.4Hz,4H),4.14-4.09(m,4H), 3.72(bs,1H),3.24(s,1H),1.81-1.78(m,2H),1.61-1.51(m,4H),1.40(s,9H),1.23-1.16(m,5H).

[0197] Step 6: Methyl 2-(4-((((1r,4r)-4-aminocyclohexyl)(tert-butoxycarbonyl)amino)methyl)-1H-pyrazole-1-yl)acetate(10) To a stirred solution of ethyl 2-(4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(tert-butoxycarbonyl)amino)methyl)-1H-pyrazole-1-yl)acetate (9) (1 g, 1.94 mmol) in MeOH (10 mL), Pd / C (207 mg, 1.94 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature under H2 balloon pressure for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered on a Celite pad, and the filtrate was concentrated under vacuum to obtain the title compound (10) as a colorless gum-like solid (800 mg, 95%). LC-MS: m / z 366 [M+H] + ;t R =1.85min.LC-MS purity:66.03%, 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.59(s,1H),7.35(s,1H),5.03-5.00(m,2H),4.14-4.09(m,4H),3.65(s,4H),1.77-1.75(m,3H),1.40(s,9H),1.20-1.03(m,4H).

[0198] Step 7: 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)ethyl acetate (12) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (11, prepared according to intermediate 6 of Example 4) (400 mg, 0.94 mmol) in MeOH / DCM (8 mL, 1:1), 2-(4-((((1r,4r)-4-aminocyclohexyl)(tert-butoxycarbonyl)amino)methyl)-1H-pyrazole-1-yl)methyl acetate (10) (518 mg, 1.41 mmol), followed by AcOH (3 drops), was added at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. Then, NaCNBH3 (177 mg, 2.83 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (80 mL) and extracted with siRNA (2 × 180 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 10% MeOH in DCM (24 g silica gel column) to obtain the title compound (12) as a white gum-like solid (170 mg, 22%). LC-MS: m / z 774.3 [M + H] + ;t R =2.29min.LC-MS purity:94.98%.

[0199] Step 8: Ethyl 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate(13) To a stirred solution of methyl 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate (12) (170 mg, 0.21 mmol) in THF (2 mL), Et3N (63 mg, 0.63 mmol), followed by (Boc)2O (71 mg, 0.32 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with ELISA (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 10% MeOH in DCM (4g silica gel column) to obtain the title compound (13) as an off-white solid (150mg, 77%). LC-MS: m / z 774.3 [M-Boc+H] + ;t R =3.17min.LC-MS purity:74.6%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.84-7.80(m,1H),7.59-7.54(m,3H),7.47-7.42(m,2H),7.35-7.25(m ,4H),7.21-7.19(m,1H),5.02(s,2H),4.34-4.32(m,3H),4.11-4.01(m ,3H),3.73-3.69(m,4H),3.64(s,3H),3.31-3.28(m,5H),2.68(s,2H), 2.67-2.66(m,1H),2.17-2.15(m,2H),1.93-1.88(m,2H),1.38(s,18H).

[0200] Step 9: Methyl 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate(15) To a stirred solution of methyl 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate (13) (150 mg, 0.17 mmol) in EtOH / H2O (5:1, 2 mL), Parkins catalyst (14) (29.4 mg, 0.06 mmol) was added at room temperature, and the reaction mixture was stirred at 80°C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with ELISA (2 × 60 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography (4 g silica gel column) using 10% MeOH in DCM to obtain the title compound (15) as a yellow liquid (70 mg, 40%). LC-MS: m / z 792.3 [M-Boc+H] + ;t R =2.95min,LC-MS purity:72.99%, 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.54(m,2H),7.39(m,2H),7.30-7.28(m,7H),5.02(s,2H),4.25(m,2H),4.05-4.01(m,2H),3.68-3.64(m, 5H),3.33-3.27(m,7H),2.63(s,3H),2.17(t,J=8.0Hz,3H),1.91-1.88(m,3H),1.38(s,9H),1.33(s,9H).

[0201] Step 10: 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetic acid (16) To a stirred solution of methyl 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl))cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate (15) (60 mg, 0.067 mmol) in THF / MeOH / H2O (1:1:1, 3 mL), LiOH·H2O (11 mg, 0.269 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with ice-cold H2O (10 mL), acidified with 1N HCl (pH=4), and extracted with ELISA (2 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was ground with Et2O (10 mL) to obtain the title compound (16) as an off-white solid (55 mg, 93%). LC-MS: m / z 876.4 [MH] + ;t R =2.82min.LC-MS purity:95.39%,HPLC purity:93.55%,t R = 10.15 min. 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.65-7.49(m,2H),7.46-7.38(m,2H),7.31-7.18(m,8H),7.11(m,1H),4.64-4.60(bs,2H),4.25(s,3H),4.05( s,2H),3.70-3.67(m,5H),3.31-3.29(m,5H),1.60-1.48(m,5H),1.33(s,9H),1.23(s,9H),1.17-1.06(m,2H).

[0202] Step 11: ((1r,4r)-4-((tert-butoxycarbonyl)((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-4-yl)methyl)amino)cyclohexyl)(2'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate (18) To a stirred solution of 2-(4-(((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetic acid (16) (11 mg, 0.012 mmol) and dimethylamine hydrochloride (17) (4 mg, 0.050 mmol) in DMF (1 ml), HATU (6 mg, 0.018 mmol), followed by DIPEA (9 mg, 0.072 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was diluted with H2O and extracted with ELISA. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (18) as a brown liquid (11 mg, 100%). LC-MS: m / z 805.4 [M-Boc+H] + ;t R =2.849min.LC-MS purity:93.32%.

[0203] Step 12: 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 14) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-4-yl)methyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (18) (11 mg, 0.012 mmol) in DCM (1 ml), TFA (4 mg, 0.036 mmol) was added at 0°C, and the reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC [column: Kinetex C18 (250 mm × 21.2 mm, 5.0 μm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 20, 10 / 50] to obtain the trifluoroacetate of the title compound (Example 14) as a white solid (3 mg, 30%). LC-MS: m / z 705.40 [M+H] + ;(t R =1.852min).LC-MS purity:99.44%.HPLC purity:99.64%(t R (6.482 min, at 210 nm). 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.762(s,1H),7.567(s,1H),7.520-7.467(m,3H),7.442-7.351(m,6H),7.325-7.267(m,2H),5.101(s,2H),4.370-4.127(m,4 H),3.757-3.714(m,4H),3.316(s,3H),3.305(s,3H),2.961(m,1H),2.855(s,3H),2.167-2.051(m,4H),1.426-1.237(m,4H).

[0204] Example 15. Synthesis of 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxoxazolidine-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: Benzyl((1r,4r)-4-(oxetane-3-ylamino)cyclohexyl)carbamate(3) To a stirred solution of benzyl((1r,4r)-4-aminocyclohexyl)carbamate (1) (1.00 g, 4.02 mmol) in MeOH / DCM (20 mL), oxetane-3-one (2) (870 mg, 12.08 mmol), followed by AcOH (0.05 mL), was added at room temperature, and the reaction mixture was stirred at room temperature for 24 hours. Then, NaCNBH3 (760 mg, 12.08 mmol) was added to the reaction mixture at 0°C, and the reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (3) as a brown viscous solid (1.0 g, crude, 83%). LC-MS: m / z 305.20[M+H] + ;t R =1.32, LC-MS purity: 64.99%.

[0205] Step 2: tert-butyl((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(oxetan-3-yl)carbamate(4) To a stirred and cooled solution of benzyl ((1r,4r)-4-(oxetane-3-ylamino)cyclohexyl)carbamate (3) (1.00 g, 3.28 mmol) in THF (20 mL), Et3N (1.57 mL, 11.49 mmol) was added, followed by (Boc)2O (1.80 g, 8.213 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with RINKAN (30 mL). The combined extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by combiflash chromatography (24 g silica gel column) using 20% ​​RINKAN in hexane to obtain the title compound (4) as an off-white solid (0.7 g, 53%). LC-MS: m / z 405.25[M+H] + ;t R =1.68,LC-MS purity:96.02%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.36-7.30(m,5H),7.21(d,J=7.6Hz,1H),4.99(s,2H),4.68(s,3H),4.54(s,2H),3.2 3-3.22(m,1H),1.83-1.70(m,4H),1.55-1.52(m,2H),1.42(s,9H),1.26-1.18(m,3H).

[0206] Step 3: tert-butyl((1r,4r)-4-aminocyclohexyl)(oxetan-3-yl)carbamate(5) To a stirred solution of tert-butyl((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (4) (700 mg, 1.73 mmol) in MeOH (20 mL), 10% Pd / C (185 mg) was added, and the reaction mixture was stirred at room temperature under hydrogen balloon pressure for 48 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with MeOH (20 mL) and filtered on a Celite pad. The filtrate was concentrated under reduced pressure. The resulting crude product was ground with Et2O (20 mL) to obtain the title compound (5) as a brown solid (450 mg, crude product, 96%). LC-MS: No ionization.

[0207] Step 4: ((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate tert-butyl(7) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonyl (6, prepared according to intermediate 6 of Example 4) (150 mg, 0.35 mmol) in MeOH / DCM (1:1, 3 mL), tert-butyl ((1r,4r)-4-aminocyclohexyl)(oxetan-3-yl)carbamate (5) (137 mg, 0.35 mmol), followed by AcOH (10 mg, 0.17 mmol), was added at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. Then, NaCNBH3 (67 mg, 1.06 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred for 12 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by combiflash chromatography (4 g silica gel column) using 2-3% MeOH in DCM to obtain the title compound (7) as a colorless gum-like solid (50 mg, 20%). LC-MS: m / z 678 [M+H] + ;tR =1.49, LC-MS purity: 47%.

[0208] Step 5: tert-butyl((1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate(9) To a stirred solution of tert-butyl((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (7) (50 mg, 0.07 mmol) in EtOH / H2O (5:1, 3 mL), Parkins catalyst (8) (10 mg, 0.02 mmol) was added at room temperature, and the reaction mixture was stirred at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (9) as an off-white solid (40 mg, crude, 96%). LC-MS: m / z 640.3[M-tBu+H] + ;t R =2.21min.LC-MS purity:46.13%.

[0209] Step 6: 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxoxazolidine-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 15) To a stirred solution of tert-butyl((1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (9) (40 mg, 0.05 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude product was purified by preparative HPLC [column: Kinetex C18 (250 × 21.2 × 5 μm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 mL / min; gradient: time (min) / %B: 0 / 10, 10 / 50] to obtain the trifluoroacetate of the title compound (Example 15) as an off-white solid (3 mg, 7%). LC-MS: m / z 640.3 [M + H] + ;t R =2.02min.LC-MS purity:99.05%;HPLC purity:98.18%,t R = 7.13 min. 1 1H NMR (400MHz, DMSO-d6) = δ ppm 8.30-8.20(m,1H),7.62-7.59(m,1H),7.47-7.28(m,10H),7.27-7.08(m,1 H),5.04(t,J=4.8Hz,1H),4.36(t,J=6.0Hz,1H),4.27-4.20(m,3H),4.06- 4.04(m,1H),3.81-3.68(m,5H),3.46-3.43(m,2H),3.31(s,4H),3.06(m,1 H),2.07(m,2H),1.83-1.75(m,3H),1.64-1.60(m,1H),1.44-1.41(m,2H).

[0210] Example 16. Synthesis of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: (1r,4r)-N1-methylcyclohexane-1,4-diamine (2) To a stirred solution of (4-aminocyclohexyl)carbamate tert-butyl (1) (500 mg, 2.33 mmol) in THF (5.0 mL), LiAlH4 (443 mg, 11.6 mmol) was added at 0°C, and the reaction mixture was stirred at 70°C for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (2) as an off-white solid (400 mg, crude, 130%). 1 H NMR(400MHz,CDCl3)=δ ppm 2.70-2.65(m,1H),2.42(s,3H),2.30(m,1H),1.95-1.85(m,4H),1.15-1.08(m,4H).

[0211] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile(4) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (3, prepared according to intermediate 6 of Example 4) (200 mg, 0.47 mmol) in MeOH / DCM (1; 1, 4 mL), (1r,4r)-N1-methylcyclohexane-1,4-diamine (2) (60 mg, 0.47 mmol), followed by AcOH (2 drops), was added at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. Then, NaCNBH3 (59 mg, 0.94 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 60 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 20% ​​MeOH in DCM (4g silica gel column) to obtain the title compound (4) as a brown liquid (35 mg, 13%). LC-MS: m / z 536.3 [MH] + ;t R =1.90min.LC-MS purity:92.84%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.80(m,1H),7.58-7.55(m,2H),7.47-7.43(m,3H),7.30-7.26(m,3H),7.19-7.18(m,1H),4.35-4.33( m,2H),3.71(t,J=4.0Hz,2H),3.36(m,6H),3.31(s,3H),3.11(s,3H),1.95-1.91(m,3H),1.23(m,4H).

[0212] Step 3: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(5) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (4) (25 mg, 0.046 mmol) in THF (1 mL), Et3N (23 mg, 0.230 mmol), followed by (Boc)2O (40 mg, 0.186 mmol), was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL), extracted with ELISA (2 × 20 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as a brown liquid (19 mg, crude, 55%). LC-MS: m / z 536.3[(M-Boc+H)] + ;t R =3.37min.LC-MS purity:92.84%.

[0213] Step 4: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(7) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (19 mg, 0.025 mmol) in EtOH / H2O (5:1, 1.2 mL), Parkins catalyst (6) (3 mg, 0.007 mmol) was added at room temperature, and the reaction mixture was then stirred at 80 °C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with H2O (5 mL) and extracted with ELISA (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the title compound (7) as a yellow liquid (19 mg, crude, 100%). LC-MS: m / z 654.3 [M-Boc+H] + ;t R =3.10min.LC-MS purity:59.23%.

[0214] Step 5: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 16) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (7) (19 mg, 0.025 mmol) in DCM (1 mL), TFA (8 mg, 0.075 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude product was purified by preparative HPLC [column: Kinetex C18 (250 × 21.2 mm; 5.0 μm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 mL / min; gradient time (min) / %B: 0 / 10, 2 / 10, 10 / 40] to obtain the trifluoroacetate of the title compound (Example 16) as an off-white solid (2.5 mg, 12%). LC-MS: m / z 554.3 [M+H] + ;t R =1.80min.LC-MS purity:97.76%,t R =6.58min,HPLC purity:95.28%, 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.50-8.46(bs,3H),7.63-7.55(m,1H),7.50-7.34(m,7H),7.30-7.27(m,2H),7.14-7.09(m,1H),6.55(s,1H),4.39-4.35(m,1H) ,4.25-4.21(m,2H),3.72-3.69(m,4H),3.31(s,6H),3.06-3.04(m,1H),2.93-2.89(m,1H),2.17-2.04(m,4H),1.39-1.23(m,4H).

[0215] Example 17. Synthesis of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidine-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 2'-Chloro-6-fluoro-5'-(hydroxy(phenyl)methyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrili(2) To a stirred and cooled solution of 5'-benzoyl-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile (1, prepared according to Example 4) (150 mg, 0.365 mmol) in MeOH (4 mL), NaBH4 (41 mg, 1.09 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction was quenched with aqueous NH4Cl (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 20% ​​siRNA in hexane (4 g silica gel column) to obtain the title compound (2) as a colorless liquid (150 mg, 98%). LC-MS: m / z 394.1 [M-OH+H] + ;t R =2.59min.LC-MS purity:97.89%. 1 H NMR(400MH,DMSO-d6)=δ ppm 7.83-7.81(m,1H),7.61-7.59(m,1H),7.55-7.19(m,7H),6.13(s,1H), 5.78-5.76(m,1H),4.34-4.33(m,2H),3.72-3.70(m,2H),3.28(s,3H).

[0216] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrole-2-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile(4) To a stirred solution of 2'-chloro-6-fluoro-5'-(hydroxy(phenyl)methyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile (2) (100 mg, 0.242 mmol) in a 20 mL sealed tube, 1H-pyrrole (3) (32 mg, 0.485 mmol), followed by BF3·OEt2 (34 mg, 0.242 mmol), was added, and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 30% siRNA in hexane (4 g silica gel column) to obtain the title compound (4) as a colorless liquid (70 mg, 90%). LC-MS: m / z 461.1[M+H] + ;t R =2.78min.LC-MS purity:95.53%.

[0217] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrole-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide(10) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrole-2-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (4) (70 mg, 0.152 mmol) in EtOH / H2O (5:1, 5 mL), Parkins catalyst (5) (20 mg, 0.045 mmol) was added at room temperature, and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with 10% MeOH / DCM (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (6) as a yellow liquid (70 mg, crude, 97%). LC-MS: m / z 479.1, t R =2.61min.LC-MS purity:76.45%.

[0218] Step 4: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidine-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 17) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrole-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide (6) (70 mg, 0.146 mmol) in EtOH (3.00 mL), one drop of concentrated HCl was added, followed by PtO2 (33 mg, 0.146 mmol) at room temperature. The reaction mixture was stirred at room temperature under hydrogen for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with 10% MeOH / DCM (30 mL), filtered on a Celite pad, and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4g silica gel column) using 15% MeOH in DCM to obtain an impure brown solid (17). This solid was then purified by HPLC [column: Luna OMEGA C18 (250×21.2mm; 5μm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 35, 10 / 50; flow rate: 15mL / min] to obtain trifluoroacetate (7mg, 11%) of stereoisomer 1 (17a) of the title compound (Example 17) as an off-white solid. LC-MS: m / z 483.1 [M+H] + ;t R =1.96min.LC-MS purity:85.72%,t R =6.95min;HPLC purity=97.37%, 1 ¹H NMR (400 MHz, DMSO-d6 and D2O) = δ ppm 7.48-7.25 (m, 10H), 4.44 (bs, 1H), 4.24-4.09 (m, 3H), 3.72-3.71 (bs, 2H), 3.31 (s, 3H), 3.22-3.20 (bs, 2H), 2.05-2.00 (m, 3H), 1.56-1.52 (m, 1H), and trifluoroacetate of stereoisomer 2 of the title compound (Example 17) (17b): Yield = 7 mg, 11%. LC-MS: m / z 483.1 [M+H] + ;t R=2.10min.LC-MS purity:99.44%,t R =7.14min;HPLC purity=86.43%, 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.56-7.25(m,10H),4.52-4.41(m,2H),4.30-3.99(m,4H),3.72-3.71(bs,2H) ,3.32-3.31(s,3H),3.25-3.18(m,2H),1.97-1.80(m,4H),1.59-1.54(m,1H).

[0219] Example 18. Synthesis of (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid trifluoroacetate [ka] Step 1: (1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylate methyl(3) To a stirred solution of (1r,4r)-4-aminocyclohexane-1-carboxylate methyl hydrochloride (2) (2.4 g, 5.67 mmol) in MeOH / DCM (1:1, 25 mL), DIPEA (1.9 mL, 11.34 mmol) was added at room temperature, and the reaction mixture was stirred for 1 hour. 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carbonitrile (1, prepared according to intermediate 6 of Example 4) (2.4 g, 5.671 mmol), then AcOH (0.5 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 4 hours. Subsequently, NaCNBH3 (0.71 g, 11.34 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with RINKAN (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by combiflash chromatography (24 g silica gel column) using 3-5% MeOH in DCM to obtain the title compound (3) as a colorless gum-like liquid (0.6 g, 19%). LC-MS: m / z 565.3 [M+H] + ;t R =2.19min,LC-MS purity:85.76%.

[0220] Step 2: Methyl(1r,4r)-4-((tert-butoxycarbonyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylate(4) To a stirred solution of methyl(1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylate (3) (600 mg, 1.063 mmol) in DCM (10 mL), Et3N (0.42 mL, 3.189 mmol), followed by (Boc)2O (348 mg, 1.59 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by combiflash chromatography (24g silica gel column) using 3-5% MeOH in DCM to obtain the title compound (4) as an off-white solid (500mg, 70%). LC-MS: m / z 565.2 [M-Boc+H] + ;t R =3.16 min and 3.20 min. LC-MS purity: 99%, 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.82-7.79(m,1H),7.59-7.42(m,4H),7.36-7.26(m,4H),7.20-7.19(m,1H),4.34-4.33(m,3H),3.73-3.69(m,4H), 3.54(s,3H),3.32(s,3H),2.09-1.98(m,1H),1.78-1.75(m,2H),1.53-1.49(m,2H),1.33(s,9H),1.17-1.10(m,5H).

[0221] Step 3: Methyl(1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylate(6) To a stirred solution of methyl(1r,4r)-4-((tert-butoxycarbonyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylate (4) (500 mg, 0.752 mmol) in EtOH / H2O (5:1, 9 mL), Parkins catalyst (5) (97 mg, 0.225 mmol) was added at room temperature, and the reaction mixture was stirred at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with  (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography (12g silica gel column) using 3-5% MeOH in DCM to obtain the title compound (6) as an off-white solid (500mg, 64%) from two batches. LC-MS: m / z 583.3 [M-Boc+H] + ;t R =2.92min.LC-MS purity:70.78%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.41-7.39(d,J=8Hz,3H),7.35-7.18(m,7H),7.08(bs,3H),4.22(bs,3H),3.71-3.68(m,5H), 3.54(s,3H),2.08(bs,2H),1.76(bs,2H),1.52-1.45(m,2H),1.33(s,9H),1.22-1.17(m,5H).

[0222] Step 4: (1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid(7) To a stirred solution of methyl(1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylate (6) (350 mg, 0.512 mmol) in THF / MeOH (3:1, 8 mL) and H2O (1.00 mL), LiOH·H2O (64.5 mg, 1.537 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with ice-cold H2O (10 mL), acidified with 1N HCl, filtered the precipitated solid, and dried under reduced pressure. The resulting crude product was pulverized with hexane (20 mL) to obtain the title compound (7) as an off-white solid (420 mg, 85%) from two batches. LC-MS: m / z 667.3 [MH] + ;t R =2.66min.LC-MS purity:74.87%,HPLC purity:74.18%, 1 H NMR(400MHz,DMSO-d6)=δ ppm 11.99(s,1H),7.61-7.39(m,3H),7.33-7.18(m,8H),7.12-7.08(m,1H),4.33-4.20(m,3H),3.77-3.67(m,4 H),3.39-3.36(m,1H),2.01-1.98(m,2H),1.75(bs,2H),1.47-1.38(m,2H),1.33(s,9H),1.19-1.15(m,6H).

[0223] Step 5: (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid (18) To a stirred solution of (1r,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid (7) (420 mg, 0.628 mmol) in DCM (5 mL), TFA (185 mg, 1.88 mmol) was added at 0 °C, and the reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The resulting crude product was pulverized with Et2O (15 mL) to obtain the trifluoroacetate of the title compound (Example 18) as an off-white solid (365 mg, 67%). LC-MS: m / z 569.25; [M+H] + (t R =1.47min),LC-MS purity:96.82%.HPLC purity:t R = 7.15 min (78.53%). 1 H NMR(400MHz,DMSO-d6)=δ ppm 12.23(bs,1H),8.34(bs,2H),7.60-7.10(m,12H),4.37(t,J=8.0Hz,1H),4.26-4.16(m,2H),3.73- 3.61(m,4H),3.31(s,3H),3.03(bs,1H),2.13-2.07(m,3H),1.96-1.93(m,2H),1.37-1.20(m,4H).

[0224] Synthesis and Chiral Purification of Example 18 [ka] The scale-up of 3.0 g of a stereoisomer mixture of compound (7) was carried out according to the same reaction procedure, and 3.0 g of compound (7) was subjected to chiral preparative HPLC (1st preparative purification: column: Chiralpak IG (250 × 10; 5 μm); mobile phase A: 0.1% DEA in hexane, mobile phase B: EtOH (100%); flow rate: 10 mL / min, isocratic: 80 (A): 20 (B); dilution: IPA / DCM (90:10); 2nd preparative purification: column: Chiralpak IA (250 × 20; 5 μm); mobile phase A: 0.1% The compound (7) was purified using TFA, mobile phase B: IPA / DCM (90:10); flow rate: 15 mL / min; isocratic: 85(A):15(B); dilution: THF (100%) to obtain four stereoisomers of compound (7). The first step of chiral preparative purification of compound 7 yielded 720 mg of a mixture of compounds 7a and 7b, and 820 mg of a mixture of compounds 7c and 7d. The second step of chiral preparative purification yielded the four stereoisomers of compound 7: compound 7a: 240 mg; chiral HPLC purity: 98.72%, compound 7b: 250 mg; chiral HPLC purity: 98.64%, compound 7c: 260 mg; chiral HPLC purity: 99.86%, compound 7d: 235 mg; chiral HPLC purity: 95.99%.

[0225] Following step 5 of the synthesis of Example 18, four stereoisomers of compounds 7a-7d were obtained by independently providing them for Boc deprotection with TFA, yielding four stereoisomers of Examples 18a-18d, each with an enantiomer excess of over 90%-97%. The absolute stereochemistry of the stereoisomers of Examples 18a-18d has not been determined.

[0226] Example 18a (stereoisomer 1): 155 mg; LC-MS: m / z=569.3 [M+H] + ;HPLC purity: 98.25% (210nm);Chiral HPLC purity: 98.03%;Optical purity: 96.06% ee. 1H NMR(400MHz,DMSO-d6)δ ppm 12.21(bs,1H),8.29(bs,1H),8.22(bs,1H),7.59(bs,1H),7.47-7.25(m,9H),7.15(bs,1H),4.36(t,J=8.0Hz,1H),4.30-4 .21(m,2H),3.80-3.67(m,4H),3.31(s,3H),3.07-3.04(bs,1H),2.16-2.04(m,3H),1.96-1.90(m,2H),1.40-1.23(m,4H).

[0227] Example 18b (stereotype 2): 50 mg was used with Boc deprotection; 30 mg; LC-MS: m / z = 569.1 [M+H] + HPLC purity: 96.11% (210nm); Kiral HPLC purity: 88.1%; Optical purity: 89.1% ee. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.20(bs,1H),8.30(bs,1H),8.22(bs,1H),7.60(bs,1H),7.47-7.25(m,10H),7.15(bs,1H),4.36(t,J=8.0Hz,1H),4.2 9-4.22(m,2H),3.78-3.69(m,4H),3.31(s,3H),3.04(bs,1H),2.16-2.04(m,3H),1.96-1.93(m,2H),1.37-1.23(m,4H).

[0228] Example 18c (stereotype 3): 28 mg; LC-MS: m / z = 569.0 [M+H] + HPLC purity: 98.20% (210nm); Kiral HPLC purity: 95.31%; Optical purity: 90.62% ee. 1H NMR(400MHz,DMSO-d6)δ ppm 12.20(bs,1H),8.36(bs,1H),8.31(bs,1H),7.57(bs,1H),7.47-7.25(m,10H),7.10(bs,1H),4.36(t,J=8.0Hz,1H),4.2 8-4.21(m,2H),3.76-3.60(m,4H),3.31(s,3H),3.03(bs,1H),2.16-2.01(m,3H),1.96-1.93(m,2H),1.37-1.23(m,4H).

[0229] Example 18d (stereoisomer 4): 54 mg; LC-MS: m / z=569.1 [M+H] + ;HPLC purity:98.25%(210nm);Chiral HPLC purity:97.07%,Optical purity:94.14% ee. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.20(bs,1H),8.34(bs,2H),7.57(bs,1H),7.47-7.26(m,10H),7.10(bs,1H),4.36(t,J=8.0Hz,1H),4.28-4.21 (m,2H),3.77-3.63(m,4H),3.31(s,3H),3.04(bs,1H),2.13-2.01(m,3H),1.96-1.93(m,2H),1.37-1.23(m,4H).

[0230] Example 19. 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide [ka] Step 1: ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate To a stirred solution of ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-phenylethyl)carbamate tert-butyl (1, prepared according to intermediate 6 Example 10)) (600 mg, 0.91 mmol) and 2-bromo-3,4-difluorobenzonitrile (2) (238 mg, 1.09 mmol), K3PO4 (609 mg, 2.745 mmol), N-xanthophos (53 mg, 0.091 mmol), and Pd2(dba)3 (42 mg, 0.045 mmol) were added at room temperature, and the reaction mixture was degassed with N2 for 5 minutes. The resulting reaction mixture was stirred at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with RINKAN (2 × 80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by combiflash chromatography (12 g silica gel column) using 20% ​​RINKAN in hexane to obtain the title compound (3) as an off-white solid (400 mg, 60%). LC-MS: m / z 564.2 [M-Boc+H] + ;t R =3.13min.LC-MS purity:96.37%.

[0231] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(3) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (100 mg, 0.150 mmol) in EtOH / H2O (5:1, 3 mL), Parkins catalyst (4) (20 mg, 0.045 mmol) was added at room temperature, and the reaction mixture was then heated at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (2 × 80 mL). The combined organic layers were washed with brine solution (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as an off-white solid (75 mg, 73%). LC-MS: m / z 584.2[M-Boc+H] + ;t R =2.91min.LC-MS purity:95.92%. 1 HNMR(400MHz,DMSO-d6)=δ ppm 7.79-7.74(m,1H),7.62-7.55(m,1H),7.45-7.43(m,2H),7.35-7.28(m,7H),7.22-7.19(m,1H),6.66(d,J=7.2Hz, 1H),4.40-4.20(bs,1H),3.77-3.64(bs,2H),3.05(bs,2H),1.62-1.50(bs,3H),1.33(s,18H),1.06-1.03(m,5H).

[0232] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 19) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (75 mg, 0.109 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was then stirred at room temperature for 4 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was pulverized with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 × 21.2 mm; 5 μm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min; gradient time (min) / %B: 0 / 20, 2 / 20, 10 / 50] to obtain the trifluoroacetate of the title compound (Example 19) as an off-white solid (55 mg, 92%). LC-MS: m / z 484.2 [M+H] + ;t R =1.81min.LC-MS purity:99.68%.HPLC:98.42%,t R = 6.59 min. 1 HNMR(400MHz,DMSO-d6)=δ ppm 8.47(bs,1H),7.86(bs,2H),7.57-7.53(m,1H),7.50-7.44(m,3H),7.40-7.33(m,5H),7.28-7.25(m,1H),7.10(bs,1H) ),4.44-4.40(m,1H),3.74-3.67(m,3H),3.06-2.94(m,2H),2.12-2.07(m,2H),2.00-1.97(m,2H),1.48-1.24(m,4H).

[0233] Example 20. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(3) To a stirred solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-ol (2) (22 mg, 0.105 mmol) in DMF (2.0 mL), NaH (11 mg, 0.30 mmol) was added at 0°C and the mixture was stirred at room temperature for 15 minutes. Tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (1, prepared according to Int.3 of Example 19) (60 mg, 0.150 mmol) was added to the reaction mixture at 0°C and the mixture was stirred for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (10 mL), and the precipitated solid was filtered through a Buchner funnel and dried under vacuum. The resulting crude product was pulverized with hexane (20 mL) to obtain the title compound (3) as an off-white solid (60 mg, 53%). LC-MS: m / z 692.3 [M-Boc+H] + ;t R =3.34,LC-MS purity:92.39%.1H NMR(400MHz,DMSO-d6)=δ ppm 7.84-7.80(m,1H),7.58-7.45(m,4H),7.36-7.34(m,2H),7.31-7.25(m,2 H),7.21-7.17(m,2H),6.64-6.62(m,1H),4.66(d,J=3.2Hz,1H),4.46-4.3 8(m,3H),3.98-3.95(m,1H),3.77-3.74(m,4H),3.43-3.40(m,1H),3.09( bs,1H),1.70-1.61(m,4H),1.46-1.44(m,6H),1.33(s,18H),1.15-0,80(m 6H).

[0234] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(5) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (60 mg, 0.075 mmol) in EtOH / H2O (5:1, 3 mL), Parkins catalyst (4) (10 mg, 0.022 mmol) was added at room temperature, and the reaction mixture was stirred at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as an off-white solid (60 mg, 97%), which was used in the next step without further purification.

[0235] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.074 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was pulverized with diethyl ether to obtain the trifluoroacetate of the title compound (Example 20) as an off-white solid (45 mg, 94%). LC-MS: m / z 526.2 [M+H] + ;t R =1.69min.LC-MS purity:99.63%,HPLC purity:95.51%,t R =5.35min.1H NMR(400MHz,DMSO-d6)=δ ppm 8.55-8.45(m,2H),7.88(bs,3H),7.63-7.61(m,1H),7.47-7.11(m,9H),7.19-7.11(m,1H),4.99-4.96(m ,1H),4.77(s,1H),4.48-4.37(m,2H),4.15-4.12(m,1H),3.80-3.66(m,3H),3.05-2.93(m,2H),2.08-1.9 1(m,4H),1.40-1.23(m,4H).

[0236] Example 21. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate (3) To a stirred solution of ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate tert-butyl (1, intermediate prepared according to Example 19) (100 mg, 0.150 mmol) in MeOH (1.0 mL), NaOMe (40 mg, 0.751 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 24 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was quenched with H2O (25 mL) and extracted with ELISA (2 × 50 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 20% ​​toluene in hexane (12 g silica gel column) to obtain the title compound (3) as an off-white solid (60 mg, 59%). LC-MS: m / z 578.3 [M-Boc+H] + ;t R =3.23,LC-MS purity:99.46%.1H NMR(400MHz,DMSO-d6)=δ ppm 7.86-7.83(m,1H),7.58-7.42(m,3H),7.36-7.34(m,2H),7.31-7.25(m,2H),7.21-7.17(m,1H),4.38(bs,1H),3. 98(d,J=3.6Hz,3H),3.77(bs,2H),3.07(bs,2H),1.62-1.39(m,4H),1.34(s,9H),1.31(s,9H),1.15-0.99(m,4H).

[0237] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(5) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (60 mg, 0.075 mmol) in EtOH / H2O (5:1, 3 mL), Parkins catalyst (11 mg, 0.024 mmol) was added at room temperature, and the reaction mixture was heated at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as an off-white solid (60 mg, 98%). LC-MS: m / z 596.3[M-Boc+H] + ;t R =2.85min.LC-MS purity:90.72%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.62-7.50(m,2H),7.43-7.38(m,2H),7.31-7.13(m,9H),4.45-4.20(m,1H),3.90(d,J=3.6Hz,3H) ,3.75-3.65(m,2H),3.06(bs,2H),1.68-1.55(m,4H),1.34(s,9H),1.33(s,9H),1.19-1.02(m,4H).

[0238] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 21) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.086 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was pulverized with diethyl ether to obtain the trifluoroacetate of the title compound (Example 21) as an off-white solid (48 mg, 90%). LC-MS: m / z 496.2 [M+H] + ;t R =1.79min.LC-MS purity:99.07%.HPLC:98.04%,t R =6.55min.HNMR(400MHz,DMSO-d6 and D2O)=δ ppm 7.51-7.26(m,10H),4.40-4.32(m,1H),3.91(s,3H),3.82-3.63(m,2H), 3.05-2.95(m,2H),2.11(bs,2H),2.00-1.97(m,2H),1.42-1.34(m,4H).

[0239] Example 22. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-3-yloxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyan-2'-fluoro-3'-(pyridine-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(3) To a stirred solution of pyridine-3-ol (2) (10.0 mg, 0.105 mmol) in DMF (2.0 mL), NaH (11 mg, 0.30 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 15 minutes. Then, tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl) carbamate (1, prepared according to Int.3 of Example 19) (100 mg, 0.150 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (10 mL), and the precipitated solid was filtered through a Buchner funnel and dried under vacuum. The obtained crude product was pulverized with 10% Et2O in hexane to obtain the title compound (3) as an off-white solid (60 mg, 54%). LC-MS: m / z 741.3 [MH] + ;t R =2.06min,LC-MS purity:87.01%. 1 HNMR(400MHz,DMSO-d6)=δ ppm 8.57-8.50(m,1H),7.86(t,J=7.2Hz,1H),7.62-7.53(m,4H),7.37-7.26(m,5H),7.21-7.18(m,1H),6.64(bs,1H),4.40(bs,1) H),3.80-3.78(bs,2H),3.08-3.06(bs,1H),1.62(bs,3H),1.53(bs,2H),1.38(s,18H),1.23-0.93(m,5H),0.86-0.83(m,1H).

[0240] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyridine-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(5) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyridine-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (60 mg, 0.081 mmol) in EtOH / H2O (5:1, 3 mL), Parkins catalyst (11 mg, 0.024 mmol) was added at room temperature. The reaction mixture was then heated at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as an off-white solid (60 mg, crude, 98%). LC-MS: m / z 759.3 [M+H] + ;t R =2.97min.LC-MS purity:74.63%.

[0241] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-3-yloxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 22) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyridine-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.079 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was pulverized with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 × 21.2 mm; 5 μm); dilution: MeCN + H2O + THF; mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10, 10 / 50; flow rate: 15 mL / min] to obtain the trifluoroacetate of the title compound (Example 22) as an off-white solid (12 mg, 23%). LC-MS: m / z 559.2 [M + H] + ;t R =1.82 min. LC-MS purity: 89%, HPLC: 99.39%;t R = 6.29 min. 1 HNMR(400MHz,DMSO-d6 and D2O)=δ ppm 8.42-8.40(m,2H),7.57-7.50(m,4H),7.45(bs,2H),7.38-7.29(m,6H),4.37(t,J=8Hz,1H) ,3.76-7.66(m,2H),3.06-2.91(m,2H),2.11(bs,2H),2.00-1.98(m,2H),1.43-1.31(m,4H).

[0242] Example 23. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate To a stirred solution of (R)-(tetrahydrofuran-2-yl)methanol (2) (16.0 mg, 0.105 mmol) in DMF (2.0 mL), NaH (11 mg, 0.30 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 15 minutes. Then, ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate (1, prepared according to intermediate 3 Example 19) (100 mg, 0.150 mmol) was added at 0°C, and the reaction mixture was stirred at the same temperature for 2 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (10 mL), and the precipitated solid was filtered through a Buchner funnel and vacuum-dried. The obtained crude product was pulverized in 10% Et2O (20 mL) in hexane to obtain the title compound (3) as an off-white solid (60 mg, 53%). LC-MS: m / z 593.15 [M-Boc,-tBu+H] + ;t R =2.06,LC-MS purity:95.89%. 1 HNMR(400MHz,DMSO-d6)=δ ppm 7.83-7.79(m,1H),7.58-7.43(m,4H),7.36-7.25(m,4H),7.22-7.19(m,1H),6.63(bs,1H),4.50-4.30(bs,1H),4.26-4.14(m,3H) ,3.81-3.70(m,4H),3.06(bs,2H),2.02(bs,1H),1.91-1.80(bs,2H),1.73-1.62(m,4H),1.50(bs,2H),1.35(s,18H),1.23(s,3H).

[0243] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(5) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (60 mg, 0.075 mmol) in EtOH / H2O (5:1, 3 mL), Parkins catalyst (4) (11 mg, 0.024 mmol) was added at room temperature, and the reaction mixture was heated at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as an off-white solid (60 mg, 97%). LC-MS: m / z 666.3 [M-Boc+H] + ;t R =2.90min.LC-MS purity:86.84%.

[0244] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 23) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.078 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude product was pulverized with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 × 21.2 × 5 μm); dilution: MeCN + H2O + THF; mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10, 10 / 50; flow rate: 15 mL / min] to obtain the trifluoroacetate of the title compound (Example 23) as an off-white solid (32 mg, 53%). LC-MS: m / z 566.3 [M + H] + ;t R =1.84min.LC-MS purity:99.63%;HPLC purity:99.65%,t R = 6.61 min. 1 HNMR(400MHz,DMSO-d6)=δ ppm 8.52-8.35(m,2H),7.86(bs,2H),7.63-7.61(m,1H),7.47-7.27(m,9H),7.16-7.11(m,1H),4.37(t,J=7.6Hz,1H ),4.19-4.10(m,3H),3.79-3.67(m,4H),2.93(bs,2H),2.08-1.84(m,6H),1.71-1.61(m,1H),1.40-1.23(m,4H).

[0245] Example 24. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: (S)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzonitrile(3) To a stirred solution of NaH (60% in mineral oil) (1.00 g, 27.5 mmol) in DMF (40 mL), (S)-(tetrahydrofuran-2-yl)methanol (2) (2.108 g, 20.64 mmol) was slowly added at 0°C, and the reaction mixture was stirred for 0.5 hours. To this reaction mixture, 2-bromo-3,4-difluorobenzonitrile (1) (5.00 g, 22.94 mmol) in DMF (10 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (150 mL). The resulting solid was filtered and vacuum-dried to obtain the title compound (3) as an off-white solid (4.00 g, 58.1%). 1 H NMR(400MHz,DMSO-d6)δ ppm 7.80(dd,J=1.6,8.8Hz,1H),7.40(t,J=8.0Hz,1H),4.23-4.13(m,3H),3.77-3.7 4(m,1H),3.70-3.67(m,1H),1.99(m,1H),1.87-1.82(m,2H),1.69-1.64(m,1H).

[0246] Step 2: 5'-Benzoyl-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carbonitrile(5) To a stirred solution of (S)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzonitrile (3) (3.5 g, 11.66 mmol) and (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (4, prepared according to a reaction procedure similar to that of Intermediate 3 Example 2) (5.99 g, 17.49 mmol) in toluene / water (50 mL, 9:1), K3PO4 (7.42 g, 35.0 mmol) was added at room temperature, and the reaction mixture was degassed with N2 for 10 minutes. To this solution, N-xanthophos (643 mg, 1.166 mmol) and Pd2(dba)3 (534 mg, 0.583 mmol) were added at room temperature, and the mixture was degassed with N2 for 5 minutes. The resulting reaction mixture was stirred at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (150 mL) and extracted with toluene (2 × 150 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography (80 g silica gel column) using 0 to 20% toluene in hexane to obtain the title compound (5) as a yellow viscous solid (3.00 g, 59%). LC-MS: m / z 436.1 [M + H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.93(s,2H),7.86-7.83(m,2H),7.80-7.78(m,2H),7.72-7,68(m,1H),7.60-7.56(m,2H),7.50-7.46(m,1H),4. 24-4.14(m,3H),3.78-3.76(m,1H).3.71-3.67(m,1H),2.02-1.99(m,1H),1.89-1.82(m,2H),1.71-1.68(m,1H).

[0247] Step 3: 2'-Chloro-6-fluoro-5'-(2-phenyloxylan-2-yl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carbonitrile(6) To a stirred solution of trimethylsulfonium iodide (2.81 g, 13.77 mmol) in THF / DMSO (40 mL, 1:1), NaH (496 mg, 20.65 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. 5'-Benzoyl-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carbonitrile (5) (3.00 g, 6.88 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (150 mL) and extracted with siRNA (2 × 120 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to obtain the title compound (6) as a yellow liquid (3.00 g, 97%), which was used in the next reaction without further purification.

[0248] Step 4: 2'-Chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carbonitrile(7) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-phenyloxiran-2-yl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carbonitrile (6) (1.50 g, 3.33 mmol) in Et2O (15 mL), BF3·Et2O (1.26 mL, 10.0 mmol) was added at 0°C, and the resulting reaction mixture was stirred at 0°C for 10 minutes. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with Et2O (2 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (7) as a yellow liquid (1.50 g), which was used in the next reaction without further purification. LC-MS: m / z 448.1 [MH] + .

[0249] Step 5: ((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)carbamate tert-butyl(9) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carbonitrile (7) (1.50 g, 3.33 mmol) in MeOH / DCM (30 mL, 1:1), ((1r,4r)-4-aminocyclohexyl)carbamate tert-butyl (8) (1.429 g, 6.67 mmol), followed by AcOH (0.019 mL, 0.33 mmol), was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours, after which NaCNBH3 (629 mg, 10.0 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ELISA (2 × 120 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography (12g silica gel column) using 40% MeOH in DCM and 20% HCl to obtain the title compound (9) as a colorless gum-like solid (1.20g, 55.5%). LC-MS: m / z 648.3 [M+H] + .

[0250] Step 6: ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate (10) To a stirred solution of ((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)carbamate tert-butyl(9) (1.20 g, 1.851 mmol) in DCM (20 mL), Et3N (0.77 mL, 5.55 mmol) and Boc2O (0.64 mL, 2.78 mmol) were added at 0°C, and the resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (80 mL) and extracted with ELISA (2 × 90 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 40% SiO2 in hexane (24 g silica gel column) to obtain the title compound (10) as a colorless gum-like solid (1.20 g, 86%). LC-MS: m / z 592.3 [(M-Boc-tBu)+H] + .

[0251] Step 7: ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl) tert-butyl carbamate (11) To a stirred solution of ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate tert-butyl(10) (1.20 g, 1.604 mmol) in EtOH / water (20 mL, 4:1), Parkins catalyst (275 mg, 0.641 mmol) was added at room temperature, and the resulting reaction mixture was stirred at 80°C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with ELISA (2 × 60 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography (12g silica gel column) using 0 to 100% phenyl in hexane to obtain the title compound (11) as an off-white, gum-like solid (1.10g, 89%). LC-MS: m / z 766.5[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm 7.53(bs,1H),7.40-7.38(m,2H),7.31-7.24(m,6H),7.21-7.16(m,1H),7.12(bs,1H),6.65-6.61(m,1H),4.41-4.37(m,1) H),4.18-4.02(m,3H),3.79-3.66(m,3H),3.30(m,1H),3.05(bs,1H),2.00-1.50(m,7H),1.34(s,18H),1.03-0.85(m,6H).

[0252] Step 8: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 24) To a stirred solution of ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate tert-butyl (11) (50 mg, 0.067 mmol) in DCM (1 mL), TFA (0.016 mL, 0.202 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The resulting crude product was washed with Et2O (10 mL) and pentane (10 mL), vacuum dried, and lyophilized to obtain the title compound (Example 24) as an off-white solid (30 mg, 82%). LC-MS: m / z 566.5 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm 8.52-8.34(m,2H),7.86(bs,3H),7.62-7.59(m,1H),7.49-7.38(m,7H),7.31-7.27(m,2H),7.15-7.10(m,1H),4.3 7(t,J=7.6Hz,1H),4.18-4.10(m,4H),3.79-3.67(m,4H),2.09-1.84(m,7H),1.70-1.68(m,1H),1.37-1.23(m,5H).

[0253] Synthesis and chiral purification of the four stereoisomers of Example 24: [ka] A mixture of stereoisomers of compound 11 (1.20 g) was purified by chiral SFC (column: Lux Cellulose-4-4.4 mm × 250 mm × 21.2 mm; 5 μm; mobile phase A: CO2 and mobile phase B: 0.1% HCOOH in IPA / MeOH (1:1); flow rate: 50 mL; homogeneous concentration: 75 (A): 25 (B); diluent: EtOH / DCM (1:1), 18 mL; injection volume: 0.2 mL; electrophoresis time: 27 min) to obtain all four stereoisomers (11a to 11d) of compound 11. Compound 11a: 135mg; Chiral HPLC purity: 99.82%, Compound 11b: 230mg; Chiral HPLC purity: 96.67%, Compound 11c: 200mg; Chiral HPLC purity: 95.11%, Compound 11d: 190mg; Chiral HPLC purity: 95.06%.

[0254] The four stereoisomers of compounds 11a to 11d were each subjected to Boc deprotection with TFA according to step 8 of the procedure in Example 24, yielding the four stereoisomers of Examples 24a to 24d, each with an enantiomer excess of over 87-98%. The absolute stereochemistry of the stereoisomers of Examples 24a to 24d has not been determined.

[0255] Example 24a (stereoisomer 1): 170 mg; LC-MS: m / z 566.3 [M+H] + HPLC purity: 98.22%; Chiral HPLC purity: 94.55%; Optical purity: 89.1% ee. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.48-8.41(m,2H),7.94(bs,3H),7.61(bs,1H),7.47-7.25(m,8H),7.15(bs,1H),4.39(t,J=7.6Hz,1H),4.17-4.14(m,2H),4.07 -4.05(m,1H),3.80-3.75(m,2H),3.71-3.65(m,2H),3.03-2.92(m,2H),2.09-1.84(m,7H),1.70-1.67(m,1H),1.41-1.11(m,4H).

[0256] Example 24b (stereoisomer 2): 160 mg; LC-MS: m / z 566.3 [M+H]+ HPLC purity: 98.22%; Kiral HPLC purity: 98.0%; Optical purity: 96% ee. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.53(bs,1H),8.44(bs,1H),7.87(bs,3H),7.59(bs,1H),7.47-7.25(m,10H),7.12(bs,1H),4.38(t,J=7.6Hz,1H),4.18-4.14(m,2H), 4.06-4.03(m,1H),3.78-3.76(m,2H),3.69-3.67(m,2H),3.02-2.93(m,2H),2.04-1.84(m,7H),1.70-1.67(m,1H),1.40-1.21(m,4H).

[0257] Example 24c (stereotype 3): 130 mg; LC-MS: m / z 566.3 [M+H] + HPLC purity: 97.1%; Kiral HPLC purity: 99.37%; Optical purity: 98.74% ee. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.45(bs,1H),8.35(bs,1H),7.89(bs,3H),7.61(bs,1H),7.47-7.29(m,10H),7.12(bs,1H),4.38(t,J=7.6Hz,1H),4.20-4.18(m,2H), 4.12-4.09(m,1H),3.79-3.75(m,2H),3.71-3.66(m,2H),3.03-2.93(m,2H),2.09-1.84(m,7H),1.70-1.67(m,1H),1.44-1.23(m,4H).

[0258] Actual treatment 24 days (stereotype 4): 190 mg; LC-MS: m / z 566.3 [M+H] + HPLC purity: 99.08%; Kiral HPLC purity: 93.88%; Optical purity: 87.76% ee. 1H NMR(400MHz,DMSO-d6)δ ppm 8.54(bs,1H),8.46(bs,1H),7.89(bs,3H),7.59(bs,1H),7.47-7.27(m,10H),7.10(bs,1H),4.38(t,J=7.6Hz,1H),4.20-4.17(m,1H), 4.11-4.08(m,2H),3.80-3.73(m,2H),3.71-3.60(m,2H),3.10-2.93(m,2H),2.08-1.84(m,7H),1.70-1.65(m,1H),1.37-1.23(m,4H).

[0259] Step 9: (3-bromo-4-chlorophenyl)(phenyl)methanone (13) A solution of 3-bromo-4-chlorobenzoic acid (12) (8.00 g, 34.20 mmol) in SOCl2 (12 mL) was stirred at 80°C for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The resulting crude product was dissolved in benzene (80 mL), and then AlCl3 (13.5 g, 101.91 mmol) was added to the reaction mixture at 0°C. The resulting reaction mixture was stirred at 80°C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum, diluted with water (50 mL), basicized with saturated NaHCO3 aqueous solution (50 mL), and extracted with ELISA (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude product was ground with pentane (100 mL) to obtain the title compound (13) as an off-white solid (8.78 g, 87%). LC-MS: m / z = 295.85 [MH] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm 8.02(s,1H),7.81-7.70(m,5H),7.58-7.57(m,2H).

[0260] Step 10: (4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone(4) To a stirred solution of (3-bromo-4-chlorophenyl)(phenyl)methanone (13) (9.0 g, 30.5 mmol) in 1,4-dioxane (90 mL), bis(pinacolate)diborone (11.6 g, 45.7 mmol) and KOAc (8.97 g, 91.0 mmol) were added at room temperature, and the mixture was degassed with N2 for 10 minutes. Pd(dppf)Cl2.DCM (2.48 g, 3.05 mmol) was added to the reaction mixture at room temperature, and the mixture was degassed with N2 for 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (300 mL) and extracted with ELISA (2 × 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The resulting crude product was purified by combiflash chromatography using 0-10% phenylethanol in hexane (80g silica gel column) to obtain the title compound (4) as a brown, gum-like liquid (10g, 96%). LC-MS: m / z = 343.2 [M + H] + .

[0261] Example 25. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 2-Bromo-3-fluoro-4-(pyridine-2-ylmethoxy)benzonitrile (3) To a stirred and cooled (0°C) solution of pyridine-2-ylmethanol (2) (0.080 g, 0.733 mmol) in DMF (8.00 mL), NaH (0.044 g, 1.100 mmol) was added, the mixture was stirred at room temperature for 15 minutes, cooled again to 0°C, and then 2-bromo-3,4-difluorobenzonitrile (1) (0.200 g, 0.917 mmol) in 2 mL of DMF was added. The reaction mixture was stirred at the same temperature for 2 hours. After completion (monitored by TLC), the reaction mixture was poured into ice-cold H2O (50 mL), the precipitated solid was filtered through a Buchner funnel, and dried under vacuum to obtain the title compound (3) as an off-white solid (0.22 g, 78%). LC-MS: No ionization; 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.60(s,1H),7.89-7.80(m,2H),7.55-7.39(m,3H),5.37(s,2H).

[0262] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyan-2'-fluoro-3'-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(5) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-phenylethyl)carbamate (4, prepared according to Int. 6 of Example 10) (100 mg, 0.152 mmol) and 2-bromo-3-fluoro-4-(pyridine-2-ylmethoxy)benzonitrile (56.0 mg, 0.183 mmol), K3PO4 (101 mg, 0.456 mmol), N-xanthophos (9 mg, 0.015 mmol), and Pd2(dba)3 (7 mg, 0.0076 mmol) were added at room temperature, and the reaction mixture was degassed with argon for 5 minutes. Next, the reaction mixture was heated at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL), and the organic matter was extracted with  (2 × 80 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography (12 g silica gel column) using 60%  in hexane to obtain the title compound (5) as an off-white solid (50 mg, 43%). LC-MS: m / z 753.4 [MH] + ;t R =3.23min.LC-MS purity:97.25%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.61(s,1H),7.87-7.81(m,2H),7.55-7.53(m,5H),7.39-7.19(m,7H),6.60(bs,1H),5.42(bs,2H),4. 5-4.53(m,1H),3.74-3.69(m,2H),3.04(bs,1H),1.61(bs,2H),1.49-1.23(m,18H),1.17-1.00(m,6H).

[0263] Step 3: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(7) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (50 mg, 0.066 mmol) in EtOH / H2O (3 ml), Parkins catalyst (6) (9 mg, 0.019 mmol) was added at room temperature, and the reaction mixture was then heated at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with Â(2 × 80 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (7) as an off-white solid (50 mg, 97%). LC-MS: m / z 773.55[M+H] + ;t R =1.88min.LC-MS purity:92.80%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.61-8.59(m,1H),7.88-7.84(m,1H),7.63-7.51(m,3H),7.41-7.51(m,3H),7.41-7.28(m,8H),7.21-7.15(m,2H),6.654(d,J=8. 0Hz,1H),5.37-5.29(m,2H),4.38(bs,1H),3.75-3.66(m,2H),3.06(bs,2H),1.63-1.57(m,3H),1.33(s,19H),1.10-0.93(m,4H).

[0264] Step 4: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(112-iridin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 25) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(112-iridin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (7) (50 mg, 0.064 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was pulverized with Et2O to obtain the trifluoroacetate of the title compound (Example 25) as an off-white solid (45 mg, 99%). LC-MS: m / z [M+H] + ;t R =3.08min.LC-MS purity:97.29%,t R =6.33min HPLC purity:96.32%. 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 8.62(bs,1H),7.96-7.92(m,1H),7.65-7.30(m,12H),5.34-5.31(bs,2H),4.41-4.34 (m,1H),3.79-3.64(m,2H),3.06-2.95(m,2H),2.11-2.00(m,4H),1.46-1.23(bs,4H).

[0265] Example 26. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyan-2'-fluoro-3'-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(3) To a stirred solution of pyrimidine-2-ylmethanol (2) (16.0 mg, 0.105 mmol) in DMF (1.0 mL), NaH (11 mg, 0.30 mmol) was added at 0°C and stirred at room temperature for 15 minutes. Then, tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carb Mate (1, prepared according to Int.3 of Example 19) (100 mg, 0.150 mmol) was added at 0°C, and the reaction mixture was stirred at the same temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (10 mL), and the precipitated solid was filtered through a Buchner funnel and dried under vacuum. The resulting crude product was pulverized with hexane (20 mL) to obtain the title compound (3) as an off-white solid (60 mg, 53%). LC-MS: no ionization. 1 HNMR(400MHz,DMSO-d6)=δ ppm 8.86(t,J=4.8HZ,1H),7.90-7.87(m,1H),7.78-7.73(m,1H),7.59-7.49(m,3H),7.38-7.35(m,2H),7.31-7.25(m,2H),7.22-7.19(m,1H) ,6.63(bs,1H),4.40(bs,1H),3.65(bs,2H),3.09-3.06(bs,2H),1.67-1.50(m,5H),1.39(s,18H),1.15-0.99(m,6H),0.87-0.80(m,1H).

[0266] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(5) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (70 mg, 0.092 mmol) in EtOH / H2O (5:1, 3 mL), Parkins catalyst (4) (12 mg, 0.027 mmol) was added at room temperature, and the reaction mixture was then heated at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (5) as an off-white solid (60 mg, crude, 84%). LC-MS: m / z 674.3[M-Boc+H] + ;t R =2.89min.LC-MS purity:59.2%. 1 HNMR(400MHz,DMSO-d6)=δ ppm 8.87-8.85(m,1H),7.75(bs,1H),7.62-7.49(m,2H),7.40-7.29(m,8H),7.20-7.13(m,2H),6.65-6.64(m,1H),5.45(s, 1H),4.40-4.33(m,1H),3.80-3.69(bs,2H),3.05(bs,1H),1.61-1.60(bs,3H),1.50-1.16(m,19H),0.92-0.83(m,7H).

[0267] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 26) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.077 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was then stirred at room temperature for 4 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was pulverized with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 × 21.2; 5 μm); dilution: MeCN + H2O + THF; mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10, 10 / 50; flow rate: 15 mL / min] to obtain the trifluoroacetate of the title compound (Example 26) as an off-white solid (16 mg, 32%). LC-MS: m / z 574.2 [M + H] + ;t R =1.78min.LC-MS purity:99.77%,HPLC purity:95.42%,t R = 6.44 min. 1 HNMR (400 MHz, DMSO-d6) = δ ppm 8.86(d,J=4.8Hz,1H),8.50-8.31(m,2H),7.83(bs,3H),7.63-7.60(m,1H) ,7.52-7.46(m,2H),7.39-7.34(m,6H),7.29-7.27(m,1H),7.23-7.21(m,1H ),7.10(bs,1H),5.47-5.46(m,1H),4.37(t,J=7.6Hz,1H),3.79-3.68(bs,2 H),3.07-2.93(m,2H),2.08(s,3H),1.96-1.94(bs,2H),1.43-1.23(m,4H).

[0268] Example 27. Synthesis of 5-(2-((1-acetylazetidine-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: Benzyl 3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate (3) To a stirred solution of benzyl 3-hydroxyazetidine-1-carboxylate (1) (1 g, 4.83 mmol) in THF (10 mL), NaH (0.21 g, 5.314 mmol) was added at 0°C and the mixture was stirred at the same temperature for 30 minutes. Then, ethyl bromoacetate (2) (0.8 g, 4.830 mmol) was added at 0°C and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete (monitored by TLC), the reaction product was diluted with saturated NH4Cl aqueous solution (20 mL) and extracted with siRNA (100 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the title compound (3) as an off-white solid (0.8 g, 57%). 1 H NMR(400MHz,CDCl3)=δ ppm 7.37-7.29(m,5H),5.09(s,2H),4.39-4.36(m,1H),4.24-4.16(m,4H),4.04-3.99(m,3H),3.90-3.83(m,1H)1.328(t,J=7.2Hz,3H).

[0269] Step 2: Benzyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (4) To a stirred solution of benzyl 3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate (3) (800 mg, 2.729 mmol) in THF (10 mL), LiAlH4 (124 mg, 3.275 mmol) was added at 0°C and the mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction product was diluted with saturated NH4Cl aqueous solution (10 mL) and extracted with  (50 mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude residue was purified by combiflash chromatography (12 g silica gel column) using 50%  in hexane to obtain the title compound (4) as an off-white solid (600 mg, 88%). LC-MS: m / z 252.2 [M+H] + t R =2.04,LC-MS purity:98.80%.

[0270] Step 3: Benzyl 3-(2-(3-bromo-4-cyano-2-fluorophenoxy)ethoxy)azetidine-1-carboxylate(6) To a stirred solution of benzyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (4) (600 mg, 2.390 mmol) in DMF (15 mL), NaH (143 mg, 3.585 mmol) was added at 0°C and the mixture was stirred at the same temperature for 30 minutes. Then, 2-bromo-3,4-difluorobenzonitrile (5) (622 mg, 2.868 mmol) in DMF (5 mL) was added at 0°C and the mixture was stirred at the same temperature for 1.5 hours. After the reaction was complete (monitored by TLC), the reaction product was diluted with saturated NH4Cl aqueous solution (20 mL) and extracted with  (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude compound was purified by combiflash chromatography using 50% toluene in hexane (12 g silica gel column) to obtain the title compound (6) as a brown liquid (600 mg, 66%). LC-MS: m / z 490.0 [M+MeCN+H] + ;t R =2.74,LC-MS purity:88.22%. 1H NMR(400MHz,DMSO-d6)=δ ppm 7.83-7.80(m,1H),7.40-7.32(m,6H),5.02(s,2H),4.40-4.31(m,3H),4.14(bs,2H),3.76-3.74(m,4H).

[0271] Step 4: Benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-cyano-2-fluoro-[1,1'-biphenyl]-3-yl)oxy)ethoxy)azetidine-1-carboxylate(8) Benzyl 3-(2-(3-bromo-4-cyano-2-fluorophenoxy)ethoxy)azetidine-1-carboxylate (6) (600 mg, 1.339 mmol) and tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-diode) in toluene / H2O (9:1, 12 mL) To a stirred solution of xaborolan-2-yl)phenyl)-2-phenylethyl)carbamate (7, prepared according to Example 10) (800 mg, 1.339 mmol), K3PO4 (850 mg, 4.017 mmol), Pd2dba3 (62 mg, 0.066 mmol), and N-xanthophos (73 mg, 0.133 mmol) were added under an argon atmosphere, and the reaction mixture was heated at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (5 mL) and extracted with siRNA (2 × 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 90% siRNA in hexane (12 g silica gel column) to obtain the title compound (8) as a viscous brown liquid (400 mg, 33%). LC-MS: m / z 797.3[M-Boc+H] + ;t R =3.25,LC-MS purity:48.66%.

[0272] Step 5: Benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-carbamoyl-2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)oxy)ethoxy)azetidine-1-carboxylate(10) To a stirred solution of benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-cyano-2-fluoro-[1,1'-biphenyl]-3-yl)oxy)ethoxy)azetidine-1-carboxylate (8) (400 mg, 0.446 mmol) in EtOH / H2O (9:1, 8 mL), Parkins catalyst (9) (76 mg, 0.178 mmol) was added at room temperature, and the reaction mixture was heated at 90 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography using 90% toluene in hexane (12 g silica gel column) to obtain the title compound (10) as a yellow liquid (300 mg, 75%). LC-MS: m / z 815.3 [M-Boc+H] + ;t R =3.08,LC-MS purity:92.31%. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.62-7.56(m,2H),7.41-7.38(m,2H),7.33-7.24(m,12H),7.21-7.14(m,2H),6.64(d,J=8.0Hz,1H),5.02(s,2H),4.41-4.38( m,2H),4.24(bs,2H),4.13(bs,2H),3.80-3.75(m,6H),3.10-2.89(m,2H),1.63-1.60(m,2H),1.34(s,20H),1.10-1.00(m,4H).

[0273] Step 6: tert-butyl(2-(3'-(2-(azetidine-3-yloxy)ethoxy)-6'-carbamoyl-6-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(11) Benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-carbamoyl-2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)oxy)ethoxy)azetidine-1-carboxylate (10) (40 mg, 0.043 mmol) was stirred in THF / MeOH (1:1, 1 mL), to which 10% Pd / C (10 mg) was added, and the mixture was stirred at room temperature under an H2 atmosphere for 3 hours. After the reaction was complete (monitored by TLC), the reaction product was filtered through a Celite bed, and the filtrate was concentrated under vacuum to obtain the title compound (11) as an off-white solid (40 mg, crude, 110%). LC-MS: m / z 781.3; [M+H] + ,t R =2.30min.LC-MS purity:46.17%.

[0274] Step 7: tert-butyl(2-(3'-(2-((1-acetylazetidine-3-yl)oxy)ethoxy)-6'-carbamoyl-6-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(12) To a stirred solution of tert-butyl(2-(3'-(2-(azetidine-3-yloxy)ethoxy)-6'-carbamoyl-6-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (11) (40 mg, 0.051 mmol) in DCM (1 mL), Et3N (0.1 mL, 0.102 mmol) and (Ac)2O (0.1 mL, 0.328 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with ELISA (50 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography (4g silica gel column) using 90% siRNA in hexane to obtain the title compound (12) as an off-white solid (30 mg, 71%). LC-MS: m / z 723.3; [M-Boc+H] + ;t R =2.76min;LC-MS purity:99.86%.

[0275] Step 8: 5-(2-((1-acetylazetidine-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 27) To a stirred solution of tert-butyl(2-(3'-(2-((1-acetylazetidine-3-yl)oxy)ethoxy)-6'-carbamoyl-6-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (12) (30 mg, 0.036 mmol) in DCM (0.4 mL), TFA (0.1 mL) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was ground with pentane and freeze-dried for 2 days to obtain the trifluoroacetate of the title compound (Example 27) as an off-white solid (15 mg, 68%). LC-MS: m / z 623.3 [M+H] + ;(t R =1.76min).LC-MS purity:98.42%,HPLC purity:98.81%,t R =6.41min, 1 H NMR(400MHz,DMSO-d6)=δ ppm 8.40-8.32(bs,2H),7.83(bs,3H),7.65-7.62(m,1H),7.48-7.44(m,3H),7.41-7.32(m,6H),7.29-7.12(m,3H),4.38-4.22(m,5H),4.01-3. 93(m,2H),3.77-3.73(m,3H),3.63-3.61(m,1H),3.11-2.93(m,2H),2 .17-2.08(m,2H),2.01-1.92(m,2H),1.74(s,3H),1.43-1.15(m,4H).

[0276] Example 28. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: N,N-dimethyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)acetamide(3) To a stirred solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-ol (2) (0.500 g, 3.420 mmol) in THF (10.00 mL), the reaction mixture was cooled to 0°C, NaH (0.164 g, 4.104 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 2-bromo-N,N-dimethylacetamide (1) (0.681 g, 4.104 mmol) in 5 mL (THF) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with H2O (100 mL) and extracted with 10% MeOH in DCM (2 × 100 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the title compound (3) as a colorless, gum-like liquid (0.7 g, 88%). LC-MS: No ionization; 1H NMR (400 MHz, DMSO-d₆) = δ ppm 4.58 (s, 1H), 4.14 (s, 2H), 3.73-3.34 (m, 6H), 2.91 (s, 3H), 2.73 (s, 3H), 1.71-1.35 (m, 6H).

[0277] Step 2: 2-(2-hydroxyethoxy)-N,N-dimethylacetamide (4) To a stirred solution of N,N-dimethyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acetamide (3) (0.400 g, 1.729 mmol) in MeOH (10.00 mL) at room temperature, PTSA monohydrate (0.032 g, 0.172 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum to obtain the title compound (4) as a colorless gum-like liquid (0.2 g, 78%). LC-MS: m / z 148.30 [M+H] + ;t R =0.35min;LC-MS purity:88.07%. 1H NMR(400MHz,DMSO-d6)=δ ppm 7.12-7.10(d,J=8Hz,1H),4.13(s,2H),3.50-3.38(m,4H),2.89(s,3H),2.79(s,3H).

[0278] Step 3: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-3'-(2-(2-(dimethylamine)-2-oxoethoxy)ethoxy)-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(6) To a stirred and cooled solution of 2-(2-hydroxyethoxy)-N,N-dimethylacetamide (4) (23.0 mg, 0.150 mmol) in DMF (2.0 mL), the reaction mixture was cooled to 0°C, NaH (12 mg, 0.31 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Then, tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl) carbamate (6, prepared according to Int.3 of Example 19) (100 mg, 0.150 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete (monitored by TLC). The reaction mixture was quenched with H2O (100 mL) and extracted with Âx (2 × 100 mL). The combined organic layers were washed with brine solution (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography (24 g silica gel column) using 3-6% MeOH in DCM to obtain the title compound (6) as an off-white solid (60 mg, 50%). LC-MS: m / z 693.3 [M-Boc+H] + ;t R =3.01min.LC-MS purity:85.07%. 1H NMR(400MHz,DMSO-d6)=δ ppm 7.84-7.80(m,1H),7.59-7.44(m,4H),7.36-7.34(m,2H),7.31-7.25(m,2H),7.22- 7.17(m,1H),6.63-6.61(m,1H),4.40-4.33(m,3H),4.22-4.21(m,2H),3.85-3.82( m,2H),3.77-3.75(m,2H),3.06(bs,1H),2.89-2.88(m,3H),2.73(s,3H),1.67-1.5 0(m,5H),1.34-1.33(m,18H),1.23(bs,3H),1.13-1.09(m,4H),0.86-0.81(m,2H).

[0279] Step 4: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-3'-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate(8) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-3'-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (6) (60 mg, 0.075 mmol) in EtOH / H2O (3 mL), Parkins catalyst (7) (10 mg, 0.022 mmol) was added at room temperature, and the reaction mixture was then heated at 80 °C for 5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (8) as an off-white solid (60 mg, 97%). LC-MS: m / z 811.1 [M+H] + ;t R =1.74min;LC-MS purity:81.54%.

[0280] Step 5: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 28) To a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-3'-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-2'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (8) (60 mg, 0.074 mmol) in DCM (1 mL), TFA (0.1 mL) was added at 0°C, and the reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was purified by HPLC [column: Kinetex C18 (250 × 21.2; 5 μm), mobile phase: 0.1% TFA in H2O(A) / MeCN(B), flow rate: 15 mL / min, gradient time (min) / %B: 0 / 50 10 / 50] to obtain the trifluoroacetate of the title compound (Example 28) as an off-white solid (42 mg, 70%). LC-MS: m / z 611.3 [M+H] + ;t R =1.76min;LC-MS purity:98.63%.HPLC purity:99.01%;t R = 6.41 min. 1 H NMR (400MHz, DMSO-d6 and D2O) = δ ppm 7.51-7.28(m,11H),4.38-4.22(m,5H),3.95-3.67(m,8H),3.05-2.89(m,2H),2.10-1.97(m,4H),1.40-1.23(m,4H).

[0281] Example 29. Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate [ka] Step 1: 3-Bromo-4-chloro-5-fluorobenzoic acid (2) To a stirred solution of 4-chloro-3-fluorobenzoic acid (1) (10 g, 57.28 mmol) in H2SO4 (80 mL), NBS (10.19 g, 57.286 mmol) was added at room temperature, and the reaction mixture was stirred at the same temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with ice H2O, and the precipitated solid was filtered through a Buchner funnel and dried under vacuum. The crude product was purified by combiflash chromatography using 10-15% toluene in hexane (80 g silica gel column) to obtain a mixture of positional isomers of the title compound (2) as an off-white solid (11 g, 75%). LC-MS: m / z 252.9;t R =2.48min,LC-MS purity:54.28%,t R =2.33min;LC-MS purity:34.96%.HPLC purity:48.96%;t R =10.19 min and 36.26%;t R =9.76 min. This mixture was used in the next step without separating the positional isomers.

[0282] Step 2: (3-bromo-4-chloro-5-fluorophenyl)(phenyl)methanone (3) 3-bromo-4-chloro-5-fluorobenzoic acid (a mixture of positional isomers) (2) (11 g, 43.401 mmol) was added to a stirred solution in SOCl2 (80 mL) at room temperature, and the reaction mixture was refluxed at 80°C for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under a nitrogen atmosphere to obtain the crude compound. The crude compound was dissolved in benzene and cooled to 0°C, and then AlCl3 (17.36 g, 130.203 mmol) was added little by little, and the reaction mixture was heated at 80°C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure, and then ice H2O was added to the reaction mixture and extracted with RINKAN (2 × 500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by combiflash chromatography (80 g silica gel column) using 10-15% RINKAN in hexane. A mixture of positional isomers was purified by preparative HPLC [column: X-select CSH, dilution: THF + MeCN + H2O, mobile phase A: 0.01 M NH4OAc in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 35, 10 / 65; flow rate: 15 mL / min] to obtain the title compound (3) as an off-white solid (3.0 g, 22%). LC-MS: m / z 311.1 [M-2H] + ;t R =2.92,LC-MS purity:99.70%.HPLC purity:99.37%,t R = 10.77 min. 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.89(s,1H),7.81-7.71(m,4H),7.61-7.57(t,J=7.6Hz,2H).

[0283] Step 3: (4-Chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone(4) To a stirred solution of (3-bromo-4-chloro-5-fluorophenyl)(phenyl)methanone (3) (3.0 g, 9.567 mmol) in 1,4-dioxane (40 mL), bis(pinacolate)diborone (3.1 g, 12.438 mmol), followed by KOAc (2.81 g, 28.703 mmol), was added at room temperature. The mixture was purged with argon for 5 minutes, then PdCl2(dppf)·DCM (0.78 g, 0.956 mmol) was added. The reaction mixture was again purged with argon for 10 minutes, and then the reaction was heated at 95°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (200 mL) and extracted with siRNA (2 × 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by combiflash chromatography using 10-15% toluene in hexane (12g silica gel column) to obtain the title compound (4) as an off-white solid (3g, 88%). 1 H NMR(400MHz,DMSO-d6)=δ ppm 7.82-7.66(m,5H),7.61-7.56(m,2H),1.12(s,12H).

[0284] Step 4: 5'-Benzoyl-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrili(6) To a stirred solution of 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (5) (0.4 g, 1.459 mmol) in toluene / H2O (2:1, 6 mL), (4-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (0.78 g, 2.189 mmol), followed by K3PO4 (0.92 g, 4.378 mmol) and N-xanthophos (0.08 g, 0.145 mmol) were added at room temperature, the mixture was purged with argon for 5 minutes, then Pd2(dba)3 (0.06 g, 0.072 mmol) was added, the reaction mixture was purged again with argon for 10 minutes, and then the reaction mixture was heated at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with siRNA (2 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (40 g silica gel column) using 30-40% siRNA in hexane to obtain the title compound (6) as a yellow viscous liquid (0.46 g, 71%). 1 ¹H NMR (400MHz, DMSO-d6) = δ ppm 7.96 (dd, J=2.0Hz and 9.2Hz, 1H), 7.88 (dd, J=1.2Hz and 8.8Hz, 1H), 7.83-7.81 (m...

Claims

1. A compound containing or essentially derived from formula (I), 【Chemistry 1】 During the ceremony, X is CH, CF, N, or C-R １ｄ Selected from, A1 is phenyl, wherein the phenyl is optionally substituted with fluoro, and is selected from the group consisting of phenyl and a 5-membered or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, S, and O. A2 is, Phenyl, wherein the phenyl is optionally a halogen, C １ -C ３ Alkoxy, C １ -C ３ Alkyl, CF ３ C such as １－３ - Phenyl, which is substituted with one or more substituents independently selected from the group consisting of haloalkyls, and A 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from the group consisting of N, S, and O, preferably S, wherein the heteroaromatic ring is optionally halogen, C １ -C ３ alkoxy, C １ -C ３ Selected from the group consisting of 5- or 6-membered heteroaromatic rings having one or more substituents independently selected from alkyl, preferably substituted with Cl R １ However, hydrogen; halogen; C １ -C ６ Haloalkoxy; O(CH) ２ ) ｎ O(CH ２ ) ｍ R １ａ NR １ｂ (CH ２ ) ｎ O(CH ２ ) ｍ ;Optional, C ３ -C ６ Cycloalkyl, COOH, (O-CH ２ ) ｍ -CONR １ｂ R １ｃ C substituted with a 5-membered or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, or a 5-membered or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O. １ -C ６ Alkoxy; a five-membered aromatic heterocycle comprising at least one heteroatom selected from N, O, and S, preferably at least one N atom; Furthermore, selected from the group consisting of 5-membered or 6-membered heteroaryloxys, R １ａ However, hydrogen, C １ -C ２ Alkyl, or NCOCH ３ Selected from a group consisting of four-membered complex rings including, R １ｂ and R １ｃ However, independently, hydrogen, C １ -C ６ Selected from the group consisting of alkyl groups, or R １ｂ and R １ｃ However, together with the nitrogen atom to which they are bonded, they form a 5-membered or 6-membered saturated heterocycle. R １ｄ and R １ However, together with the carbon atoms to which they are bonded, they form a five-membered or six-membered aromatic ring, heteroaromatic ring, cyclic ring, or heterocycle. R ２ However, hydrogen, C １ -C ３ Selected from the group consisting of alkyls and halogens, R ３ However, hydrogen, hydroxyl C １ -C ３ Alkyl, (CH ２ ) ｎ OCH ２ CONR ９ R ９ , optional, NCOCH ３ C substituted with a four-membered hetero ring containing １ -C ３ Selected from the group consisting of alkyl groups, R ４ However, hydrogen, optionally, and C substituted with OH. １ -C ５ Alkyl, or optionally, OH-substituted C １ -C ４ Alkyl; optional, C １ -C ３ Alkyl, NHR ９ CONR ９ R ９ , NHCO (C １ -C ３ -Alkyl), CONR ６ R ６ NH-CH ２ -R ７ COOH, CHO, CO(C １ -C ３ -alkyl), or OH, CH ２ NH ２ , or C １ -C ３ Alkyl and OH, or CH ２ Selected from the group consisting of 4-membered, 5-membered, 6-membered, or 7-membered saturated rings or heterocycles substituted with OH and =O, Or NH-R ４ However, NH-R ４ It forms a 5-membered or 6-membered saturated heterocycle with respect to the bonded carbon, R ５ However, selected from hydrogen, OH, and Fluor, R ６ However, independently, hydrogen, C １ -C ３ Selected from the group consisting of alkyl groups, or R ６ R ６ However, together with the nitrogen atoms to which they are bonded, they form a five-membered or six-membered ring, and optionally, the five-membered or six-membered ring further contains oxygen. R ７ is a 5- or 6-membered aromatic ring containing at least one NR ８ and R ８ However, hydrogen and CH ２ CONR ９ Selected from the group consisting of, R ９ However, independently selected from the group consisting of hydrogen and methyl, Each n is 1, 2, or 3 individually. Each m is either 0 or 1 in the compound. or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

2. A2, R １ and / or R ２ The compound according to claim 1, wherein the halogen in A2 and / or R is selected from the group consisting of chloro and fluoro.

3. The compound according to claim 1 or 2, wherein X is selected from CH, CF, and N.

4. The compound according to any one of claims 1 to 3, wherein X is CH.

5. The compound according to any one of claims 1 to 3, wherein X is N.

6. The compound according to any one of claims 1 to 5, wherein A1 is phenyl.

7. The compound according to any one of claims 1 to 6, wherein A2 is selected from the group consisting of phenyl substituted with at least one halogen and a five-membered heteroaromatic ring, for example, A2 is phenyl substituted with at least one halogen.

8. R １ However, hydrogen; halogen; C １ -C ６ Haloalkoxy, O(CH) ２ ) ｎ O(CH ２ ) ｍ R １ａ NR １ｂ (CH ２ ) ｎ O(CH ２ ) ｍ ;Optional, C ３ -C ６ Cycloalkyl, (O-CH ２ ) ｍ -CONR １ｂ R １ｃ C substituted with a six-membered heteroaromatic ring containing at least one N, or a five-membered saturated heterocycle containing one heteroatom selected from N and O. １ -C ６ Selected from the group consisting of alkoxys; 5-membered aromatic heterocycles containing at least one N; and 5-membered or 6-membered heteroaryloxys, R １ａ However, hydrogen, C １ -C ２ Alkyl, and NCOCH ３ Selected from a group consisting of four-membered complex rings including, R １ｂ and R １ｃ However, independently, hydrogen, C １ -C ３ A compound according to any one of claims 1 to 7, selected from the group consisting of alkyl groups.

9. R １ However, the compound according to any one of claims 1 to 8, selected from the group consisting of the following. 【Chemistry 2】

10. R ２ The compound according to any one of claims 1 to 9, wherein the compound is selected from the group consisting of hydrogen and F.

11. R ３ However, hydrogen, (CH ２ ) ２ OCH ２ CON(CH ３ ) ２ , NCOCH ３ C substituted with a four-membered hetero ring containing ２ - Selected from the group consisting of alkyl groups, for example, R ３ The compound according to any one of claims 1 to 10, wherein the compound is hydrogen.

12. R ４ However, hydrogen; C １ -C ４ Alkyl; C substituted with OH ２ -C ４ Alkyl; 4-membered, 5-membered, 6-membered, or 7-membered saturated cyclic ring or heterocycle; C １ -C ３ Alkyl, NHR ９ CONR ９ R ９ , NHCO (C １ -C ３ -Alkyl), CONR ６ R ６ NH-CH ２ -R ７ , COOH, or OH, or C １ -C ３ Alkyl and OH, or CH ２ Selected from the group consisting of six-membered saturated cyclic rings or heterocyclic rings substituted with OH and =O, or NH-R ４ However, NH-R ４ The compound according to any one of claims 1 to 11, wherein it forms a five-membered saturated heterocycle with respect to the carbon to which it is bonded.

13. R ４ However, hydrogen, and CHO, COOH, CONHR ６ , or NH ２ A compound according to any one of claims 1 to 12, selected from the group consisting of a six-membered saturated ring substituted with .

14. R ５ The compound according to any one of claims 1 to 13, wherein the compound is hydrogen.

15. The compound according to any one of claims 1 to 14, wherein in formula I, A2 is bonded to the ring having X and the carbon to which A1 is bonded, such that they are at positions 1 and 3 relative to each other.

16. The aforementioned compound, 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxoxazolidine-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidine-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide, (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-3-yloxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4S)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidine-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide, 5-(2-((1-acetylazetidine-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-3',6-difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-(methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H-pyrazole-1-yl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-N-(2-(2-(dimethylamino)-2-oxoethoxy)ethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, N-((1-acetylazetidine-3-yl)methyl)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)benzamide, 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)-3-fluorobenzamide, Selected from the group consisting of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-3'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide and / or 2'-Chloro-6-fluoro-5'-(2-((3-hydroxy-3-methylbutyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(morpholine-4-carbonyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(((1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl)amino)ethyl)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-4',6-difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 3'-(2-amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide, (1r,4r)-4-((2-(6'-carbamoyl-4,6-dichloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and its stereoisomers, (1r,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and its stereoisomers, 2'-Chloro-6-fluoro-5'-{1-fluoro-1-phenyl-2-[(propan-2-yl)amino]ethyl}-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-4'-methyl-[1,1'-biphenyl]-2-carboxamide, 5'-(2-((1-acetylpiperidine-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 5'-(2-(((R)-1-acetylpiperidine-3-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide, 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-((2-methoxyethyl)(methyl)amino)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate, 2'-Chloro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(propylamino)ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(2-(isobutylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide, (5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4,6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide hydrochloride, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-acetamidocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(methylcarbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, The compound according to claim 1, selected from the group consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

17. Formula II: A conjugate that includes or is essentially derived from A-B-C (Formula II), In the formula, A is a compound of formula I as described in any one of claims 1 to 16, provided that R in formula I is... １ , R ３ , or R ４ One of these is a bond to B, or includes a bond to B, or A-B is a condensation product formed from the compound of formula I and B according to any one of claims 1 to 16. B is a linker that covalently bonds A to C, C is the ligase binder, or conjugate.

18. The aforementioned linker B is given by: -L1-X1-L2-X2-L3-(B) and the conjugate is of the formula: It has A-L1-X1-L2-X2-L3-C, In the formula, L1 is selected from the group consisting of bond, -O-, -NR'-, -C(O)-, C1-C9 alkylene, C1-C9 heteroalkylene, *C(O)-C1-C6 alkylene, *C(O)-C1-C6 heteroalkylene, *C1-C6 alkylene-C(O), *C1-C6 heteroalkylene-C(O), cyclohexyl, and *L1a-C4-C7 cycloalkylene, or is cyclohexyl, where * indicates the bond of L1 to X1. L1a is selected from the group consisting of C(O), *NH-C(O), and *C1-C6 alkylene-NH-C(O), where * indicates the binding of L1a to X1. X1 and X2 are each independently selected from the group consisting of 4-7 membered heterocyclenes containing 1-3 heteroatoms independently selected from the group consisting of a bond, C4-C7 cycloalkylene, N, O, and S, and 5- or 6-membered heteroarylenes containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S. L2 is selected from the group consisting of bond, -O-, -NR'-, -C(O)-, C1-C6 alkylene, -NR'-C1-C9 alkylene-NR'-, *C1-C9 alkylene-NR'-, *NR'-C1-C9 alkylene, *C(O)NR'-C1-C5 alkylene, polyethylene glycol, -NR'-polyethylene glycol-NR'-, polyethylene glycol, *NR'-polyethylene glycol, and *polyethylene glycol-NR', where * indicates the bond of L2 to X2, or X1-L2-X2 forms a 7-13 member spiroheterocycline containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S. The conjugate according to claim 17, wherein L3 is selected from the group consisting of bonded, C1-C5 alkylene, C2-C5 alkenylene, C1-C6 alkylene, C1-C6 heteroalkylene, -C(O)-, -S(O)r, -O-, *C(O)-C1-C6 alkylene, *C(O)-C1-C5 alkylene-O, *C(O)-C1-C6 heteroalkylene, *C1-C5 alkylene-NH, and *NH-C1-C5 alkylene, where * indicates the bond of L3 to X2, and each R' is independently hydrogen or C1-C6 alkyl, preferably each R' is hydrogen.

19. The aforementioned linker B is given by: -L1-X1-L2-X2-L3-X3-L4-(B) The aforementioned conjugate is given by the formula: It has A-L1-X1-L2-X2-L3-X3-L4-C, and in the formula, X1, X2, and X3 are each independently selected from the group consisting of a bond, -O-, -CH2-, and -NH-, and L1, L2, L3, and L4 are each individually, join, A heterospiro ring or spiro ring having 7 to 11 ring atoms, Ring or heteroring, A bicyclic or biheterocyclic ring, or two rings or heterocyclic rings bonded to each other via carbon, nitrogen, or oxygen, C １ -C ３ Alkyl, C1-C3 alkoxy, CO(C １ -C ６ -Alkyl), (C １ -C ３ -Alkyl)CO(C １ -C ３ -Alkyl), CO, CO(CH ２ )O, NHCO, NHCO(CH ２ ) Selected from the group consisting of O, or the linker is the bond between A and C in formula II, R １ａ However, hydrogen, C １ -C ２ Alkyl, or The conjugate according to claim 17, selected from the group consisting of aromatic rings or heteroaromatic rings having 5 to 6 ring atoms, wherein the heteroaromatic ring optionally contains one or two nitrogen atoms, and the linker optionally is substituted with F, Me, and / or OH.

20. L1, L2, L3, and L4 are each individually, bond, -CH ２ -, -C(=O)-, -O-, -NH-, -NH-C １ -C ３ Alkyl, -NH-hydroxyC １ -C ３ Alkyl, 【Transformation 3】 Selected from the group consisting of, During the ceremony, each 【Chemistry 4】 The conjugate according to claim 17 or 19, wherein L1, L2, L3, and / or L4 are optionally substituted with F, Me, and / or OH.

21. The linker is selected from the group consisting of the following: 【Transformation 5】 【change】 【change】 The conjugate according to any one of claims 17 and 19 to 20, wherein A is a compound of formula I and C is a ligase binder.

22. The linker is selected from the group consisting of the following: 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 The conjugate according to any one of claims 17 and 19 to 21, wherein A is a compound of formula I and C is a ligase binder.

23. The linker is selected from the group consisting of the following: 【Transformation 7】 【change】 During the ceremony, each 【Transformation 8】 The conjugate according to any one of claims 17 and 19-20, wherein the conjugate is a link point to A or C.

24. The conjugate according to any one of claims 17 to 23, having approximately 2 to approximately 50 bonds between A and C, for example, 3 to approximately 45 bonds, for example, 3 to approximately 40 bonds, for example, 3 to approximately 35 bonds, for example, 3 to approximately 30 bonds, for example, 4 to approximately 23 bonds, for example, 4 to 23 bonds, or for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 bonds between A and C.

25. The conjugate according to any one of claims 17 to 24, wherein the ligase binder comprises two or three five-membered or six-membered cyclic rings or heterocycles, and at least one of the cyclic heterocycles is aromatic.

26. The conjugate according to any one of claims 17 to 25, wherein the ligase binder comprises a six-membered heterocyclic group having one or two nitrogen atoms and / or two oxo substituents in the ring.

27. The ligase binder is selected from the group consisting of the following: 【Chemistry 9】 During the ceremony, 【Chemistry 10】 The conjugate according to any one of claims 17 to 26, wherein R is a bond site to a linker or a bond to a linker, and R is H, F, Cl, methyl, or methoxy.

28. The ligase binder is selected from the group consisting of the following: 【Chemistry 11】 During the ceremony, 【Chemistry 12】 The conjugate according to any one of claims 17 to 27, wherein the linking point to the linker.

29. The ligase binder is selected from the group consisting of the following: 【Chemistry 13】 During the ceremony, 【Chemistry 14】 The conjugate according to any one of claims 17 to 28, wherein the linking point to the linker is a conjugate.

30. The ligase binder is selected from the group consisting of the following: 【Chemistry 15】 During the ceremony, 【Chemistry 16】 The conjugate according to any one of claims 17 to 29, wherein the linking point is to the linker (B).

31. The aforementioned conjugate, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetamide)cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(8-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]oxy}octanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethoxy}propanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-N-[(1r,4r)-4-[(2-{6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl}-2-phenylethyl)amino]cyclohexyl]piperidine-4-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propanamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxyphenyl]formamide}ethoxy)ethoxy]ethoxy}propanamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5,6-difluoro-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]oxy}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}-2-oxoethyl)-1H-pyrazole-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)-2-oxoethyl]-1H-pyrazole-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-N-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}methyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-[2-({1-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propanoyl]azetidine-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-[2-({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetyl]azetidine-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-{2-[(1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-carbonyl}azetidine-3-yl)oxy]ethoxy}-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and Selected from the group consisting of 2'-chloro-5-(2-{[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide and / or 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-3-methoxybenzoyl]piperazine-1-carbonyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(2-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(4-{[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxyphenyl]formamide}butyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{9-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]-3,9-diazaspiro[5;5]undecane-3-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}oxy)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoyl]-2,9-diazaspiro[5;5]undecane-9-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(2-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-({4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-yl}methyl)cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzamide]piperidine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxyphenyl]formamide}methyl)piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3S)-3-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzamide]piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3R)-3-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzamide]piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(4-{4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-carbonyl}phenyl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[4-({4-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperazine-1-yl}methyl)phenyl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)piperidine-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)piperidine-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)piperidine-4-yl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)ethyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetamide}piperidine-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetamide}methyl)piperidine-1-yl]methyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl-[4,4'-bipiperidine]-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl}piperidine-4-yl)oxy]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1'-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]-[4,4'-bipiperidine]-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{9-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]-3,9-diazaspiro[5;5]undecane-3-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(2-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}ethyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}piperazine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4- [Iyl]oxy)cyclohexaneamide]cyclohexyl]aminoethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-4-yl}oxy)cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-{4-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-1-yl}cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}-N-[(1r,4r)-4-{[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxolan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1-{1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidine-4-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methylphenoxy]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(9-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-3,9-diazaspiro[5;5]undecane-3-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)methyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)ethyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetamide}piperidine-1-yl)methyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)piperazine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)methyl]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]piperidine-1-yl}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(4-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperazine-1-yl)cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 1-(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)-N-[(1r,4r)-4-{[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxolan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-methylphenoxy]acetyl-[4,4'-bipiperidine]-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}oxy)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-5-(dimethylcarbamoyl)methoxy]-3',6-difluoro-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,6-dioxopiperidine-3-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and The conjugate according to claim 17, selected from the group consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl]piperidine-1-yl}methyl)piperidine-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

32. The aforementioned conjugate, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}-2-oxoethyl)-1H-pyrazole-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamyl do2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)-2-oxoethyl]-1H-pyrazole-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetyl)piperidine-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]oxy}acetamide)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]azetidine-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}acetyl)azetidine-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and The conjugate according to claim 17, selected from the group consisting of 2'-chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-5-[(pyridine-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide.

33. The aforementioned conjugate, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-carbonyl}piperidine-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and The conjugate according to claim 17, selected from the group consisting of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

34. The aforementioned conjugate, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diadinane-1-yl)benzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxybenzoyl]piperidine-4-yl}methyl)piperidine-1-yl]acetamide}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide, and The conjugate according to claim 17, selected from the group consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methylphenoxy]acetyl}piperidine-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

35. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, and at least one pharmaceutically acceptable diluent, carrier, and / or excipient.

36. A compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35, for use as a pharmaceutical.

37. A compound according to any one of claims 1 to 16, a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35, for use in the treatment of a disease or disorder in which the Hippo pathway is hyperactivated, and optionally the Hippo pathway is hyperactivated due to any one of YAP overexpression, LATS2 mutation or deletion, neurofibromatosis type 2 (NF2), or hypermethylation of the LATS2 promoter.

38. A compound according to any one of claims 1 to 16, a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35, for use in the treatment of cancer by administration to a patient in need thereof.

39. The aforementioned cancer is selected from the group consisting of bone cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma, and the compound according to any one of claims 1 to 16, or the conjugate according to any one of claims 17 to 34, or the pharmaceutical composition according to claim 35, for use according to claim 38.

40. The aforementioned administration includes AKT inhibitors such as afresertib, capivacertib, ipatasertib, mirancertib, perifosin, and uprosertib; CDK4 / 6 inhibitors such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors such as binimetinib, cobimetinib, and trametinib, and FGFR inhibitors. A compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35, for use according to claim 36 or 39, which is combined with at least one compound selected from the group consisting of an agent, an mTOR inhibitor, a MEK1 inhibitor, an ALK inhibitor, an HSP90 inhibitor, a CDK8 inhibitor, a PI3K-alpha inhibitor, an ABL1 inhibitor, and an XPO1 inhibitor.

41. A compound according to any one of claims 1 to 16, a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35, for use in the treatment of fibrosis by administration of the compound, conjugate, or composition to a patient in need thereof.

42. The fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, scleroderma, or fibrosis associated with chronic diseases of major organs such as the liver (cirrhosis), heart, lungs, and / or kidneys, and the compound according to any one of claims 1 to 16, or the conjugate according to any one of claims 17 to 34, or the pharmaceutical composition according to claim 35, for use according to claim 41.

43. The compound according to any one of claims 1 to 16, or the conjugate according to any one of claims 17 to 34, or the pharmaceutical composition according to claim 35, for use according to claim 41 or 42, wherein the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

44. A method for treating cancer, comprising administering a therapeutically effective amount of the compound described in any one of the claims to a patient in need thereof.

45. The method according to claim 44, wherein the cancer is selected from the group consisting of bone cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma.

46. The method according to claim 44 or 45, wherein the administration is combined with at least one compound selected from the group consisting of AKT inhibitors such as afresertib, capivacertib, ipatasertib, mirancertib, perifosin, and uprosertib; CDK4 / 6 inhibitors such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors such as binimetinib, cobimetinib, and trametinib; FGFR inhibitors; mTOR inhibitors; MEK1 inhibitors; ALK inhibitors; HSP90 inhibitors; CDK8 inhibitors; PI3K-alpha inhibitors; ABL1 inhibitors; and XPO1 inhibitors.

47. A method for treating fibrosis, comprising administering a therapeutically effective amount of the compound described in any one of the claims to a patient in need thereof.

48. The method according to claim 47, wherein the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, scleroderma, or fibrosis associated with chronic diseases of major organs such as the liver (cirrhosis), heart, lungs, and kidneys.

49. The method according to claim 47 or 48, wherein the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

50. Use of a compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35, for the manufacture of a pharmaceutical for use in the treatment of cancer.

51. The use according to claim 50, wherein the cancer is selected from the group consisting of bone cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma.

52. Use of a compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35, for the manufacture of a medicament for use in the treatment of fibrosis.

53. The use according to claim 52, wherein the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, scleroderma, or fibrosis associated with chronic diseases of major organs such as the liver (cirrhosis), heart, lungs, and kidneys, and preferably selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

54. A method for preparing the conjugate described in Formula II, wherein the method is - Reacting a ligase binder according to any one of claims 25 to 30 with a linker according to any one of claims 18 to 24 to form an intermediate, A method comprising reacting the intermediate with a compound of formula I according to any one of claims 1 to 16 to form a conjugate of formula II according to any one of claims 17 to 34.

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