Aromatic amides and conjugates thereof as binding agents with TEAD

Abstract

The present invention provides novel binding compounds of formula (I), conjugates comprising compounds of formula (I), pharmaceutical compositions containing such compounds, and methods for treating disease using such compounds and methods for preparing such conjugates; wherein R1, R2, R3, R4 and R5 are defined in the specification.

Description

Technical Field

[0001] This invention provides novel compounds and conjugates comprising said compounds. The compounds may be binding agents to TEA domain transcription factors (TEADs). The conjugates may contain a ligase-binding moiety. This invention further provides pharmaceutical compositions comprising such compounds and / or conjugates, and methods for using such pharmaceutical compositions to treat diseases such as cancer and fibrosis.

[0002] Bifunctional Degrading Agent

[0003] Many diseases, including cancer, are caused by the overactivation of proteins within signal transduction networks [1]. This overactivation can lead to abnormal growth, metabolism, or other pathological consequences. Traditional small molecule drugs can inhibit, antagonize, or block these overactivated proteins by binding to ortho- or allosteric sites on proteins. In this way, they can restore normal cellular homeostasis and alleviate the pathological consequences caused by these dysregulated proteins [2].

[0004] As alternatives to small molecule drugs that block protein function, bifunctional molecules that bind to both dysregulated proteins and E3 ligases can promote ubiquitination of proteins by ligases and thereby target the proteins for proteasomal degradation[3]. Bifunctional molecules do not inhibit proteins but reduce intracellular protein levels[4]. Degradative agents can have good biochemical efficiency[5] and long duration of action that persists even after the drug is eliminated from the body[6].

[0005] Hippo signal transduction pathway

[0006] The growth, repair, and remodeling of normal tissues require 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 transcription coactivator (TAZ) with a PDZ-binding motif, leading to their retention in the cytosol and degradation by the proteasome. When the Hippo pathway is inactivated, YAP and TAZ remain unphosphorylated. This allows them to move to the nucleus, where they can coactivate TEAD-mediated transcription [7].

[0007] The Hippo pathway plays a key role in regulating cell proliferation and apoptosis by controlling TEAD-mediated transcription. The Hippo pathway also controls stem cell self-renewal 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 self-renewal, and enhance the immunosuppressive tumor microenvironment by recruiting tumor-associated M2 macrophages

[10] and myeloid-derived suppressor cells (MDSCs) to the tumor

[11] . Therefore, blocking TEAD-regulated gene expression in tumors has a triple action pattern. The blocker has a direct antiproliferative effect on cancer cells, promotes terminal differentiation of cancer stem cells, and reduces the immunosuppressive tumor microenvironment, giving the immune system a better chance to recognize and eliminate the tumor.

[0008] The Hippo signaling pathway plays a role in regulating wound healing. When this pathway is disrupted, it can lead to fibrosis.

[0009] TEAD transcription factor

[0010] TEA domain transcription factors (TEADs) are a family of transcription factors that regulate gene transcription by binding to upstream response elements of genes regulated by TEADs

[14] . In humans, there are four TEAD orthologs, named TEAD1, TEAD2, TEAD3, and TEAD4. Co-regulatory factors of TEAD transcription factors include Yes-associated protein (YAP), transcription coactivator with PDZ binding motif (TAZ), and remnant-like family members (VGLL1-4)

[15] . TEAD-regulated gene expression is the penultimate step in the Hippo signaling pathway. Therefore, inhibition or degradation of TEADs may have therapeutic potential in the treatment of diseases with abnormal activation of the Hippo pathway, such as cancer and fibrosis

[13] .

[0011] YAP and TAZ interact with the C-terminal trans-activation domain of TEAD through three surface interfaces. Interface 1 is an intermolecular β-sheet formed between the YAP and TEAD β chains. At interface 2, YAP forms an α-helix that fits into the groove of the TEAD helix-turn-helix motif. At interface 3, YAP / TAZ adopts a cyclic structure that interacts with TEAD. In addition, TEAD contains an internal hydrophobic cavity that is occupied by palmitate due to autopalmitoylation. Only palmitoylated TEAD can bind to YAP with high affinity.

[16]

[0012] Several small molecules have been reported in the literature that can prevent YAP from binding to TEAD and thereby block the transcription of TEAD-regulated genes. To date, the most common target of these small molecules is the internal lipophilic binding pocket.

[16] A few inhibitors that bind to the outer interface 2 or 3 have also been reported.

[16]

[0013] WO 2023 / 031801 describes a bifunctional degrader synthesized in 13 steps, which includes a TEAD binder. Summary of the Invention

[0014] One 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 bind to TEAD1, TEAD2, TEAD3, and / or TEAD4 and can be used to treat diseases such as cancer and / or fibrosis. The 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 an E3 ligase to form a stable ternary complex consisting of TEADx, the E3 ligase, and the novel compound. Yet another object is to provide conjugates comprising novel compounds that bind to TEAD1, TEAD2, TEAD3, and / or TEAD4, the conjugates being capable of at least partially degrading TEAD1, TEAD2, TEAD3, and / or TEAD4.

[0015] Therefore, according to a first aspect of the invention, a compound is provided comprising (Formula I), substantially consisting of (Formula I), or being (Formula I).

[0016]

[0017] in:

[0018] X is selected from: CH; CF; and N, or X is CR. 1d ;

[0019] A1 is selected from the group consisting of: phenyl, wherein the phenyl is optionally substituted with fluorine; and a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, S and O;

[0020] A2 is selected from the group consisting of: phenyl, wherein the phenyl is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen; C1-C3 alkoxy; C1-C3 alkyl; C 1-3- Haloalkyl, such as CF3; and 5- or 6-membered heteroaromatic rings containing at least one heteroatom selected from the group consisting of N, S and O, preferably S, wherein the heteroaromatic ring is optionally substituted by one or more substituents independently selected from halogens, C1-C3 alkoxy groups, C1-C3 alkyl groups, preferably Cl;

[0021] R 1 Choose the group consisting of: hydrogen; halogens; C1-C6 haloalkoxy groups; O(CH2). n O(CH2) m R 1a NR 1b (CH2) n O(CH2) m ;C1-C6 alkoxy group, optionally substituted with: C3-C6 cycloalkyl group; COOH group; (O-CH2 group) 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 5- 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 heteroatom;

[0022] And 5- or 6-membered heteroaryloxy groups;

[0023] R 1a Choose from the group consisting of: hydrogen, C1-C2 alkyl groups, or 4-membered heterocycles containing NCOCH3;

[0024] R 1b and R 1c Independently selected from the group consisting of hydrogen, C1-C6 alkyl groups, or R 1b and R 1c Together with the nitrogen atom it is attached to, it forms a 5- or 6-membered saturated heterocycle;

[0025] R 1d and R 1 Together with the carbon atoms they are attached to, they form 5- or 6-membered aromatic rings, heteroaromatic rings, cyclic rings, or heterocycles;

[0026] R 2 Choose from the group consisting of hydrogen, C1-C3 alkyl groups, and halogens;

[0027] R 3 Choose from the group consisting of: hydrogen; hydroxyl C1-C3 alkyl; (CH2) n OCH2CONR 9 R 9;C1-C3 alkyl groups, optionally substituted with a 4-membered heterocycle containing NCOCH3;

[0028] R 4 Choose from the group consisting of: hydrogen; C1-C5 alkyl groups optionally substituted with OH or C1-C4 alkyl groups optionally substituted with OH; 4-, 5-, 6-, or 7-membered saturated cyclic rings or heterocycles optionally substituted with: C1-C3 alkyl groups, NHR 9 CONR 9 R 9 NHCO (C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 、COOH, CHO, CO (C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O;

[0029] Or NH-R 4 With NH-R 4 The attached carbon atoms form 5- or 6-membered saturated heterocycles;

[0030] R 5 Selected from hydrogen, OH, and fluorine;

[0031] R 6 Independently selected from the group consisting of hydrogen, C1-C3 alkyl groups, or R 6 R 6 Together with the nitrogen to which it is attached, it forms a 5- or 6-membered ring, optionally wherein the 5- or 6-membered ring further comprises oxygen.

[0032] R 7 For containing at least one NR 8 The 5 or 6 yuan Fangzu ring;

[0033] R 8 Choose free hydrogen and CH2CONR 9 The group formed;

[0034] R 9 Independently selected from the group consisting of hydrogen and methyl groups;

[0035] Each n is individually 1, 2, or 3;

[0036] Each m is individually 0 or 1;

[0037] Or its pharmaceutically acceptable salt, tautomer or stereoisomer.

[0038] Those skilled in the art will understand that when R 1d and R 1Together with the carbon atoms to which they are attached, they form 5- or 6-membered aromatic rings, heteroaromatic rings, cyclic rings, or heterocyclic rings. This means that the resulting ring contains the carbon atoms attached to X and R1, as well as the atoms required to form 5- or 6-membered aromatic rings, heteroaromatic rings, cyclic rings, or heterocyclic rings.

[0039] In some embodiments, X is selected from: CH; CF; and N;

[0040] A1 is selected from the group consisting of: phenyl, wherein the phenyl is optionally substituted with fluorine; and a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, S and O;

[0041] A2 is selected from the group consisting of: phenyl, wherein the phenyl is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen; C1-C3 alkoxy; C1-C3 alkyl; C 1-3 - Haloalkyl, such as CF3; and 5- or 6-membered heteroaromatic rings containing at least one heteroatom selected from the group consisting of N, S and O, preferably S, wherein the heteroaromatic ring is optionally substituted by one or more substituents independently selected from halogens, C1-C3 alkoxy groups, C1-C3 alkyl groups, preferably Cl;

[0042] R 1 Choose the group consisting of: hydrogen; halogens; C1-C6 haloalkoxy groups; O(CH2). n O(CH2) m R 1a NR 1b (CH2) n O(CH2) m ;C1-C6 alkoxy group, optionally substituted with: C3-C6 cycloalkyl group; COOH group; (O-CH2 group) 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 5- 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 heteroatom;

[0043] And 5- or 6-membered heteroaryloxy groups;

[0044] R 1a Choose from the group consisting of: hydrogen, C1-C2 alkyl groups, or 4-membered heterocycles containing NCOCH3;

[0045] R 1b and R 1cIndependently selected from the group consisting of hydrogen, C1-C6 alkyl groups, or R 1b and R 1c Together with the nitrogen atom it is attached to, it forms a 5- or 6-membered saturated heterocycle;

[0046] R 2 Choose from the group consisting of hydrogen, C1-C3 alkyl groups, and halogens;

[0047] R 3 Choose from the group consisting of: hydrogen; hydroxyl C1-C3 alkyl; (CH2) n OCH2CONR 9 R 9 ;C1-C3 alkyl groups, optionally substituted with a 4-membered heterocycle containing NCOCH3;

[0048] R 4 Choose from the group consisting of: hydrogen; C1-C5 alkyl groups optionally substituted with OH or C1-C4 alkyl groups optionally substituted with OH; 4-, 5-, 6-, or 7-membered saturated cyclic rings or heterocycles optionally substituted with: C1-C3 alkyl groups, NHR 9 CONR 9 R 9 NHCO (C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 、COOH, CHO, CO (C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O;

[0049] Or NH-R 4 With NH-R 4 The attached carbon atoms form 5- or 6-membered saturated heterocycles;

[0050] R 5 Selected from hydrogen, OH, and fluorine;

[0051] R 6 Independently selected from the group consisting of hydrogen, C1-C3 alkyl groups, or R 6 R 6 Together with the nitrogen to which it is attached, it forms a 5- or 6-membered ring, optionally wherein the 5- or 6-membered ring further comprises oxygen.

[0052] R 7 For containing at least one NR 8 The 5 or 6 yuan Fangzu ring;

[0053] R 8 Choose free hydrogen and CH2CONR 9 The group formed;

[0054] R 9 Independently selected from the group consisting of hydrogen and methyl groups;

[0055] Each n is individually 1, 2, or 3;

[0056] Each m is individually 0 or 1;

[0057] Or its pharmaceutically acceptable salt, tautomer or stereoisomer.

[0058] In some embodiments, X is selected from: CH; and N;

[0059] A1 is selected from the group consisting of: phenyl, wherein the phenyl is optionally substituted with fluorine; and a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, S and O;

[0060] A2 is selected from the group consisting of: phenyl, wherein the phenyl is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens; C1-C3 alkoxy groups; C1-C3 alkyl groups; 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 substituted with one or more substituents, which are independently selected from halogens, C1-C3 alkoxy groups, C1-C3 alkyl groups, preferably Cl;

[0061] R 1 Choose the group consisting of: hydrogen; halogens; C1-C6 haloalkoxy groups; O(CH2). n O(CH2) m R 1a ;C1-C6 alkoxy group, optionally substituted with: C3-C6 cycloalkyl group; COOH group; (O-CH2 group) 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 5- 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 heteroatom;

[0062] And 5- or 6-membered heteroaryloxy groups;

[0063] R 1a Choose from the group consisting of: hydrogen, C1-C2 alkyl groups or 4-membered heteroaliphatic rings containing NCOCH3;

[0064] R 1b and R 1cIndependently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C3 alkyl, or R 1b and R 1c Together with the nitrogen atom it is attached to, it forms a 5- or 6-membered saturated heterocycle;

[0065] R 2 Choose from the group consisting of hydrogen, C1-C3 alkyl groups, and halogens;

[0066] R 3 Choose from the group consisting of: hydrogen; hydroxyl C1-C3 alkyl; (CH2) n OCH2CONR 9 R 9 ;C1-C3 alkyl groups, which are optionally substituted with a 4-membered heteroaliphatic ring containing NCOCH3;

[0067] R 4 Selected from the group consisting of: hydrogen; C1-C4 alkyl (straight-chain C1-C4 alkyl, or in some embodiments, branched alkyl when the alkyl is C3-C4 alkyl), optionally substituted with OH; 4-membered, 5-membered, 6-membered or 7-membered saturated cyclic rings or heterocycles, optionally substituted with: 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 C1-C3 alkyl and OH, or CH2OH and =O;

[0068] Or NH-R 4 With NH-R 4 The attached carbon atoms form 5- or 6-membered saturated heterocycles;

[0069] R 5 Selected from hydrogen, OH, and fluorine;

[0070] R 6 Independently selected from the group consisting of hydrogen, C1-C3 alkyl groups, or R 6 R 6 Together with the nitrogen to which it is attached, it forms a 5- or 6-membered ring, optionally wherein the 5- or 6-membered ring further comprises oxygen.

[0071] R 7 For containing at least one NR 8 The 5 or 6 yuan Fangzu ring;

[0072] R 8 Choose free hydrogen and CH2CONR 9 The group formed;

[0073] R 9 Independently selected from the group consisting of hydrogen and methyl groups;

[0074] Each n is individually 1, 2, or 3;

[0075] Each m is individually 0 or 1;

[0076] Or its pharmaceutically acceptable salt, tautomer or stereoisomer.

[0077] Compounds according to Formula I can be used as TEAD binders. This is illustrated in Example 202, which shows an SPR analysis used to determine the binding affinity of exemplary compounds 1 to 46 to 84 to 110 for TEAD1 to TEAD4.

[0078] According to this disclosure, the compound of formula I may further include a second compound having a binding affinity for another target present in the body of a mammal. Such a compound may be connected directly or via a suitable linker, optionally wherein R in formula I... 1 R 3 Or R 4 For connection points with or containing the connector or second compound.

[0079] In some embodiments, the halogen is selected from the group consisting of chlorine and fluorine.

[0080] In some embodiments, X is CF, CH, or N. In some embodiments, X is CH or N. In some embodiments, X is CH.

[0081] In some embodiments, A1 is phenyl or a 6-membered heteroaromatic compound. In some embodiments, A1 is phenyl or pyridine. In some embodiments, A1 is phenyl.

[0082] In some embodiments, A2 is a phenyl group substituted with at least one halogen. In some embodiments, A2 is a phenyl group substituted with one or two chlorines and / or one or two fluorines. In some embodiments, A2 is selected from the group consisting of phenyl groups substituted with at least one halogen and 5-membered heteroaromatic rings.

[0083] As will be apparent to those skilled in the art, according to Formula I, A2 binds to the remainder of the molecule at an ortho, meta, or para position. Those skilled in the art will understand that this describes how A2 binds to the ring with X and the carbon atom to which A1 is attached. In other words, A2 binds in Formula I such that the ring with X and the carbon atom to which A1 is attached are ortho, meta, or para positioned relative to each other.

[0084] In one embodiment, A2 binds ortho-to the remaining portion of the molecule. In one embodiment, A2 binds meta-to the remaining portion of the molecule. In one embodiment, A2 binds para-to the remaining portion of the molecule.

[0085] In some embodiments, R 1 Choose the group consisting of: hydrogen; halogens; C1-C6 haloalkoxy groups; O(CH2). n O(CH2) m R 1a NR 1b (CH2) n O(CH2) m ;C1-C6 alkoxy groups, optionally substituted with: C3-C6 cycloalkyl groups; (O-CH2) m -CONR 1b R 1c ; a 6-membered heteroaromatic ring containing at least one N; or a 5-membered saturated heterocycle containing a heteroatom selected from N and O; a 5-membered aromatic heterocycle containing at least one N; and a 5- or 6-membered heteroaryloxy group;

[0086] R 1a Choose from the group consisting of: hydrogen, C1-C2 alkyl groups, and 4-membered heterocyclic rings containing NCOCH3;

[0087] R 1b and R 1c The group consisting of hydrogen and C1-C3 alkyl groups is selected independently.

[0088] In some embodiments, R 1 Choose the group consisting of: hydrogen; halogens; C1-C6 haloalkoxy groups; O(CH2). n O(CH2) m R 1a ;C1-C6 alkoxy groups, optionally substituted with: C3-C6 cycloalkyl groups; (O-CH2) m -CONR 1b R 1c ; a 6-membered heteroaromatic ring containing at least one N; or a 5-membered saturated heterocycle containing a heteroatom selected from N and O; a 5-membered aromatic heterocycle containing at least one N; and a 5- or 6-membered heteroaryloxy group;

[0089] R 1a Choose from the group consisting of: hydrogen, C1-C2 alkyl groups, and 4-membered heterocyclic rings containing NCOCH3;

[0090] R 1b and R 1c The group consisting of hydrogen and C1-C3 alkyl groups is selected independently.

[0091] In some embodiments, R1 is selected from the group consisting of the following:

[0092]

[0093] In some embodiments, R 1 Choose from the following groups:

[0094]

[0095] As is obvious to those skilled in the art, The location of the key to R1 is shown, and it can be seen that it is the connection point to R1. As will be obvious to those skilled in the art, a key can also be referred to as a connection point.

[0096] In some embodiments, R 2 Choose the group consisting of: hydrogen and F.

[0097] In some embodiments, R 3 The group consisting of: hydrogen; (CH2)2OCH2CON(CH3)2; C2 alkyl groups substituted with a 4-membered heteroaliphatic ring containing NCOCH3. In some embodiments, R 3 It is hydrogen.

[0098] In some embodiments, R 4 Choose from the group consisting of: hydrogen; C1-C4 alkyl; C2-C4 alkyl substituted with OH; 4-, 5-, 6-, or 7-membered saturated cyclic rings or heterocycles; 6-membered saturated cyclic rings or heterocycles substituted with: 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 C1-C3 alkyl and OH, or CH2OH and =O; or NH-R 4 With NH-R 4 The attached carbon atoms form a 5-membered saturated heterocycle. Alternatively, NH-R... 4 With NH-R 4 The attached carbon atoms form a 6-membered saturated heterocycle.

[0099] In some embodiments, R 4 Choose from the group consisting of: hydrogen; C1-C4 alkyl; C2-C4 alkyl substituted with OH; 4-, 5-, 6-, or 7-membered saturated cyclic rings or heterocycles; 6-membered saturated cyclic rings or heterocycles substituted with: C1-C3 alkyl, NHR 9CONR 9 R 9 NHCO (C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 COOH, OH, C1-C3 alkyl groups and OH, or CH2OH and =O; or NH-R 4 With NH-R 4 The attached carbon atoms form a 5-membered saturated heterocycle. Alternatively, NH-R... 4 With NH-R 4 The attached carbon atoms form a 6-membered saturated heterocycle.

[0100] In some embodiments, R 4 Choose from the following groups: hydrogen; and a 6-membered saturated ring, which is bonded by CHO, COOH, and CONHR. 6 Or NH2 can be substituted.

[0101] In some preferred embodiments, R 4 Choose the group consisting of: hydrogen; and a 6-membered saturated ring replaced by NH2.

[0102] In some embodiments, R 5 It is hydrogen.

[0103] In some embodiments, A2 is combined in Formula I such that the ring with X and the carbon connected to A1 are positioned adjacent, meta, or para to each other.

[0104] In one embodiment, the compound of formula I is selected from the list of the following:

[0105] 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0106] 5'-(2-(((R)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0107] 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0108] 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0109] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0110] 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0111] 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0112] 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0113] 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0114] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0115] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0116] 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0117] 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0118] 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0119] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0120] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidone-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide;

[0121] (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;

[0122] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide;

[0123] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0124] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide;

[0125] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-3-yloxy)-[1,1'-biphenyl]-2-carboxamide;

[0126] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide;

[0127] 5'-(2-(((1r,4s)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide;

[0128] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0129] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0130] 5-(2-((1-acetylazetane-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0131] 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;

[0132] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0133] 2'-Chloro-3',6-Difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile;

[0134] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide;

[0135] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-(methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0136] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0137] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0138] 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0139] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0140] 2'-Chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0141] 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-2-carboxamide;

[0142] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-[1,1'-biphenyl]-2-carboxamide;

[0143] 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;

[0144] N-((1-acetylazacyclobutane-3-yl)methyl)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0145] 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)benzamide;

[0146] 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)-3-fluorobenzamide;

[0147] 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 selected from the group consisting of:

[0148] 2'-Chloro-6-fluoro-5'-(2-((3-hydroxy-3-methylbutyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0149] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0150] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(morpholin-4-carbonyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0151] 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;

[0152] 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0153] 2'-Chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0154] 2'-Chloro-4',6-Difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0155] 2'-Chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0156] 3'-(2-amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0157] 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide;

[0158] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide;

[0159] (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;

[0160] (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;

[0161] 2'-Chloro-6-fluoro-5'-{1-fluoro-1-phenyl-2-[(propane-2-yl)amino]ethyl}-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0162] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0163] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-4'-methyl-[1,1'-biphenyl]-2-carboxamide;

[0164] 5'-(2-((1-acetylpiperidin-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0165] 5'-(2-(((R)-1-acetylpiperidin-3-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0166] 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide;

[0167] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-((2-methoxyethyl)(methyl)amino)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate;

[0168] 2'-Chloro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0169] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(propylamino)ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0170] 2'-Chloro-6-fluoro-5'-(2-(isobutylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0171] (5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4,6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide hydrochloride;

[0172] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-acetamidocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0173] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(methylcarbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0174] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0175] In some embodiments, the compounds are selected from a list of the following:

[0176] 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0177] 5'-(2-(((R)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0178] 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0179] 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0180] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0181] 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0182] 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0183] 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0184] 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0185] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0186] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0187] 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0188] 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0189] 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0190] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0191] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidone-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide;

[0192] (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;

[0193] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide;

[0194] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0195] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide;

[0196] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-3-yloxy)-[1,1'-biphenyl]-2-carboxamide;

[0197] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide;

[0198] 5'-(2-(((1r,4S)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxamide;

[0199] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0200] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0201] 5-(2-((1-acetylazetane-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0202] 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;

[0203] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0204] 2'-Chloro-3',6-Difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile;

[0205] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide;

[0206] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2-(methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0207] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0208] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0209] 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0210] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0211] 2'-Chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0212] 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-2-carboxamide;

[0213] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-[1,1'-biphenyl]-2-carboxamide;

[0214] 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;

[0215] N-((1-acetylazacyclobutane-3-yl)methyl)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0216] 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)benzamide;

[0217] 2-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)-3-fluorobenzamide;

[0218] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-3'-methoxy-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0219] 2'-Chloro-6-fluoro-5'-(2-((3-hydroxy-3-methylbutyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0220] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0221] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(morpholin-4-carbonyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide;

[0222] 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;

[0223] 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0224] 2'-Chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0225] 2'-Chloro-4',6-Difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0226] 2'-Chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0227] 3'-(2-amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0228] 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide;

[0229] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide;

[0230] (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;

[0231] (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;

[0232] 2'-Chloro-6-fluoro-5'-{1-fluoro-1-phenyl-2-[(propane-2-yl)amino]ethyl}-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0233] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2-oxoethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide;

[0234] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-4'-methyl-[1,1'-biphenyl]-2-carboxamide;

[0235] 5'-(2-((1-acetylpiperidin-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0236] 5'-(2-(((R)-1-acetylpiperidin-3-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0237] 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide;

[0238] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-((2-methoxyethyl)(methyl)amino)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate;

[0239] 2'-Chloro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0240] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(propylamino)ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0241] 2'-Chloro-6-fluoro-5'-(2-(isobutylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide;

[0242] (5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4,6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide hydrochloride;

[0243] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-acetamidocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0244] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(methylcarbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0245] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0246] This invention discloses a compound of formula I according to a first aspect of the invention, which targets TEAD. A conjugate comprising a compound of formula I and a ligase binding agent can recruit TEAD to an E3 ubiquitin ligase for degradation. Therefore, according to a second aspect of the invention, a conjugate is provided, comprising, or substantially composed of: Formula II:

[0247] ABC (Form II)

[0248] Where A is a compound of formula I according to any one of the embodiments of the first aspect, provided that R in formula I is... 1 R 3 Or R 4 One of them is a bond with B or contains that bond. In other words, the condition includes R in equation I. 1 R 3 Or R 4 One of them is a connection point with B or contains such a connection point. Alternatively, AB is a condensation product formed from a compound of formula I according to the first aspect and a connector B. 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 can be formed from a carboxylic acid (-COOH) and an amine (-NHR or -NH2) (forming an amide bond (-CONR- or -CONH-) and water (H2O)). Thus, when formula I is connected to connector B via -COOH, the resulting conjugate lacks the OH previously present in the carboxylic acid of formula I, as will be apparent to those skilled in the art.

[0249] B is a connector. B can be a connector that covalently connects A and C.

[0250] C is a ligase binding agent. Conjugates according to Formula II can serve as TEAD binding agents. This is illustrated in Example 202, which demonstrates SPR analysis for determining the binding affinity of exemplary compounds 1 to 46 to 84 to 110 and exemplary conjugates 47 to 83 to 111 to 200 for TEAD1 to TEAD4.

[0251] Unbound by any particular theory, the conjugate of Formula II can induce the formation of: a ternary complex containing the Formula II conjugate, TEAD and E3 ligase; or a ternary complex containing the Formula II conjugate, TEAD and Cerebrolysin.

[0252] The conjugates according to Formula II can be used as TEAD degrading agents. This is illustrated by some of the conjugates according to the second aspect; see Example 204. Figure 1 and / or Figure 2 This can be seen in the figure, which shows the amount of TEAD after incubation with the conjugate according to the second aspect of the invention.

[0253] As will be apparent to those skilled in the art, a linker is a group that covalently links a compound of formula I (A) to a ligase binder (C). Those skilled in the art will understand which linkers are suitable for conjugates according to the second aspect of the invention. For example, a linker may have between 1 and 13, preferably less than 10, rotatable bonds. Furthermore, a linker may have between 5 and 30, preferably less than 26, non-hydrogen atoms. Additionally, a linker may have a certain number of hydrogen bond donors, preferably up to 2. Those skilled in the art are well aware of the meaning of rotatable bonds, as well as the meaning of non-hydrogen atoms and hydrogen bond donors. Linkers according to the invention may be diamine linkers, spirocyclic or heterocyclic linkers, cyclic or heterocyclic linkers, straight-chain or branched C1-C10 alkyl linkers, ether linkers, amino acid linkers; that is, a linker may contain any of these groups or combinations of these groups.

[0254] The ligase conjugate is a group capable of binding to ligases, such as ubiquitin ligases, such as Cereblon E3 ubiquitin ligases. Other ligase conjugates suitable for Formula II conjugates are also part of this disclosure.

[0255] As discussed above, those skilled in the art understand which connectors are suitable as part of a conjugate according to Formula II. In some embodiments, connector B has the formula -L1-X1-L2-X2-L3- (B), and the conjugate has the following formula:

[0256] A-L1-X1-L2-X2-L3-C, and where

[0257] L1 is selected from the group consisting of the following: 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) and *L1a-C4-C7 cycloalkylene, where * represents the bond between L1 and X1;

[0258] L1a is selected from the group consisting of the following: C(O), *NH-C(O) and *C1-C6 alkylene-NH-C(O), where * represents the bond between L1a and X1;

[0259] X1 and X2 are each independently selected from the group consisting of: bonds; C4-C7 cycloalkylene groups; 4- to 7-membered heterocyclic groups containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; and 5- or 6-membered heteroarylene groups containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S.

[0260] 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 a bond between L2 and X2; or X1-L2-X2 forms a 7- to 13-membered spiroheterocyclic subcyclic group, which contains one to four heteroatoms independently selected from the group consisting of N, O and S;

[0261] L3 is selected from the group consisting of the following: bonds, C1-C5 alkylene groups, C2-

[0262] C5-olefinic, C1-C6-ynyleneic, 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; wherein * denotes the bond between L3 and X2; and wherein each R' is independently hydrogen or C1-C6 alkyl, preferably wherein each R' is hydrogen.

[0263] In some embodiments, L1 is *L1a-C4-C1 cycloalkylene**, and L1a is selected from the group consisting of: bond, C(O), *NH-C(O), and *C1-C5 alkylene-NH-C(O). * indicates a bond with X1, and ** indicates a bond with A. In some embodiments, L1 is *L1a-C6 cycloalkylene**, and 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 a bond with X1.

[0264] In some embodiments, the connector B has the formula -L1-X1-L2-X2-L3- or L1-X1-L2-X2-L3-X3-L4-(B), and the conjugate has the following formula:

[0265] A-L1-X1-L2-X2-L3-C or A-L1-X1-L2-X2-L3-X3-L4-C, where

[0266] X1 and X2 are each independently selected from the group consisting of the following items: bond, -O-, -CH2-, and -NH-, and among which...

[0267] L1, L2, and L3, or L1, L2, L3, and L4, are each individually selected from the following groups:

[0268] key;

[0269] Heterocyclic or spirocyclic rings having 7 to 11 ring atoms;

[0270] Cyclic or heterocyclic rings;

[0271] Bicyclic or biheterocyclic, or two rings or heterocycles bonded together by carbon, nitrogen or oxygen;

[0272] 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, wherein R 1a Choose from the group consisting of hydrogen and C1-C2 alkyl groups; or

[0273] An aromatic or heteroaromatic ring having five to six ring atoms. Optionally, the heteroaromatic ring contains one or two nitrogen atoms.

[0274] According to this embodiment, the connector may optionally be replaced with F, Me, or OH. Those skilled in the art will understand which positions are suitable for such replacement.

[0275] In some embodiments, L1, L2, and L3, or L1, L2, L3, and L4, are each individually selected from the group consisting of: bond, -CH2-, -C(=O)-, -O-, -NH-, -NH-C1-C3 alkyl, -NH-hydroxyC1-C3 alkyl,

[0276]

[0277] As will be apparent to those skilled in the art, each For the connection point with A, X1, X2, or C. Additionally, the connector can be substituted with F, Me, or OH at any suitable location in 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 location in L1, L2, and / or L3, or at any location in L1, L2, L4, and / or L4 in addition to the location of the connection point.

[0278] In some embodiments, the connector is selected from the group consisting of:

[0279]

[0280] Wherein A is a compound of formula I, and C is a ligase binding agent.

[0281] In some embodiments, the connector is selected from the group consisting of:

[0282]

[0283] Wherein A is a compound of formula I, and C is a ligase binding agent. In this embodiment, it is particularly preferred that R in formula I... 4 This refers to the portion of A that acts as or contains a bond with B. In other words, this group of the connector is particularly suitable for R in formula I. 4 Connect at the specified location.

[0284] In some embodiments, the connector is selected from the group consisting of:

[0285]

[0286] Wherein A is a compound of formula I, and C is a ligase binding agent. In this embodiment, it is particularly preferred that R in formula I... 4This refers to the portion of A that acts as or contains a bond with B. In other words, this group of the connector is particularly suitable for R in formula I. 4 Connect at the specified location.

[0287] In some embodiments, the connector is selected from the group consisting of:

[0288]

[0289] Wherein A is a compound of formula I, and C is a ligase binding agent. In this embodiment, it is particularly preferred that R in formula I... 1 Or R 3 This refers to the portion of A that acts as or contains a bond with B. In other words, this group of the connector is particularly suitable for R in formula I. 1 Or R 3 Connect at the specified location.

[0290] In some embodiments, the connector is selected from the group consisting of:

[0291]

[0292] As will be apparent to those skilled in the art, each This is the connection point with A or C. Additionally, the connector can be substituted with F, Me, or OH at any suitable location in L1, L2, L3, and / or L4, or at any suitable location in L1, L2, and / or L3. Those skilled in the art will understand that such substituents can be at any location in L1, L2, L3, and / or L4, or at any location in L1, L2, and / or L3 other than the connection point. In this embodiment, it is particularly preferred that R in Formula I... 4 This refers to the portion of A that acts as or contains a bond with B. In other words, this group of the connector is particularly suitable for R in formula I. 4 The connection is made at the location specified in the example. According to this embodiment, the most preferred configuration is that R in Formula I... 4 It is cyclohexyl-4-amine or cyclohexyl-4-formyl.

[0293] In some embodiments, the connector is selected from the group consisting of:

[0294]

[0295] In some embodiments, the connector is selected from the group consisting of:

[0296]

[0297] In some embodiments, the connector is selected from the group consisting of:

[0298]

[0299] In some embodiments, the connector is selected from the group consisting of:

[0300]

[0301] In some embodiments, the connector is selected from the group consisting of:

[0302]

[0303] In some embodiments, the connector is selected from the group consisting of:

[0304]

[0305] In some embodiments, the connector is selected from the group consisting of:

[0306]

[0307] In some embodiments, the connector is selected from the group consisting of:

[0308]

[0309] In some embodiments, the connector is selected from the group consisting of:

[0310]

[0311] In some embodiments, the connector is selected from the group consisting of:

[0312]

[0313] In some embodiments, the connector is selected from the group consisting of:

[0314]

[0315] In some embodiments, the connector is selected from the group consisting of:

[0316]

[0317] The conjugate according to a second aspect of the invention comprises a joint of a certain length. This length can be calculated as the shortest distance between A and C in the conjugate. In some embodiments, the length of the joint is between 2 and about 50 bonds, such as 3 to about 45 bonds, such as 3 to about 40 bonds, such as 3 to about 35 bonds, such as 3 to 30 bonds, such as 4 to about 23 bonds, such as 4 to 23 bonds, or between A and C such as 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.

[0318] The ligase binder according to this disclosure may comprise two or three 5- or 6-membered cyclic rings or heterocycles, wherein at least one of the two or three heterocycles is aromatic. When the ligase binder comprises two rings, one of these rings may be phenyl or a phenyl substituted with an alkoxy group such as a methoxy group. In some embodiments, the second ring is glutarimide or dihydrouracil.

[0319] When the ligase binder contains three rings, two of these rings can together form a bicyclic ring, such as phthalimide. In some embodiments, the third ring is glutarimide or dihydrouracil.

[0320] The ligase binder may contain a 6-membered heterocyclic group, which includes one or two nitrogen atoms and / or two oxygen substituents in the ring. In a preferred embodiment, the ligase binder contains a glutarimide or dihydrouracil group, or a similar group.

[0321] In some embodiments, the ligase binding agent is selected from the group consisting of:

[0322]

[0323] In some embodiments, the ligase binding agent is selected from the group consisting of:

[0324]

[0325] in For connection points with connectors such as connector B according to this disclosure, or for bonds with connectors, and wherein 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 on the benzene ring. In other words, when R is not H, R can replace the H on the benzene ring.

[0326] In some embodiments, the ligase binding agent is selected from the group consisting of:

[0327]

[0328] in For a key to a connector, such as the connector B according to this disclosure, or for a key to a connector.

[0329] In some embodiments, the ligase binding agent is selected from the group consisting of:

[0330]

[0331] in For a key to a connector, such as the connector B according to this disclosure, or for a key to a connector.

[0332] The conjugates according to this disclosure can be prepared as shown in the examples. In some embodiments, the conjugate comprises compound A of formula I according to the first aspect of the invention, which is prepared by reacting said compound with an intermediate formed according to the present disclosure from a ligase binding agent C and a linker B. Therefore, the intermediate may be represented by BC. In some embodiments, the intermediate is selected from the group consisting of:

[0333] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-carboxylic acid;

[0334] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-carboxylic acid;

[0335] 2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetic acid;

[0336] 3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}propionic acid;

[0337] 3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propionic acid;

[0338] 2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetic acid;

[0339] 2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetic acid;

[0340] 2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetic acid;

[0341] 2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetic acid;

[0342] 3-{2-[2-(2-{[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxyphenyl]formamido}ethoxy)ethoxy]ethoxy}propionic acid;

[0343] 2-{4-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperazin-1-yl}acetic acid;

[0344] 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetic acid;

[0345] 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione;

[0346] 4-({2-[2-(2-aminoethoxy)ethoxy]ethyl}amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;

[0347] 4-[4-(2-aminoethyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;

[0348] 4-{[4,4'-bipiperidin]-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;

[0349] 2-(2,6-dioxopiperidin-3-yl)-4-[4-(piperidin-4-yloxy)piperidin-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione;

[0350] 4-[4-(aminomethyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;

[0351] 5-(3-aminoazacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;

[0352] 5-[3-(aminomethyl)azacyclobutane-1-yl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;

[0353] 2-(2,6-dioxopiperidin-3-yl)-4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione;

[0354] 2-(2,6-dioxopiperidin-3-yl)-4-[4-(piperidin-4-carbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione;

[0355] 2-(2,6-dioxopiperidin-3-yl)-5-{2-oxo-2-[4-(piperidin-4-yloxy)piperidin-1-yl]ethoxy}-2,3-dihydro-1H-isoindole-1,3-dione; and

[0356] 5-{2-[4-(2-aminoethyl)piperidin-1-yl]-2-oxoethoxy}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione; in order to form the conjugate of formula II.

[0357] In one embodiment, the conjugate is selected from the group consisting of:

[0358] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0359] 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetamido)cyclohexyl]amino}ethyl)-5-[(pyridin-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide;

[0360] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0361] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0362] 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-5-[(pyridin-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide;

[0363] 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(8-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}octamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0364] 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}propamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0365] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-N-[(1r,4r)-4-[(2-{6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl}-2-phenylethyl)amino]cyclohexyl]piperidin-4-carboxamide;

[0366] 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0367] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxyphenyl]formamido}ethoxy)ethoxy]ethoxy}propamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0368] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]piperazin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0369] 2'-Chloro-5,6-difluoro-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide;

[0370] 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide;

[0371] 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide;

[0372] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0373] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0374] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0375] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0376] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0377] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-[4,4'-bipiperidin]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0378] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0379] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]oxy}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0380] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0381] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0382] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0383] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0384] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-3-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0385] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}-2-oxoethyl)-1H-pyrazol-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0386] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0387] 2'-Chloro-N-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}ethyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0388] 2'-Chloro-N-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-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;

[0389] 2'-Chloro-N-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-3-yl}methyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0390] 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetyl)azacyclobutane-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0391] 2'-Chloro-5-[2-({1-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propionyl]azacyclobutane-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0392] 2'-Chloro-5-[2-({1-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetyl]azacyclobutane-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0393] 2'-Chloro-5-{2-[(1-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-carbonyl}azacyclobutane-3-yl)oxy]ethoxy}-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and

[0394] 2'-Chloro-5-(2-{[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)azacyclobutane-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and

[0395] 2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylphenoxy)acetic acid;

[0396] 4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid;

[0397] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoic acid;

[0398] (1r,4r)-4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)oxy)cyclohexane-1-carboxylic acid;

[0399] (1r,4r)-4-((1-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylphenoxy)acetyl)piperidin-4-yl)oxy)cyclohexane-1-carboxylic acid;

[0400] (1r,4r)-4-(4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazin-1-yl)cyclohexane-1-carboxylic acid--2,2,2-trifluoroacetic acid;

[0401] (1r,4r)-4-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylphenoxy)acetyl)piperazin-1-yl)cyclohexane-1-carboxylic acid;

[0402] 4-[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoyl]-4-piperidinyl]oxy]cyclohexanecarboxylic acid;

[0403] 1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]piperidine-4-carboxylic acid;

[0404] 2-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]-4-piperidinyl]acetic acid;

[0405] 1-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl]piperidine-4-carboxylic acid;

[0406] 2-[1-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]piperidin-4-carbonyl]-4-piperidinyl]acetic acid;

[0407] 1-[1-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]piperidine-4-carbonyl]piperidine-4-carboxylic acid;

[0408] 2-[4-[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]-4-piperidinyl]methyl]-1-piperidinyl]acetic acid;

[0409] 2-[3-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]-3,9-diazaspiro[5.5]undecane-9-yl]acetic acid;

[0410] 2-[4-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]-4-piperidinyl]-1-piperidinyl]acetic acid;

[0411] 2-[4-[[1-[4-chloro-3-(2,4-dioxohexahydropyrimidin-1-yl)benzoyl]-4-piperidinyl]methyl]-1-piperidinyl]acetic acid;

[0412] 2-[4-[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoyl]-4-piperidinyl]oxy]-1-piperidinyl]acetic acid;

[0413] 2-[4-[2-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxybenzoyl]-4-piperidinyl]ethyl]-1-piperidinyl]acetic acid;

[0414] 2-(4-{1-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]piperidin-4-yl}piperazin-1-yl)acetic acid;

[0415] 2-[4-[[1-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]-4-piperidinyl]methyl]-1-piperidinyl]acetic acid;

[0416] 2-[4-[1-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]-4-piperidinyl]-1-piperidinyl]acetic acid;

[0417] 2-[3-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]-3,9-diazaspiro[5.5]undecane-9-yl]acetic acid;

[0418] 2-[4-[2-[1-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]-4-piperidinyl]ethyl]-1-piperidinyl]acetic acid;

[0419] 2-[4-[[4-[[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]amino]-1-piperidinyl]methyl]-1-piperidinyl]acetic acid;

[0420] 2-[4-[4-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]piperazin-1-yl]-1-piperidinyl]acetic acid;

[0421] 2-[4-[[4-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]piperazin-1-yl]methyl]-1-piperidinyl]acetic acid;

[0422] 2-[4-[[1-[2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]acetyl]-4-piperidinyl]oxy]-1-piperidinyl]acetic acid;

[0423] 2-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-methylphenoxy]acetic acid;

[0424] 2-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-methylphenoxy]acetic acid;

[0425] 2,2-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]-4-piperidinyl]methyl]-1-piperidinyl]acetic acid;

[0426] 1-[2-methoxy-5-[4-(4-piperidinylmethyl)piperidin-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione;

[0427] N-(4-aminobutyl)-3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzamide;

[0428] 1-[2-methoxy-5-(piperazine-1-carbonyl)phenyl]hexahydropyrimidine-2,4-dione;

[0429] 1-[5-[4-(2-aminoethyl)piperidin-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0430] 1-[5-[4-(2-aminoethoxy)piperidine-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0431] 1-[5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0432] 1-[5-(2,9-diazaspiro[5.5]undecane-2-carbonyl)-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0433] 1-[2-methoxy-5-[4-(4-piperidinyl)piperidin-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione;

[0434] 1-[2-methoxy-5-[4-(4-piperidinyloxy)piperidin-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione;

[0435] 1-[2-chloro-5-[4-(4-piperidinylmethyl)piperidin-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione;

[0436] 1-[2-methoxy-5-[4-[2-(4-piperidinyl)ethyl]piperidin-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione;

[0437] 1-[2-methoxy-5-(4-piperazin-1-ylpiperidin-1-carbonyl)phenyl]hexahydropyrimidine-2,4-dione;

[0438] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-(4-piperidinyl)benzamide;

[0439] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-(4-piperidinylmethyl)benzamide;

[0440] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-[(3R)-3-piperidinyl]benzamide;

[0441] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-[(3S)-3-piperidinyl]benzamide;

[0442] 1-[5-[4-(4-aminopiperidine-1-carbonyl)piperidine-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0443] 1-[5-[4-[4-(aminomethyl)piperidine-1-carbonyl]piperidine-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0444] 1-[5-[4-[4-(2-aminoethyl)piperidine-1-carbonyl]piperidine-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0445] 1-[5-[4-[4-(aminomethyl)benzoyl]piperazine-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0446] 1-[5-[4-[[4-(aminomethyl)phenyl]methyl]-piperazine-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0447] 1-[2-methoxy-5-(4-{[(1r,3r)-3-aminocyclobutyl]methyl}piperazine-1-carbonyl)phenyl]-1,3-diazine-2,4-dione;

[0448] 1-[2-methoxy-5-[4-[[1-(4-piperidinylmethyl)-4-piperidinyl]methyl]piperidin-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione;

[0449] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide;

[0450] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-[[1-(4-piperidinylmethyl)-4-piperidinyl]methyl]benzamide;

[0451] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-[(3S)-1-(4-piperidinylmethyl)-3-piperidinyl]benzamide;

[0452] 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-N-[(3R)-1-(4-piperidinylmethyl)-3-piperidinyl]benzamide;

[0453] 1-[2-methoxy-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]hexahydropyrimidine-2,4-dione;

[0454] 1-(2-Methyl-5-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride;

[0455] 1-[5-[2-[4-(2-aminoethyl)-1-piperidinyl]-2-oxo-ethoxy]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione hydrochloride;

[0456] 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidinylmethyl)-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione hydrochloride;

[0457] 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidinyl)-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0458] 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidinyloxy)-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0459] 1-[2-methyl-5-[2-oxo-2-[4-[2-(4-piperidinyl)ethyl]-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0460] 2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]-N-(4-piperidinyl)acetamide;

[0461] 2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]-N-(4-piperidinylmethyl)acetamide;

[0462] 1-[2-methyl-5-[2-oxo-2-(4-piperazin-1-yl-1-piperidinyl)ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0463] 1-[5-[2-(3,9-diazaspiro[5.5]undecane-3-yl)-2-oxo-ethoxy]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione;

[0464] 1-[5-[2-[4-(4-aminopiperidin-1-carbonyl)-1-piperidinyl]-2-oxo-ethoxy]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione;

[0465] 1-[5-[2-[4-[4-(aminomethyl)piperidin-1-carbonyl]-1-piperidinyl]-2-oxo-ethoxy]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione;

[0466] 1-[5-[2-[4-[[4-(aminomethyl)phenyl]methyl]piperazin-1-yl]-2-oxo-ethoxy]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione;

[0467] 1-[5-[4-[(3-aminocyclobutyl)methyl]piperazine-1-carbonyl]-2-methoxy-phenyl]hexahydropyrimidine-2,4-dione;

[0468] 2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]-N-[1-(4-piperidinylmethyl)-4-piperidinyl]acetamide;

[0469] 2,2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methylphenoxy]-N-[[1-(4-piperidinylmethyl)-4-piperidinyl]methyl]acetamide;

[0470] 1-[2-methyl-5-[2-oxo-2-[4-[[1-(4-piperidinylmethyl)-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0471] 1-[2-methyl-5-[2-oxo-2-[4-[1-(4-piperidinylmethyl)-4-piperidinyl]-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0472] 1-[2-methyl-5-[2-oxo-2-[4-(4-piperidinylmethyl)piperazin-1-yl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0473] 1-[2-methyl-4-[2-oxo-2-[4-(4-piperidinyloxy)-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0474] 1-[2-methyl-4-[2-oxo-2-[4-(4-piperidinylmethyl)-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0475] 1-[2-methyl-4-[2-oxo-2-[4-(4-piperidinyl)-1-piperidinyl]ethoxy]phenyl]hexahydropyrimidine-2,4-dione;

[0476] 2-(2,6-dioxo-3-piperidinyl)-4-[4-(4-piperidinylmethyl)-1-piperidinyl]isoindoline-1,3-dione; and

[0477] 3-(3-{4-[(piperidin-4-yl)methyl]piperidin-1-carbonyl}phenyl)piperidin-2,6-dione. The intermediate may be in the form of a salt, such as a trifluoroacetate.

[0478] This disclosure presents non-limiting examples of conjugates according to the invention. In some embodiments, the conjugates are selected from a list consisting of:

[0479] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0480] 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetamido)cyclohexyl]amino}ethyl)-5-[(pyridin-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide;

[0481] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0482] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0483] 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-5-[(pyridin-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide;

[0484] 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(8-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}octamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0485] 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}propamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0486] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-N-[(1r,4r)-4-[(2-{6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl}-2-phenylethyl)amino]cyclohexyl]piperidin-4-carboxamide;

[0487] 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0488] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(3-{2-[2-(2-{[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxyphenyl]formamido}ethoxy)ethoxy]ethoxy}propamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0489] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]piperazin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0490] 2'-Chloro-5,6-difluoro-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide;

[0491] 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide;

[0492] 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide;

[0493] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0494] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0495] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0496] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0497] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0498] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-[4,4'-bipiperidin]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0499] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0500] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]oxy}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0501] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0502] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0503] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0504] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0505] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-3-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0506] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}-2-oxoethyl)-1H-pyrazol-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0507] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0508] 2'-Chloro-N-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}ethyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0509] 2'-Chloro-N-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-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;

[0510] 2'-Chloro-N-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-3-yl}methyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0511] 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetyl)azacyclobutane-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0512] 2'-Chloro-5-[2-({1-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propionyl]azacyclobutane-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0513] 2'-Chloro-5-[2-({1-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetyl]azacyclobutane-3-yl}oxy)ethoxy]-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0514] 2'-Chloro-5-{2-[(1-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-carbonyl}azacyclobutane-3-yl)oxy]ethoxy}-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and

[0515] 2'-Chloro-5-(2-{[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)azacyclobutane-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and / or selected from the group consisting of:

[0516] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[4-(2,4-dioxo-1,3-diazinyl-1-yl)-3-methoxybenzoyl]piperazine-1-carbonyl}piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0517] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0518] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0519] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0520] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0521] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(2-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0522] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0523] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0524] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(4-{[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxyphenyl]formamido}butyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0525] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0526] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0527] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{9-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]-3,9-diazaspiro[5;5]undecane-3-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0528] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]-[4,4'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0529] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperazine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0530] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diazin-1-yl)benzoyl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0531] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0532] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}oxy)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0533] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]-2,9-diazaspiro[5;5]undecane-9-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0534] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{1'-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-[4,4'-bipiperidin]-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0535] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0536] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(2-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0537] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0538] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0539] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-({4-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperazin-1-yl}methyl)cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0540] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzamido]piperidin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0541] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxyphenyl]formamido}methyl)piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0542] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3S)-3-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzamido]piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0543] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3R)-3-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzamido]piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0544] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0545] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1-{1-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0546] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0547] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(4-{4-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperazine-1-carbonyl}phenyl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0548] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[4-({4-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperazin-1-yl}methyl)phenyl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0549] 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0550] 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-carbonyl)piperidin-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0551] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-carbonyl)piperidin-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0552] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[1-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-carbonyl)piperidin-4-yl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0553] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0554] 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0555] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0556] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-[(4-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0557] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)ethyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0558] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}piperidin-1-yl)methyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0559] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}methyl)piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0560] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0561] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1'-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0562] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0563] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0564] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0565] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diazin-1-yl)-3-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0566] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diazin-1-yl)-3-methylphenoxy]acetyl}piperidin-4-yl)oxy]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0567] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[4-(2,4-dioxo-1,3-diazinyl)-3-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0568] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0569] 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0570] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0571] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0572] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diazinyl-1-yl)benzoyl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0573] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1'-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]-[4,4'-bipiperidine]-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0574] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{9-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]-3,9-diazaspiro[5;5]undecane-3-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0575] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(2-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0576] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{1-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperidin-4-yl}piperazin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0577] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidine-4-

[0578] [1,1'-biphenyl]-2-carboxamide;

[0579] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[4-chloro-3-(2,4-dioxo-1,3-diazinyl-1-yl)benzoyl]piperidin-4-yl}oxy)cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0580] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-{4-[4-chloro-3-(2,4-dioxo-1,3-diazinyl)benzoyl]piperidin-1-yl}cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0581] 1-{1-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}-N-[(1r,4r)-4-{[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxacyclopentan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide;

[0582] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1-{1-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0583] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0584] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0585] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(9-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}-3,9-diazaspiro[5;5]undecane-3-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0586] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0587] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)ethyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0588] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}piperidin-1-yl)methyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0589] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)piperazin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0590] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0591] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0592] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(4-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperazinyl)cyclohexanylamino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0593] 1-(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)-N-[(1r,4r)-4-{[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxacyclopentan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide;

[0594] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0595] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[4-(2,4-dioxo-1,3-diazinyl)-3-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0596] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0597] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiridine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0598] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0599] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0600] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0601] 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0602] 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-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0603] 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-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0604] 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-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0605] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,6-dioxopiperidin-3-yl)benzoyl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0606] as well as

[0607] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]piperidin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0608] In one embodiment, the conjugate is selected from a list of the following:

[0609] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0610] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}-2-oxoethyl)-1H-pyrazol-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0611] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0612] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0613] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0614] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0615] 2',4'-Dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(1R)-1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]-[1,1'-biphenyl]-2-carboxamide

[0616] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0617] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0618] 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetyl)azacyclobutane-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide and

[0619] 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-5-[(pyridin-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide.

[0620] In a particularly preferred embodiment, the conjugate is selected from the group consisting of:

[0621] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazine-1-carbonyl}piperidine;

[0622] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0623] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and

[0624] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

[0625] In one embodiment, the conjugate is selected from the group consisting of:

[0626] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diazinyl-1-yl)benzoyl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2 '-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;

[0627] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and

[0628] 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide

[0629] Conjugates that can be obtained by reacting the intermediate BC with a compound of formula I are within the scope of this disclosure.

[0630] In a third aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect or a conjugate according to any one of the embodiments of the second aspect, and at least one pharmaceutically acceptable diluent, carrier, and / or excipient. Typically, the compositions or conjugates of the present invention, or their pharmaceutically acceptable salts, are formed together with at least one pharmaceutically acceptable diluent, carrier, and / or excipient 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.

[0631] In a fourth aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound or a conjugate according to any one of the embodiments of the first aspect or any one of the embodiments of the second aspect, or the pharmaceutical composition according to the third aspect, for use as a medicine.

[0632] A pharmaceutical composition is also provided comprising a therapeutically effective amount of a compound or a conjugate according to any one of the embodiments of the first aspect or any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect, for binding to a TEAD. The TEAD can be any or all of TEAD 1, 2, 3, and / or 4. The compound and / or conjugate can bind with TEAD1, TEAD2, TEAD3, and / or TEAD4 (TEADx) with high affinity, as discussed above. High affinity according to this disclosure can include KD values ​​of less than 500 µM, such as less than 400 µM, such as less than 300 µM, such as less than 200 µM, such as less than 100 µM, such as less than 50 µM, such as less than 40 µM, such as less than 30 µM, such as less than 20 µM, such as less than 15 µM, such as less than 10 µM, such as less than 7.5 µM, or preferably less than 5 µM, such as less than 4 µM, such as less than 3 µM.

[0633] A pharmaceutical composition is also provided comprising a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect or a conjugate according to any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect, the pharmaceutical composition being used to suppress or inactivate the Hippo pathway, and / or to suppress or block TEAD-mediated gene transcription.

[0634] In a fifth aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect or a conjugate according to any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect, for treating a disease or condition in which the Hippo pathway is hyperactivated. According to this aspect, 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 understand that NF2-deficient tumors include schwannomas and meningiomas.

[0635] In a sixth aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound or conjugate according to any one of the embodiments of the first aspect or any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect, for treating cancer by administering the compound, conjugate, or composition to a patient in need. In some embodiments of the sixth 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.

[0636] In some embodiments of the sixth aspect, administration is performed with at least one compound selected from the group consisting of: AKT inhibitors, such as afuresertib, capivasertib, ipatasertib, miransertib, perifosine, 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-α inhibitors; ABL1 inhibitors; and XPO1 inhibitors. In some embodiments, administration is performed in combination with at least one compound selected from the group consisting of: AKT inhibitors, such as afluctinib, capipecetib, palbociclib, miracetib, perifoxetine, and euprocetib; CDK4 / 6 inhibitors, such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors, such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors, such as bemetinib, cmetinib, and trametinib.

[0637] As mentioned in the background of the invention, the Hippo signaling pathway plays a role in regulating wound healing. When this pathway is disrupted, it can lead to fibrosis due to the overexpression of pro-fibrotic genes such as CTGF and ANKRD1 regulated by TEAD

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

[13] . Accordingly, in a seventh aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound or a conjugate according to any one of the embodiments of the first aspect or any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect, for treating fibrosis by administering said compound, conjugate, or composition to a patient in need.

[0638] 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 disease 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.

[0639] In an eighth aspect, a method for treating cancer is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect or a conjugate according to any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect.

[0640] In some embodiments of the eighth aspect, 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.

[0641] As will be apparent to those skilled in the art, treatment may be beneficial when combined with targeted cancer therapies. For example, combination therapies according to this disclosure may be relevant when seeking to overcome resistance caused by TEAD overactivation. Therefore, in some embodiments, administration is performed with at least one compound selected from the group consisting of: AKT inhibitors, such as afluctinib, capipecetib, palbociclib, miracetib, perifoxetine, and euprocetib; 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-α inhibitors; ABL1 inhibitors; and XPO1 inhibitors. In some embodiments, administration is performed in combination with at least one compound selected from the group consisting of: AKT inhibitors, such as afluctinib, capipecetib, palbociclib, miracetib, perifoxetine, and euprocetib; CDK4 / 6 inhibitors, such as abemaciclib, palbociclib, and ribociclib; EGRF inhibitors, such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; and MAP2K inhibitors, such as bemetinib, cmetinib, and trametinib.

[0642] In a ninth aspect, a method for treating fibrosis is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect or a conjugate according to any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect.

[0643] 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.

[0644] In some embodiments, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

[0645] In a tenth aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect or a conjugate according to any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect, the pharmaceutical composition being used to manufacture a medicament for treating cancer. 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.

[0646] In an eleventh aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect or a conjugate according to any one of the embodiments of the second aspect, or a pharmaceutical composition according to the third aspect, the pharmaceutical composition being used to manufacture a medicament for treating fibrosis. 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.

[0647] The conjugate according to the second aspect of the invention can be prepared according to the examples presented below. Therefore, in a twelfth aspect, a method for preparing the conjugate according to formula II is provided. The method comprises:

[0648] The ligase binding agent C is reacted with the adapter B, the ligase binding agent and the adapter being as shown in the second aspect of this disclosure. Through this reaction, intermediate BC is formed. Furthermore, the method further includes:

[0649] The intermediate is reacted with a compound of formula I according to the first aspect to form a conjugate of formula II according to the second aspect. As will be apparent to those skilled in the art, this method is carried out under conditions that allow for the formation of the intermediate and the conjugate, conditions that are clear to those skilled in the art.

[0650] Racemic mixtures and diastereomeric mixtures, as well as single stereoisomers, of the disclosed and claimed compounds are all within the scope of this invention. Depending on the choice of starting materials and processes, the conjugates may exist as one of the possible stereoisomers or as mixtures thereof, for example, as pure optical isomers or as mixtures of stereoisomers (such as racemic and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. This invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)- stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the conjugate contains a double bond, the substituent may be E or Z configuration. If the conjugate contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomer forms are also intended to be included.

[0651] The compounds of the present invention can form salts that are within the scope of the invention. Salts of the compounds of formula (I) suitable for medical use are, for example, those in which the counterion is pharmaceutically acceptable.

[0652] Suitable salts according to the invention include those formed with organic or inorganic acids or bases. Specifically, suitable acid addition salts according to the invention include those formed with mineral acids, strong organic carboxylic acids, or organic alkyl or aryl sulfonic acids, which are optionally substituted with halogens.

[0653] 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, hydroxyethylsulfonic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid or glutamic acid, and lysine or arginine.

[0654] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., salts of potassium and sodium), alkaline earth metal salts (e.g., salts of calcium and magnesium), and salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucosamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-alkylamines (e.g., ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethylpropylamine), or mono-, di-, or tri-hydroxyalkylamines (e.g., mono-, di-, or triethanolamine).

[0655] Furthermore, corresponding internal salts of the compounds of this invention can be formed.

[0656] The compounds of the present invention can also be isotopically labeled. Therefore, compounds that are structurally identical to those disclosed above, but in which one or more atoms are replaced by atoms having a different atomic mass or mass number than atoms normally found in nature, are within the scope of the present invention. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 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 Cl.

[0657] Compounds of the present invention containing any of the isotopes mentioned above and / or other isotopes, as well as their pharmaceutically acceptable salts, tautomers, and stereoisomers, are within the scope of the present invention.

[0658] The isotope-labeled compounds of this invention can be used in the fields of drug discovery and development, for example, for determining drug and / or substrate tissue distribution and target occupancy. Furthermore, in the discussion, certain positions of the molecule are labeled with heavier isotopes (such as...). 2 Compounds labeled with H may offer certain therapeutic advantages due to a reduced metabolic rate, which may result in an increased in vivo half-life or a reduced dose requirement.

[0659] The isotope-labeled compounds of the present invention can be prepared by methods known in the field of organic chemistry, for example by performing known synthetic processes and by replacing the corresponding non-isotope-labeled reagents with available isotope-labeled reagents.

[0660] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. As used herein, the term "halogenated" refers to fluorine, chlorine, bromine, or iodine.

[0661] As used herein, the term “C1-C2 alkyl” refers to a saturated hydrocarbon group having one or two carbon atoms. Examples of “C1-C2 alkyl” groups are methyl and ethyl.

[0662] As used herein, the term "C1-C3 alkyl" refers to both straight-chain and branched saturated hydrocarbon groups having one to three carbon atoms. Non-limiting examples of C1-C3 alkyl groups include methyl, ethyl, n-propyl, and isopropyl groups.

[0663] As used herein, the term "C2-C3 alkyl" refers to both straight-chain 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.

[0664] As used herein, the term “C2-C6 alkyl” refers to both straight-chain and branched saturated hydrocarbon groups having 2 to 6 carbon atoms. Non-limiting examples of C2-C6 alkyl groups include ethyl, n-propyl, isopropyl groups, n-butane, sec-butane, tert-butane, n-pentane, isopentane, and hexane.

[0665] As used herein, the term “C1-C2 haloalkyl” means a saturated hydrocarbon group having one or two carbon atoms and one or all of its hydrogen atoms substituted with different or the same type of halogen. Examples of C1-C2 haloalkyl groups include methyl groups substituted with one to three halogen atoms and ethyl groups substituted with one to five halogen atoms.

[0666] As used herein, the term “C2-C3 haloalkyl” refers to both straight-chain and branched saturated hydrocarbon groups having two or three carbon atoms and having one or all of their hydrogen atoms substituted with different or the same type of halogen. Examples of C2-C3 haloalkyl groups include ethyl groups substituted with one to five halogen atoms and n-propyl or isopropyl groups substituted with one to seven halogen atoms.

[0667] As used herein, the term "halomethyl" means a methyl group that is substituted with one to three halogen atoms. Examples of halomethyl groups include, but are not limited to, difluoromethyl, trifluoromethyl, dichloromethyl, and trichloromethyl.

[0668] As used herein, the term CHO refers to an aldehyde. As used herein, the term =O refers to a double oxygen bond.

[0669] As used herein, “C1-C3 alkoxy” refers to the O-C1-C3 alkyl group, where “C1-C3 alkyl” is used as described above. Examples of C1-C3 alkoxy groups include methoxy, ethoxy, isopropoxy, and n-propoxy.

[0670] As used herein, the term "C1-C3 haloalkoxy" refers to both straight-chain and branched saturated alkoxy groups having one to three carbon atoms and one to all hydrogen atoms substituted with different or the same type of halogen. Examples of C1-C3 haloalkoxy groups include methoxy groups substituted with one to three halogen atoms, ethoxy groups substituted with one to five halogen atoms, and n-propoxy or isopropoxy groups substituted with one to seven halogen atoms.

[0671] As used herein, “monocyclic heteroaryl” means a monocyclic aromatic group of a carbon atom in which one or three of the carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0672] Examples of monocyclic heteroaryl groups include furanyl, thiophene, pyrrole, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

[0673] As used herein, the terms heteroaliphatic ring and heterocycle are used interchangeably and refer to a non-aromatic ring having at least one heteroatom selected from N, O, and S.

[0674] As used herein, “C3-C6 cycloalkyl” refers to a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Examples of C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0675] As used herein, the terms "heterocyclic group," "heterocyclic ring," and "heterocycle" refer to a cyclic group of carbon atoms in which one to three carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups and heterocycles include oxobutyryl, tetrahydrofuranyl, tetrahydropyranyl, azaheterobutyryl, pyrroliyl, piperidinyl, piperazinyl, morpholinyl, and dioxane.

[0676] As used in this article, the term TEAD refers to the TEA domain transcription factor and includes all four TEAD orthologs, named TEAD1, TEAD2, TEAD3 and TEAD4.

[0677] As used herein, the term "excipient" encompasses both adjuvants and diluents. Those skilled in the art will understand that any adjuvant and diluent disclosed herein is suitable for the pharmaceutical composition, and that appropriate selection thereof is within the knowledge of those skilled in the art. Those skilled in the art will understand that the pharmaceutical composition can be adapted to suit the desired dosage.

[0678] It should be noted that, as used in the specification and appended claims, the singular forms “a” and “the” also include plural indicators, unless the context clearly indicates otherwise.

[0679] The term "therapeutic effective amount" in this disclosure refers to the amount of the conjugate of this disclosure that will elicit a biological or medical response in a subject (e.g., reduce, inhibit, or degrade enzyme or protein activity), or alleviate symptoms, reduce condition, slow or delay disease progression, or prevent disease, etc.

[0680] As used herein, the term “treat, treating, or treatment” means any disease or condition that is: lessened or relieved (i.e., slowed or stopped from developing at least one of the disease or its clinical symptoms); or lessened or relieved at least one physical parameter or biomarker associated with the disease or condition, including those parameters or biomarkers that the patient may not be aware of.

[0681] Those skilled in the art understand that numerical values ​​related to a measurement are subject to measurement errors that limit their accuracy. For this reason, the general convention in scientific and technical literature applies: the position of the last decimal place of a numerical value indicates its degree of accuracy. In the absence of other margins of error, the maximum margin is determined by rounding to the last decimal place; for example, for a measurement of 3.5 cm, the margin of error is 3.45 to 3.54. When interpreting the range of numerical values ​​in the patent specification, those skilled in the art continue on the same basis.

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[0691] 9. Matthaios D, Tolia M, Mauri D, Kamposioras K, Karamouzis M. YAP / Hippo Pathway and Cancer Immunity: It Takes Two to Tango. 《生物医药(Biomedicines)》.2021;9(12)。

[0692] 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.

[0693] 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.

[0694] 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.

[0695] 13. Kim CL, Choi SH, Mo JS. Role of the Hippo Pathway in Fibrosis and Cancer. Cells. 2019;8(5).

[0696] 14. Piccolo S, Dupont S, Cordenonsi M. The biology of YAP / TAZ: hippo signaling and beyond. Physiol Rev. 2014;94(4):1287-312.

[0697] 15. Yamaguchi N. Multiple Roles of Vestigial-Like Family Members in Tumor Development. Front Oncol. 2020;10:1266.

[0698] 16. Pobbati AV, Kumar R, Rubin BP, Hong W. Therapeutic targeting of TEADtranscription factors in cancer. Trends Biochem Sci. 2023;48(5):450-62. Attached Figure Description

[0699] Figure 1 The Western imprints of panTEAD detection for representative examples after 4 h of incubation with example compounds are shown.

[0700] Figure 2 Bar graphs highlighting the normalized HSP90 level of panTEAD and the relative expression of DMSO after 4 h of incubation with example compounds are shown.

[0701] Figure 3 The inhibitory effects of example conjugates 165, 166, 167, 178, and 188 on cell proliferation in NCI-H226, NCI-H2052, NCI-H2452, and NCI-H28 cell lines are shown.

[0702] Figure 4 The inhibitory effects of the reference TEAD palmitoylation inhibitors IK-930, VT-103, and GNE-7883 on cell proliferation in NCI-H226, NCI-H2052, NCI-H2452, and NCI-H28 cell lines are shown.

[0703] Example

[0704] The following are several non-limiting examples of the present invention.

[0705] Preparation of compounds

[0706] The compounds of this invention can be prepared as free bases or pharmaceutically acceptable salts thereof by the methods described below. In the following description of such methods, it should be understood that, where appropriate, suitable protecting groups will be added to and subsequently removed from various reactants and intermediates in a manner readily understood by those skilled in the art of organic synthesis. Conventional processes for using such protecting groups and examples of suitable protecting groups are described, for example, in TW Greene and PGM Wutz, Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006. It should be understood that microwaves can also be used for heating the reaction mixture.

[0707] General Method

[0708] All reactions were carried out in oven-dried glassware. Unless otherwise specified, all reagents were used as is, at the highest commercially available quality, and without further purification. The progress of the reactions was monitored by thin-layer chromatography (Merck Silica gel 60 F-254, pre-coated plates on alumina) using UV light (254 nm) as the visualization agent. For heating of the reactions, an oil bath or heating block was used as the heat source. Unless otherwise specified, yields refer to separated and homogeneous materials. LC-MS data were collected using the following methods on a Shimadzu LC-MS-2020 or an Agilent 1260 Infinity lab LC / MSD: Kinetex C18 column (4.6 x 30 mm), 2.6 µm, 100 A; mobile phase A: H2O containing 0.1% HCO2H or 0.1% TFA; mobile phase B: MeCN (100%). HPLC was collected using a UHPLC (or) HPLC Arc system with the following: Kinetex EVO C18, 4.6 x 150 mm, 5 µm, or YMC Triart ExRS C18 4.6 x 150 mm, 5 µm; mobile phase A: H2O containing 0.1% HCO2H / H2O containing 0.01 M NH4OAc / 0.1% TFA H2O; mobile phase B: MeCN (100%). The crude reaction mixture was then subjected to silica gel column chromatography (E. Merck silica gel, 100 to 200 mesh) and / or preparative reversed-phase HPLC with the following: mobile phase A: H2O containing 0.1% HCO2H / H2O containing 0.01 M NH4OAc / H2O containing 0.1% TFA; mobile phase B: MeCN (100%), wherein the column was a Kinetex EVO C18 (20 * 21.2 mm), 5 µm. 1 H NMR spectra were recorded at 400 MHz on a JEOL NMR or Varian spectrometer. 1 The chemical shifts of H NMR were obtained via the following internal standard with tetramethylsilane (= 0): residual solvent signal ( 1 H, CDCl3, at 7.26 ppm; 1 H, DMSO-d6, at 2.45 ppm; 1 H, methanol-d4 (at 3.31 ppm), and abbreviated as follows: s (single peak), d (double peak), t (triple peak), q (quartet), m (multiple peak), br (broad peak).

[0709] Abbreviations: The following abbreviations have been used in the examples.

[0710]

[0711] Example 1.

[0712] Synthesis of 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0713]

[0714] Step 1: (3-Bromo-4-chlorophenyl)(phenyl)methyl ketone (2)

[0715] SOCl2 (8.0 mL) was added to a stirred solution of 3-bromo-4-chlorobenzoic acid (1) (5.0 g, 21.37 mmol) in a 50 mL round-bottom flask under RT and stirred at 80 °C for 4 h. After the reaction was complete (monitored by TLC), excess SOCl2 was removed under vacuum. The obtained crude product was dissolved in 60 mL benzene, AlCl3 (7.3 g, 64.11 mmol) was added partically, and the reaction mixture was heated to 90 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum and diluted with ice-cold H2O. The obtained solid was filtered and washed with saturated NaHCO3 aqueous solution to provide the title compound (2) (4 g, 63%) as a grayish-white solid. LC-MS: non-ionized, 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).

[0716] Step 2: 2-(3-bromo-4-chlorophenyl)-2-phenylethylene oxide (4)

[0717] NaH (270 mg, 6.75 mmol) was added to a stirred solution of Me3SI (3) (1.37 g, 6.75 mmol) in DMSO / THF (1:1, 12 mL) at 0 °C, and the reaction mixture was stirred at RT for 2 h. Then, (3-bromo-4-chlorophenyl)(phenyl)methyl ketone (2) (1.0 g, 3.37 mmol) was added at 0 °C and stirred at the same temperature for 18 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to provide the title compound (4) (850 mg, crude, 81%) as a yellow liquid. LC-MS: m / z 308.9 [MH] + ;t R = 1.95 min, LC-MS purity: 70%. 1 H NMR (400 MHz, DMSO-d6) = δ ppm7.61 (s, 1H), 7.35 (s, 6H), 7.26-7.22 (m, 1H), 3.32 (s, 1H), 3.20 (s, 1H).

[0718] Step 3: 2-(3-bromo-4-chlorophenyl)-2-phenylacetaldehyde (5)

[0719] BF3·Et2O (779 mg, 5.49 mmol) was added to a stirred solution of 2-(3-bromo-4-chlorophenyl)-2-phenylethylene oxide (4) (850 mg, 2.74 mmol) in Et2O (6 mL) at 0 °C, and the reaction mixture was then stirred at the same temperature for 10 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (5) (600 mg, crude, 100%) as a yellow liquid. The crude compound was ready for use in the next step without further purification.

[0720] Step 4: 2-(3-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-2-phenylethane-1-amine (7)

[0721] (4-Methoxyphenyl)methylamine (6) (1.3 g, 9.69 mmol) was added 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) at RT, followed by the addition of AcOH (0.01 mL), and the reaction mixture was stirred at the same temperature for 4 h. Then, NaCNBH3 (608 mg, 9.69 mmol) was added, and the reaction mixture was stirred at RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product obtained was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 35% EtOAc to provide the title compound (7) (0.82 g, 58%) as a brown gel-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 (400 MHz, DMSO-d6) = δ ppm 7.66 (d, J= 1.6 Hz, 1H), 7.52-7.50 (d, J = 8.4 Hz, 1H), 7.31-7.24 (m, 5H), 7.20-7.15(m, 3H), 6.84-6.82 (d, J = 8.4 Hz, 2H), 4.19-4.17 (t, J = 8.0 Hz, 1H), 3.71(s, 3H), 3.63(s, 2H), 3.10-2.99 (m, 2H).

[0722] Step 5: 2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)-N-(4-methoxybenzyl)-2-phenylethane-1-amine (9)

[0723] KOAc (546 mg, 5.57 mmol) and bis(pinacol)diboron (8) (613 mg, 2.41 mmol) were added 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), and the reaction mixture was degassed with argon for 5 min. Then, Pd(dppf)Cl2·DCM (151 mg, 0.18 mmol) was added, and the mixture was again degassed with argon for 5 min. The reaction mixture was then heated to 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (70 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with a brine solution (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (9) as a brown liquid (1.0 g, crude, 110%). LC-MS: m / z 478.0 [M+H] + ;t R = 1.52 min. LC-MS purity: 35.62%. 1 H NMR (400 MHz, 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),3.68 (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).

[0724] Step 6: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (11)

[0725] K3PO4 (799 mg, 3.76 mmol), N-XantPhos (69 mg, 0.12 mmol), and Pd2(dba)3 (57 mg, 0.06 mmol) were added to a stirred, cooled solution of 2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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) under RT. The reaction mixture was then degassed with argon for 5 min. The reaction mixture was then heated to 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 x 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 (2 x 4 g silica gel columns) using hexane containing 50% EtOAc to provide the title compound (11) (250 mg, 41%) as a brown liquid. LC-MS: m / z 471.1 [M+H] + ;t R = 2.24 min. LC-MS purity: 69.7%. 1 H NMR (400 MHz, DMSO-d6) = δppm 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).

[0726] Step 7: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide (13)

[0727] Perkins catalyst (12) (68 mg, 0.15 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (11) (250 mg, 0.53 mmol) in EtOH / H2O (5:1, 8 mL) under RT, and the reaction mixture was then heated to 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 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 (4 g silica gel column) using DCM containing 7% MeOH to provide the title compound (13) (160 mg, 60%) as a brown solid. LC-MS: m / z 489.2 [M+H] + ;t R = 2.14 min. LC-MS purity: 68.4%.

[0728] Step 8: 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 1)

[0729] Cerium ammonium nitrate (179 mg, 0.32 mmol) was added 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) at 0 °C, and the reaction mixture was then heated to RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to provide a crude compound. This crude compound was subjected to preparative HPLC [column: ZORBAX BONUS-RP (150 x 4.6 mm; 5 μm); mobile phase A: H₂O containing 0.1% TFA; 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]. The pure preparative fraction was lyophilized to provide a trifluoroacetate of the title compound (Example 1) as a grayish-white solid (5 mg, 4.7%). LC-MS: m / z 369.1 [M+H] +;t R = 1.92 min. LC-MS purity: 98.52%, t R = 5.50 min. 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).

[0730] Example 2.

[0731] Synthesis of 5'-(2-(((R)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0732]

[0733] Step 1: (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)(phenyl)methyl ketone (3)

[0734] Bis(pinacol)diborone (2) (1.288 g, 5.07 mmol) and KOAc (0.995 g, 10.1 mmol) were added to a stirred solution of (3-bromo-4-chlorophenyl)(phenyl) ketone (1) (1.0 g, 3.38 mmol) in 1,4-dioxane (20.0 mL), and the reaction mixture was degassed with nitrogen for 10 min. To this solution, a PdCl2(dppf)·DCM complex (0.276 g, 0.338 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, the precipitated solid was filtered through a Buchner funnel lined with diatomaceous earth, and washed with EtOAc (2 x 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 (40 g silica gel column) using hexane containing 8% EtOAc to provide the title compound (3) as a grayish-white solid (700 mg, 60.86%). LC-MS: m / z 343.1 [M+H] + ;t R = 3.20 min. LC-MS purity: 44.93%.

[0735] Step 2: 5'-benzoyl-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxylonitrile (5)

[0736] K₂CO₃ (0.829 g, 5.999 mmol) was added to a stirred solution of 2-bromo-3-fluorobenzonitrile (4) (0.400 g, 1.999 mmol) and (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)(phenyl)methyl ketone (3) (0.685 g, 1.999 mmol) in DME / H₂O (4:1, 15 mL). The reaction mixture was degassed with nitrogen for 5 min, Pd(PPh₃)₄ (0.231 g, 0.199 mmol) was added, and the reaction mixture was stirred at 120 °C for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, the precipitated solid was filtered through diatomaceous earth, and the filtrate was washed with EtOAc (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 (24 g silica gel column) using hexane containing 10% EtOAc to provide the title compound (5) (250 mg, 37.09%) as a white solid. LC-MS: m / z 336.25 [M+H] + ;t R =1.81 min. LC-MS purity: 89.52%. 1 H NMR (400 MHz, DMSO-d6) = δ ppm 7.92-7.91 (m, 4H), 7.82-7.69 (m, 5H), 7.60-7.56 (m, 2H).

[0737] Step 3: 2'-Chloro-6-fluoro-5'-(2-phenylethylene-2-yl)-[1,1'-biphenyl]-2-carboxynitrile (7)

[0738] NaH (0.15 g, 3.871 mmol, 60% dispersion in mineral oil) was added to a stirred solution of Me3SI (6) (0.790 g, 3.871 mmol) in DMSO (10.0 mL) at RT, and the reaction mixture was stirred at RT for 2 h. Then, 5'-benzoyl-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxynitrile (5) (0.650 g, 1.935 mmol, dissolved in 5.00 mL THF) was added, and the reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to RT, and H2O (50 mL) was added, followed by extraction with EtOAc (2 x 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 (4 g silica gel column) using hexane containing 8% EtOAc to provide the title compound (7) as a grayish-white solid (550 mg, 81.24%). LC-MS: m / z 350.10 [M+H] + ;t R = 1.86 min. LC-MS purity: 93.03%. 1 H NMR (400 MHz, DMSO-d6) = δ ppm7.90-7.33 (m, 11H), 3.39-3.35 (m, 1H), 3.29-3.25 (m, 1H).

[0739] Step 4: 2'-Chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (8)

[0740] BF3·Et2O (81 mg, 0.57 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-phenylethyleneoxy-2-yl)-[1,1'-biphenyl]-2-carboxynitrile (7) (100 mg, 0.28 mmol) in THF (2 mL) at 0 °C, and the reaction mixture was stirred at the same temperature for 10 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with Et2O (2 x 30 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum to provide 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= 2.71 min. LC-MS purity: 69.39%.

[0741] Step 5: tert-butyl(4R)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptane-1-carboxylate (10)

[0742] Tert-butyl(4R)-4-aminoazacycloheptan-1-carboxylate (9) (61 mg, 0.28 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (8) (100 mg, 0.28 mmol) in MeOH / DCM (2 mL) under RT, followed by the addition of AcOH (2 drops). The reaction mixture was stirred under RT for 4 h, then NaCNBH3 (35 mg, 0.28 mmol) was added, and the reaction mixture was stirred under RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 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 (4 g silica gel column) using DCM containing 2% MeOH to provide the title compound (10) (55 mg, 35%) as a yellow liquid. LC-MS: m / z 548.3 [M+H] + ;t R = 2.29 min. LC-MS purity: 98.10%. 1 H NMR (400 MHz, 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 = 5.6 Hz, 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).

[0743] Step 6: tert-butyl(4R)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptane-1-carboxylate (11)

[0744] Perkins catalyst (12 mg, 0.029 mmol) was added to a stirred solution of tert-butyl(4R)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptan-1-carboxylate (10) (53 mg, 0.096 mmol) in EtOH / H2O (2.4 mL, 1:1) at RT, and the reaction mixture was then heated to 80 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to RT, diluted with H2O (10 mL), and extracted with EtOAc (2 x 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 provide the title compound (11) (50 mg, 91%) as an off-white solid. LC-MS: m / z 566.3 [M+H] + ;t R = 2.19 min. LC-MS purity: 91.37%. HPLC purity: 93.55%, t R = 7.30 min. 1 H NMR (400 MHz, 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).

[0745] Step 7: 5'-(2-(((R)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 2)

[0746] TFA (30 mg, 0.264 mmol) was added to a stirred solution of tert-butyl(4R)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptane-1-carboxylate (11) (50 mg, 0.088 mmol) in DCM (1 mL), and the reaction mixture was then heated to RT and stirred for 2 h. 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 x 19 mm; 5.0 μm); mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 12 mL / min; gradient time (min) / %B: 0 / 25, 2 / 25, 10 / 55] to provide the trifluoroacetate of the title compound (Example 2) (23 mg, 46%) as a white solid. LC-MS: m / z 466.2 [M+H] + ;t R = 1.77 min. LC-MS purity: 99.95%, HPLC purity: 97.01%, t R = 6.66 min, 1 H NMR (400 MHz, DMSO-d6) = δ ppm8.770 - 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).

[0747] Example 3.

[0748] Synthesis of 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0749]

[0750] Step 1: tert-butyl(4S)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptane-1-carboxylate (3)

[0751] Tert-butyl(S)-4-aminoazacycloheptan-1-carboxylate (2) (61 mg, 0.28 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (1) (100 mg, 0.28 mmol) in MeOH / DCM (2 mL) under RT, followed by the addition of AcOH (2 drops), and the reaction mixture was stirred at the same temperature for 4 h. Then, NaCN(BH3) (35 mg, 0.28 mmol) was added, and the reaction mixture was stirred at RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 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 (4 g silica gel column) using DCM containing 2% MeOH to provide the title compound (3) (75 mg, 48%) as a grayish-white solid. LC-MS: m / z 548.3 [M+H] + ;t R = 2.31 min. LC-MS purity: 98.45%.

[0752] Step 2: tert-butyl(4S)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptane-1-carboxylate (5)

[0753] Perkins catalyst (17 mg, 0.039 mmol) was added to a stirred solution of tert-butyl(4S)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptane-1-carboxylate (3) (73 mg, 0.133 mmol) in EtOH / H2O (2.4 mL) under RT. The reaction mixture was heated to 80 °C and stirred for 18 h. TLC showed 20% of the starting material. Perkins catalyst (17 mg, 0.039 mmol) was added again under RT, and the reaction mixture was stirred at 80 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with H₂O (200 mL) and brine (200 mL), dried over Na₂SO₄, and concentrated under vacuum to provide a crude title compound (4) as a grayish-white solid (70 mg, crude, 101%). LC-MS: m / z 566.3 [M+H] + ;t R = 2.20 min. LC-MS purity: 79.92%.

[0754] Step 3: 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide

[0755] TFA (42 mg, 0.370 mmol) was added to a stirred solution of tert-butyl(4S)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)azacycloheptan-1-carboxylate (5) (70 mg, 0.123 mmol) in DCM (1 mL), and the reaction mixture was then heated to RT and stirred at the same temperature for 2 h. 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 x 21.2 mm; 5.0 µm); mobile phase: H2O (A) / MeCN (B) containing 0.1% TFA; flow rate: 15 mL / min; gradient, time (min) / %B: 0 / 25, 3 / 25, 10 / 50]. The pure preparative fraction was lyophilized to provide a trifluoroacetate of the title compound as a grayish-white solid (Example 3) (28 mg, 40%). LC-MS: m / z 466.2 [M+H] + ;t R= 1.73 min. LC-MS purity: 99.48%. HPLC purity: 98.54%. 1 H NMR (400 MHz, 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).

[0756] Example 4.

[0757] Synthesis of 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0758]

[0759] Step 1: 5'-benzoyl-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3)

[0760] (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)(phenyl)methyl ketone (1, prepared according to a similar reaction procedure for intermediate 3, Example 2) (4.2 g, 12.08 mmol), K3PO4 (5.1 g, 24.015 mmol) and XantPhos (466 mg, 0.80 mmol) were added 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) under RT. The resulting reaction mixture was degassed with N2 for 10 min, and then Pd2(dba)3 (368 mg, 0.405 mmol) was added to the reaction mixture under RT, degassed again with N2 for 5 min, and then the reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 15% EtOAc to provide the title compound (3) (3.20 g, 97%) as a colorless liquid. 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, 2H), 7.50-7.44 (m, 1H), 4.38-4.31 (m, 2H), 3.73-3.69 (m, 2H), 3.31 (s, 3H).

[0761] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenylethyleneoxy-2-yl)-[1,1'-biphenyl]-2-carboxynitrile (5):

[0762] NaH (683 mg, 60% mineral oil, 17.0 mmol) was added to a stirred solution of Me3SI (4) (3.4 g, 17.0 mmol) in THF (18 mL) and DMSO (18 mL) at 0 °C, and the reaction mixture was stirred at RT for 2 h. 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenylazacycloheptane-2-yl)-[1,1'-biphenyl]-2-carboxynitrile (3) (3.5 g, 8.53 mmol) was added to the reaction mixture at 0 °C, and the reaction mixture was stirred at RT for 18 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (5) as a yellow liquid (3.0 g, crude, 82%). 1 H NMR (400 MHz, 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).

[0763] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (6)

[0764] BF3·OEt2 (133 mg, 0.943 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenylethyleneoxy-2-yl)-[1,1'-biphenyl]-2-carboxynitrile (5) (200 mg, 0.471 mmol) in Et2O (2 ml) at 0 °C, and the reaction mixture was stirred at the same temperature for 10 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with Et2O (2 x 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (6) (200 mg, crude, 100%) as a yellow liquid. LC-MS: m / z 422.0 [MH] + ;t R = 2.68, LC-MS purity: 57.9%.

[0765] Step 4: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (8)

[0766] (4-Methoxyphenyl)methylamine (7) (194 mg, 1.41 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (6) (200 mg, 0.47 mmol) in MeOH / DCM (3 mL) under RT, followed by the addition of AcOH (3 drops), and the reaction mixture was stirred under RT for 3 h. Then, NaCNBH3 (88 mg, 1.41 mmol) was added, and the reaction mixture was stirred under RT for 21 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (4 g silica gel column) using DCM containing 2% MeOH to provide the title compound (8) (70 mg, 25%) as a grayish-white solid. LC-MS: m / z 545.2 [M+H] + ;t R = 2.21 min. LC-MS purity: 90.85%.

[0767] Step 5: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide (10)

[0768] Perkins catalyst (9) (15 mg, 0.03 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (8) (50 mg, 0.09 mmol) in EtOH / H2O (5:1, 1 mL) under RT, and the reaction mixture was then heated to 80 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (10) (50 mg, crude) as a yellow liquid. LC-MS: m / z 563.2 [M+H]+ ;t R = 2.12 min. LC-MS purity: 74.31%.

[0769] Step 6: 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 4)

[0770] Cerium ammonium nitrate (292 mg, 0.53 mmol) was added 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) at 0 °C, and the reaction mixture was stirred at RT for 24 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with aqueous brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC [column: X-SELECT CSH; mobile phase A: H₂O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min, gradient, time (min) / %B: 0 / 30, 10 / 50]. The pure preparative fraction was lyophilized to provide the trifluoroacetate of the title compound (Example 4) (5 mg, 8%) as a grayish-white solid. LC-MS: m / z 443.1 [M+H] + ;t R =1.93 min. LC-MS purity: 99.88%, t R = 8.09 min, HPLC purity: 99.78%. 1 H NMR (400 MHz, 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).

[0771] Example 5.

[0772] Synthesis of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0773]

[0774] Step 1: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3)

[0775] [(4-methoxyphenyl)methyl](methyl)amine (2) (53 mg, 0.35 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (1, prepared according to a similar reaction procedure for Example 4, Intermediate 6) (100 mg, 0.23 mmol) in MeOH / DCM (2 ml) under RT, followed by the addition of AcOH (2 drops), and the reaction mixture was stirred at the same temperature for 4 h. Then, NaCNBH3 (43 mg, 0.69 mmol) was added, and the reaction mixture was stirred at the same temperature for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 60 mL). 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 hexane containing 40% EtOAc to provide the title compound (3) (30 mg, 38%) as a yellow liquid. LC-MS: m / z 559.2 [M+H] + ;(t R = 2.21 min). LC-MS purity: 84.99%.

[0776] Step 2: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide (5)

[0777] Perkins catalyst (4) (11 mg, 0.026 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3) (50 mg, 0.089 mmol) in EtOH / H2O (2.4 mL) under RT. The reaction mixture was then heated to 80 °C and stirred for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to provide the title compound (5) (30 mg, crude, 58%) as a yellow liquid. 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.

[0778] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 5)

[0779] DDQ (35 mg, 0.15 mmol) was added 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) at 0 °C, and the reaction mixture was then stirred at RT for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 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 x 21.2 mm, 5.0 µm); mobile phase A: H₂O containing 0.1% TFA, 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 provide the trifluoroacetate of the title compound (Example 5) (3 mg, 10%) as a white solid. LC-MS: m / z 457.2 [M+H] + ;(t R= 1.988 min). LC-MS purity: 98.502%. HPLC purity: 98.89%, (t R = 6.949 min, at 210 nm). 1 H NMR (400 MHz, 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).

[0780] Example 6.

[0781] Synthesis of 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0782]

[0783] Step 1: tert-butyl(4S)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)zaheptan-1-carboxylate (3)

[0784] tert-butyl(S)-4-aminoazacycloheptan-1-carboxylate (2) (83 mg, 0.38 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (1, prepared according to Example 4, Intermediate 6) (150 mg, 0.35 mmol) in MeOH / DCM (3 ml) under RT, followed by the addition of AcOH (2 drops). After stirring the reaction mixture under RT for 4 h, NaCNBH3 (44 mg, 0.71 mmol) was added, and the reaction mixture was stirred under RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. 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 hexane containing 40% to 80% EtOAc to provide the title compound (3) (56 mg, 25%) as a grayish-white solid. LC-MS: m / z 622.4 [M+H] + ;t R = 2.21 min. LC-MS purity: 90.32%.

[0785] Step 2: tert-butyl(4S)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)zaheptan-1-carboxylate (5)

[0786] Perkins catalyst (4) (11 mg, 0.026 mmol) was added 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)azacycloheptan-1-carboxylate (3) (55 mg, 0.088 mmol) in EtOH / H2O (2.4 mL) under RT. The reaction mixture was then heated to 80 °C and stirred for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to provide the title compound (5) (50 mg, 88%) as a yellow liquid. LC-MS: m / z 640.4 [MH] + ;t R = 2.2 min. LC-MS purity: 76%.

[0787] Step 3: 5'-(2-(((S)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 6)

[0788] TFA (26 mg, 0.23 mmol) was added 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)azacycloheptane-1-carboxylate (50 mg, 0.078 mmol) in DCM (1 ml), and the reaction mixture was stirred at RT for 2 h. 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 x 21.2 mm, 5.0 µm); mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 20, 2 / 20, 10 / 40]. The pure fraction was lyophilized to provide a trifluoroacetate of the title compound (Example 6) as a white solid (11 mg, 22%). LC-MS: m / z 540.3 [M+H] + ;(t R = 1.34 min). 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 (400 MHz, 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).

[0789] Example 7.

[0790] Synthesis of 2'-chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0791]

[0792] Step 1: 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3)

[0793] Cyclobutylamine (50 mg, 0.70 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (1, prepared according to a similar reaction procedure for Example 4, Intermediate 6) (150 mg, 0.35 mmol) in MeOH / DCM (3 ml) under RT, followed by the addition of AcOH (2 drops). The reaction mixture was stirred at the same temperature for 4 h, then NaCNBH3 (44 mg, 0.71 mmol) was added, and the reaction mixture was stirred at the same temperature for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). 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 DCM containing 4% MeOH to provide the title compound (3) (52 mg) as a grayish-white solid. LC-MS (ESI): m / z 479.2 [M+H] + ;t R = 2.158 min; LC-MS purity: 54.85%.

[0794] Step 2: 2'-Chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 7)

[0795] Perkins catalyst (4) (13 mg, 0.032 mmol) was added to a stirred solution of 2'-chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3) (52 mg, 0.108 mmol) in EtOH / H2O (2.4 ml) under RT. The reaction mixture was then heated to 80 °C and stirred for 6 h. 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 x 21.2 mm, 5.0 µm); mobile phase A: H₂O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 20, 2 / 20, 10 / 50] to provide the trifluoroacetate of the title compound (Example 7) (8 mg, 13%) as a white solid. LC-MS: m / z 497.2 [M+H] + ;(t R = 2.058 min). LC-MS purity: 99.77%. HPLC purity: 95.66% (t). R = 7.2 min, at 210 nm). 1 H NMR (400 MHz, 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 – 3.423 (m, 2H), 3.312 (s, 3H), 2.143-2.113 (m,2H), 2.019-1.996 (m, 2H), 1.730 – 1.708 (m, 2H).

[0796] Example 8.

[0797] 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

[0798]

[0799] Step 1: 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3)

[0800] (1r,4r)-4-amino-1-methylcyclohexane-1-ol (85 mg, 0.66 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (1, prepared according to a similar reaction procedure for Example 4, Intermediate 6) (140 mg, 0.33 mmol) in MeOH / DCM (3 ml) under rt, followed by the addition of AcOH (2 drops). After stirring the reaction mixture for 4 h, NaCNBH3 (41 mg, 0.66 mmol) was added, and the reaction mixture was stirred at the same temperature for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). 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 DCM containing 2% MeOH to provide the title compound (3) (50 mg, 28%) as a grayish-white solid. LC-MS (ESI): m / z 537.2 [M-Boc+H] + ;t R = 2.122 min; LC-MS purity: 78.56%.

[0801] 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)

[0802] Perkins catalyst (4) (11 mg, 0.02 mmol) was added 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-carboxynitrile (3) (50 mg, 0.09 mmol) in EtOH / H2O (2.4 mL) under RT. The reaction mixture was then heated to 80 °C and stirred for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 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 x 21.2 mm, 5.0 µm); mobile phase A: H₂O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 25, 2 / 25, 10 / 50] to provide a trifluoroacetate of the title compound (Example 8) (50 mg, 28%) as a white solid. LC-MS: m / z 555.20 [M+H] + ;(t R = 1.995 min). LC-MS purity: 99.48%. HPLC purity: 95.73% (t). R = 6.183 min, at 210 nm). 1 H NMR (400 MHz, 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).

[0803] Example 9.

[0804] Synthesis of 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0805]

[0806] Step 1: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile

[0807] BF3·Et2O (100 mg, 0.707 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenylethyleneoxy-2-yl)-[1,1'-biphenyl]-2-carboxynitrile (1, prepared according to a similar process to that for Example 4, Intermediate 5) (150 mg, 0.353 mmol) in Et2O (2 mL) at 0 °C, and the reaction mixture was then stirred at the same temperature for 10 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with Et2O (2 x 30 mL). The organic layer was washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum to provide the title compound (2) (150 mg, crude, 100%) as crude. The crude material was used for the next step without further purification.

[0808] Step 2: 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3)

[0809] Isopropylamine (62 mg, 1.06 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (crude, 2) (150 mg, 0.35 mmol) in MeOH / DCM (3 mL) under RT, followed by the addition of AcOH (2 drops), and the reaction mixture was stirred for 4 h. Then, NaCNBH3 (44 mg, 0.70 mmol) was added, and the reaction mixture was stirred under RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 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 (4 g silica gel column) using DCM containing 2% MeOH to provide the title compound (3) (52 mg, 31%) as a grayish-white solid. LC-MS: m / z 467.2 [M+H] + ;t R= 2.09 min. LC-MS purity: 95.76%. 1 H NMR (400 MHz, DMSO-d6) = δ ppm7.84-7.82 (d, J =8.8 Hz, 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).

[0810] Step 3: 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 9)

[0811] Perkins catalyst (4) (13.5 mg, 0.032 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (3) (50 mg, 0.107 mmol) in EtOH / H2O (2.4 mL) under RT, and the reaction mixture was then heated to 80 °C for 18 h. TLC showed 20% of the starting material, and Perkins catalyst (13.5 mg, 0.032 mmol) was added again under RT, and the reaction mixture was stirred at 80 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude compound was purified by preparative HPLC [column: X-Select CSH (250 mm x 21.2 mm; 5.0 μm), mobile phase: H₂O (A) / MeCN (B) containing 0.1% TFA; gradient, time (min) / %B: 0 / 55, 10 / 85; flow rate: 15 mL / min] to provide the trifluoroacetate of the title compound (Example 9) (25 mg, 40%) as a grayish-white solid. LC-MS: m / z 485.2 [M+H] + , t R = 1.99 min, LC-MS purity: 99.17%, HPLC purity: 99.45%. 1H 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 = 7.6 Hz, 1H), 4.29-4.21 (m, 2H), 3.75-3.68 (m, 5H), 3.31(s, 3H), 1.22-1.19 (t, J = 4.8 Hz, 6H).

[0812] Example 10.

[0813] Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0814]

[0815] Step 1: tert-butyl((1r,4r)-4-((2-(3-bromo-4-chlorophenyl)-2-phenylethyl)amino)cyclohexyl)carbamate (3)

[0816] Tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (2) (631 mg, 2.94 mmol) was added to a stirred solution of 2-(3-bromo-4-chlorophenyl)-2-phenylacetaldehyde (1, prepared according to intermediate 5, Example 1) (600 mg, 1.96 mmol) in methanol / DCM (1:1, 6 mL) under RT, followed by the addition of AcOH (3 drops). After stirring the reaction mixture for 4 h, NaCNBH3 (369 mg, 5.88 mmol) was added, and the reaction mixture was allowed to stand overnight. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. 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 hexane containing 40% to 80% EtOAc to provide the title compound (3) (400 mg, 40%) as an off-white solid. LC-MS: m / z 507.2 [M+H] + ;t R = 2.21 min. LC-MS purity: 86.87%.

[0817] Step 2: tert-butyl(2-(3-bromo-4-chlorophenyl)-2-phenylethyl)((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (4)

[0818] NaHCO3 (132 mg, 1.56 mmol) was added 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) at 0 °C, followed by the addition of di-tert-butyl dicarbonate (257 mg, 1.18 mmol). The reaction mixture was then stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. 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 hexane containing 30% EtOAc to provide the title compound (4) (300 mg, 62%) as a grayish-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 = 2.23 min. LC-MS purity: 52.41%.

[0819] Step 3: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)-2-phenylethyl)carbamate (6)

[0820] KOAc (121 mg, 1.23 mmol) and bis(pinacol)diborone (5) (135 mg, 0.53 mmol) were added 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), and the reaction mixture was degassed with argon for 5 min. Then, Pd(dppf)Cl2-DCM (33 mg, 0.041 mmol) was added, and the reaction mixture was again degassed with argon for 5 min. The reaction mixture was then stirred in a sealed tube at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to provide the title compound (6) as a brown liquid (220 mg, crude, 81%). LC-MS: m / z 555.3 [M-Boc+H] + ;t R = 3.58 min. LC-MS purity = 49.83%.

[0821] Step 4: tert-butyl((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 (8)

[0822] K3PO4 (222 mg, 1.005 mmol), N-XantPhos (18.5 mg, 0.033 mmol) and Pd2(dba)3 (15.3 mg, 0.016 mmol) were added 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-dioxacyclopentaborane-2-yl)phenyl)-2-phenylethyl)carbamate (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) under RT, and the reaction mixture was degassed with argon for 5 min. The reaction mixture was then stirred at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 60% EtOAc to provide the title compound (8) (180 mg, 74%) as a grayish-white solid. LC-MS: m / z 566.15 [M-Boc-tBu +H] + ;t R = 2.04 min. LC-MS purity: 98.33%, HPLC purity: 99.35%, t R = 8.118 min, 1 H NMR (400 MHz, DMSO-d6) = δ ppm7.84-7.80 (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 = 7.2 Hz, 3H), 3.32-3.31 (d, J = 3.6 Hz, 3H), 3.05 (bs, 1H), 1.71-1.33 (m, 18H), 1.03 (m, 7H).

[0823] Step 5: tert-butyl((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 (10)

[0824] Perkins catalyst (9) (32 mg, 0.074 mmol) was added to a stirred solution of tert-butyl((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 (8) (180 mg, 0.249 mmol) in EtOH / H2O (5:1, 12 mL), and the reaction mixture was then heated to 80 °C and stirred for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). 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 DCM containing 4% MeOH to provide the title compound (10) (140 mg, 76%) as a grayish-white solid. LC-MS (ESI): m / z 640.40 [M-Boc+H] + , t R = 1.85 min. 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 (400 MHz, 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 = 8.6 Hz, 2H), 3.31 (s, 3H), 3.05 (bs, 1H), 1.68-1.62 (bs, 3H), 1.33 (m, 22H).

[0825] 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)

[0826] TFA (107 mg, 0.945 mmol) was added to a stirred solution of tert-butyl((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 (10) (140 mg, 0.189 mmol) in DCM (2 mL) at 0 °C, and the reaction mixture was then stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was ground with pentane to provide a crude compound (130 mg), which was then purified by preparative HPLC [column: Luna Omega C18 (250 mm x 21.2 mm, 5.0 μm); mobile phase A: H₂O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min, gradient time (min) / %B: 0 / 25, 3 / 25, 10 / 60] to provide a trifluoroacetate of the title compound (Example 10) as a white solid (83 mg, 63%). LC-MS: m / z 541.40 [M+H] + ;(t R = 1.34 min). LC-MS purity: 98.69%. HPLC purity = 99.88% (t) R = 6.43 min 31.56% and t R = 6.51 min68.32%, at 210 nm). 1 H NMR (400 MHz, 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 = 6.8 Hz, 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).

[0827] Chiral separation in Example 10 was performed using chiral HPLC (see Examples 11 and 12).

[0828] Examples 11 and 12.

[0829] 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)

[0830] Example 10 was separated by chiral HPLC to provide two pairs of stereoisomers, Example 11 and Example 12. Column: Chiral Pak IC (250 x 4.6 mm; 5 μm); Mobile phase A: hexane containing 0.1% DEA, 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 min) and Example 12 (t R = 19.06 min). The relative / absolute stereochemistry of Examples 11 and 12 has not yet been determined.

[0831] Example 13.

[0832] Synthesis of 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide

[0833]

[0834] Step 1: tert-butyl ((1r,4r)-4-acetamidocyclohexyl)carbamate (3)

[0835] Et3N (944 mg, 9.33 mmol) and acetyl chloride (2) (439 mg, 5.59 mmol) were added to a stirred solution of tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (1) (400 mg, 1.86 mmol) in DCM (5 mL) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with aqueous brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (4 g silica gel column) using DCM containing 2% MeOH to provide the title compound (3) (300 mg, 60%) as an off-white solid. LC-MS: m / z 548.3 [M–tBu+H]+ ;t R = 2.09 min. LC-MS purity: 88.92%. 1 H NMR (400 MHz, DMSO-d6) = δ ppm 7.72-7.70 (d, J =7.6 Hz, 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).

[0836] Step 2: N-((1r,4r)-4-aminocyclohexyl)acetamide (4)

[0837] TFA (667 mg, 5.85 mmol) was added to a stirred solution of tert-butyl((1r,4r)-4-acetamidocyclohexyl)carbamate (3) (300 mg, 1.86 mmol) in DCM (3 mL) at 0 °C, and the reaction mixture was then stirred at RT for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was alkalized with saturated aqueous NaHCO3 solution (15 mL) and extracted with 10% MeOH / DCM (2 x 60 mL). The combined organic layers were washed with H2O (50 mL) and brine (500 mL), dried over Na2SO4, and concentrated under vacuum to provide the title compound (4) (250 mg, crude, 120%) as a grayish-white solid. LC-MS: m / z 157.2 [M+H] + ;t R = 0.37 min. LC-MS purity: 93.98%. 1 H NMR (400 MHz, 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).

[0838] 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)

[0839] N-((1r,4r)-4-aminocyclohexyl)acetamide (4) (82 mg, 0.53 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (5, prepared according to Example 4, Intermediate 6) (150 mg, 0.35 mmol) in MeOH / DCM (3 mL) under RT, followed by the addition of AcOH (2 drops). The reaction mixture was stirred at the same temperature for 4 h. Then, NaCNBH3 (66 mg, 1.05 mmol) was added under RT, and the reaction mixture was stirred under RT for 20 h. After completion (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 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 (4 g silica gel column) using DCM containing 7% MeOH to provide the title compound (6) (7 mg, 3.5%) as a grayish-white solid. LC-MS: m / z 564.3 [M+H] + ;t R = 2.06 min. LC-MS purity: 97.26%.

[0840] 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)

[0841] Perkins catalyst (7) (1.5 mg, 0.003 mmol) was added 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), and the reaction mixture was then heated to 80 °C for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 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 x 21.2 mm; 5.0 μm); mobile phase A: H₂O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min; gradient time (min) / %B: 0 / 10, 10 / 60] to provide a trifluoroacetate of the title compound (Example 13) (1.5 mg, 18%) as a grayish-white solid. LC-MS: m / z 582.3 [M+H] + ;t R = 2.00 min. 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).

[0842] Example 14.

[0843] Synthesis of 2'-chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0844]

[0845] Step 1: Ethyl 2-(4-formyl-1H-pyrazole-1-yl)acetate (3)

[0846] KOtBu (2.8 g, 24.9 mmol) was added fractionally to a stirred solution of 1H-pyrazole-4-carboxaldehyde (1) (2 g, 20.8 mmol) in DMF (15 mL) at 0 °C, and the mixture was stirred for 10 min. Ethyl 2-bromoethyl acetate (2) (3.5 g, 22.8 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at RT for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 30% EtOAc to provide the title compound (3) (1.4 g, 40%) as a yellow liquid. 1 H NMR (400 MHz, DMSO-d6) = δ ppm 9.83 (s, 1H), 8.48 (s,1H), 8.02 (s, 1H), 5.18 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2Hz, 3H).

[0847] Step 2: Benzyl N-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]carbamate (6)

[0848] DIPEA (12.2 mL, 70.08 mmol) and benzyl chloroformate (5) (3.98 g, 23.36 mmol) were added to a stirred solution of tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (4) (5 g, 23.36 mmol) in DCM (50 mL) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with DCM (2 x 150 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (2 x 4 g silica gel column) using DCM containing 2% MeOH to provide the title compound (6) (6.5 g, 80%) as an off-white solid. LC-MS: m / z 249.2 [M-Boc+H] + ;t R = 2.58 min, LC-MS purity: 96%. 1 H NMR (400 MHz, DMSO-d6) = δppm 7.38-7.28 (m, 5H), 7.19 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 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).

[0849] Step 3: Benzyl ((1r,4r)-4-aminocyclohexyl)carbamate (7)

[0850] TFA (7.8 mL, 93.3 mmol) was added 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) under RT, and the reaction mixture was stirred under RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude product was ground with pentane to provide trifluoroacetate (7) of the title compound (5 g, 98%) as an off-white solid. LC-MS: m / z 249.2 [M+H] + ;t R = 1.77 min, LC-MS purity: 98.38%. 1H NMR (400 MHz, DMSO-d6) = δ ppm 7.38-7.28 (m, 5H), 7.15 (d, J = 7.6 Hz, 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).

[0851] Step 4: Ethyl 2-(4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)amino)methyl)-1H-pyrazole-1-yl)acetate (8)

[0852] Benzyl ((1r,4r)-4-aminocyclohexyl)carbamate (7) (1.9 g, 7.69 mmol) was added 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) under RT, followed by the addition of AcOH (0.23 mL, 3.84 mmol), and the reaction mixture was stirred under RT for 4 h. Then, NaCNBH3 (1.4 g, 3.84 mmol) was added to the reaction mixture under RT, and the reaction mixture was stirred under RT for 12 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (40 g silica gel column) using DCM containing 20% ​​MeOH to provide the title compound (8) (1.3 g, 42%) as a colorless gel-like solid. LC-MS: m / z 415.2 [M+H] + ;t R = 1.38, LC-MS purity: 93.9%. 1H NMR (400 MHz, 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).

[0853] Step 5: Ethyl 2-[4-({[(tert-butoxy)carbonyl][(1r,4r)-4-{[(benzyloxy)carbonyl]amino}cyclohexyl]amino}methyl)-1H-pyrazole-1-yl]acetate (9)

[0854] NaHCO3 (0.788 g, 9.39 mmol) was added to a stirred solution of ethyl 2-(4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)amino)methyl)-1H-pyrazol-1-yl)acetate (8) (1.3 g, 3.13 mmol) in THF / H2O (3:1, 20 mL) under RT, followed by the addition of (Boc)2O (1.3 g, 3.13 mmol). The reaction mixture was then stirred at RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (4 g silica gel column) using hexane containing 80% EtOAc to provide the title compound (9) (1.2 g, 75%) as a colorless colloidal liquid. LC-MS: m / z 459 [M-tBu+H] + ;t R = 2.74 min, LC-MS purity: 88.22%. 1H NMR (400 MHz, DMSO-d6) = δ ppm 7.59 (s, 1H),7.38-7.28 (m, 5H), 7.19 (d, J = 7.2 Hz, 1H), 5.00 (d, J = 8.4 Hz, 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).

[0855] Step 6: Methyl 2-(4-((((1r,4r)-4-aminocyclohexyl)(tert-butoxycarbonyl)amino)methyl)-1H-pyrazole-1-yl)acetate (10)

[0856] Pd / C (207 mg, 1.94 mmol) was added to a stirred solution of ethyl 2-(4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)acetate (9) (1 g, 1.94 mmol) in MeOH (10 mL) under RT, and the reaction mixture was then stirred under H2 balloon pressure for 6 h at RT. After the reaction was complete (monitored by TLC), the reaction mixture was filtered on a diatomaceous earth mat, and the filtrate was concentrated under vacuum to provide the title compound (10) (800 mg, 95%) as a colorless colloidal solid. LC-MS: m / z 366 [M+H] + ;t R = 1.85 min. LC-MS purity: 66.03%. 1 H NMR (400 MHz, 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).

[0857] Step 7: Ethyl 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)

[0858] Methyl 2-(4-(4-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (11, prepared according to Example 4, Intermediate 6) (400 mg, 0.94 mmol) in a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (11, prepared according to Example 4, Intermediate 6) (8 mL, 1:1) was added to a stirred solution in MeOH / DCM (10) with 518 mg, 1.41 mmol, followed by the addition of AcOH (3 drops), and the reaction mixture was stirred at RT for 4 h. Then NaCNBH3 (177 mg, 2.83 mmol) was added, and the reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (80 mL) and extracted with EtOAc (2 x 180 mL). The combined organic layers were then rinsed with brine (100 mL). The sample was washed with mL of the solution, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (24 g silica gel column) using DCM containing 10% MeOH to provide the title compound (12) (170 mg, 22%) as a white gelatinous solid. LC-MS: m / z 774.3 [M+H] + ;t R = 2.29 min. LC-MS purity: 94.98%.

[0859] 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)

[0860] Et3N (63 mg, 0.63 mmol) was added 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-pyrazol-1-yl)acetate (12) (170 mg, 0.21 mmol) in THF (2 mL), followed by (Boc)2O (71 mg, 0.32 mmol), and the reaction mixture was stirred at RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (4 g silica gel column) using DCM containing 10% MeOH to provide the title compound (13) (150 mg, 77%) as a grayish-white solid. LC-MS: m / z 774.3 [M-Boc+H] + ;t R = 3.17 min. LC-MS purity: 74.6%. 1 H NMR (400 MHz, 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).

[0861] 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)

[0862] Perkins catalyst (14) (29.4 mg, 0.06 mmol) was added 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-pyrazol-1-yl)acetate (13) (150 mg, 0.17 mmol) in EtOH / H2O (5:1, 2 mL), and the reaction mixture was stirred at 80 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (4 g silica gel column) using DCM containing 10% MeOH to provide the title compound (15) (70 mg, 40%) as a yellow liquid. LC-MS: m / z 792.3 [M-Boc+H] + ;t R = 2.95 min, LC-MS purity: 72.99%, 1 H NMR (400 MHz, 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 = 8.0 Hz, 3H), 1.91-1.88 (m,3H), 1.38 (s, 9H), 1.33 (s, 9H).

[0863] 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)

[0864] LiOH·H2O (11 mg, 0.269 mmol) was added 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-pyrazol-1-yl)acetate (15) (60 mg, 0.067 mmol) in THF / MeOH / H2O (1:1:1, 3 mL), and the reaction mixture was stirred at RT for 3 h. 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 EtOAc (2 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was ground with Et₂O (10 mL) to provide the title compound (16) (55 mg, 93%) as a grayish-white solid. LC-MS: m / z 876.4 [MH] + ;t R = 2.82 min. LC-MS purity: 95.39%, HPLC purity: 93.55%, t R = 10.15 min. 1 H NMR (400 MHz, 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).

[0865] Step 11: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)methyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (18)

[0866] HATU (6 mg, 0.018 mmol) was added 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-pyrazol-1-yl)acetic acid (16) (11 mg, 0.012 mmol) and dimethylamine hydrochloride (17) (4 mg, 0.050 mmol) in DMF (1 ml), followed by DIPEA (9 mg, 0.072 mmol), and the reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to provide the title compound (18) as a brown liquid (11 mg, 100%). LC-MS: m / z 805.4 [M-Boc+H] + ;t R = 2.849 min. LC-MS purity: 93.32%.

[0867] Step 12: 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)methyl)amino)cyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 14)

[0868] TFA (4 mg, 0.036 mmol) was added to a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)((1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-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), and the reaction mixture was stirred at rt for 2 h. 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 x 21.2 mm, 5.0 µm); mobile phase A: H₂O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min; gradient, time (min) / %B: 0 / 20, 10 / 50] to provide a trifluoroacetate of the title compound (Example 14) (3 mg, 30%) as a white solid. LC-MS: m / z 705.40 [M+H] + ;(t R = 1.852 min). LC-MS purity: 99.44%. HPLC purity: 99.64% (t). R = 6.482 min, at 210 nm). 1 H NMR (400 MHz, 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, 4H), 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).

[0869] Example 15.

[0870] Synthesis of 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxooxazolidine-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0871]

[0872] Step 1: Benzyl ((1r,4r)-4-(oxetane-3-ylamino)cyclohexyl)carbamate (3)

[0873] Oxycyclobutane-3-one (2) (870 mg, 12.08 mmol) was added to a stirred solution of benzyl ((1r,4r)-4-aminocyclohexyl)carbamate (1) (1.00 g, 4.02 mmol) in MeOH / DCM (20 mL) under RT, followed by the addition of AcOH (0.05 mL), and the reaction mixture was stirred under RT for 24 h. Then, NaCNBH3 (760 mg, 12.08 mmol) was added to the reaction mixture at 0 °C, and the reaction mixture was stirred under RT for 24 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to provide the title compound (3) (1.0 g, crude, 83%) as a brown viscous solid. LC-MS: m / z 305.20 [M+H] + ;t R = 1.32, LC-MS purity: 64.99%.

[0874] Step 2: tert-butyl((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(oxetane-3-yl)carbamate (4)

[0875] Et3N (1.57 mL, 11.49 mmol) was added to a stirred, cooled solution of benzyl((1r,4r)-4-(oxetane-3-ylamino)cyclohexyl)carbamate (3) (1.00 g, 3.28 mmol) in THF (20 mL) under RT, followed by the addition of (Boc)2O (1.80 g, 8.213 mmol). The reaction mixture was then stirred under RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was flushed with H2O. Dilute (50 mL) and extract with EtOAc (30 mL). Wash the combined extract with brine (50 mL), dry to anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the crude product by Combiflash chromatography (24 g silica gel column) with hexane containing 20% ​​EtOAc to provide the title compound (4) (0.7 g, 53%) as a grayish-white solid. LC-MS: m / z 405.25 [M+H] + ;t R = 1.68, LC-MS purity: 96.02%. 1 H NMR(400 MHz, DMSO-d6) = δ ppm 7.36-7.30 (m, 5H), 7.21 (d, J = 7.6 Hz, 1H), 4.99(s, 2H), 4.68 (s, 3H), 4.54 (s, 2H), 3.23-3.22 (m, 1H), 1.83-1.70 (m, 4H), 1.55-1.52 (m, 2H), 1.42 (s, 9H), 1.26-1.18 (m, 3H).

[0876] Step 3: tert-butyl ((1r,4r)-4-aminocyclohexyl)(oxetane-3-yl)carbamate (5)

[0877] 10% Pd / C (185 mg) was added to a stirred solution of tert-butyl((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(oxetane-3-yl)carbamate (4) (700 mg, 1.73 mmol) in MeOH (20 mL), and the reaction mixture was stirred at RT under hydrogen balloon pressure for 48 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with MeOH (20 mL) and filtered on a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude product obtained was milled with Et2O (20 mL) to provide the title compound (5) (450 mg, crude, 96%) as a brown solid. LC-MS: non-ionized.

[0878] Step 4: tert-butyl((1r,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetane-3-yl)carbamate (7)

[0879] 137 mg, 0.35 mmol, of tert-butyl((1r,4r)-4-aminocyclohexyl)(oxetane-3-yl)carbamate (5) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxylonitrile (6, prepared according to Example 4, intermediate 6) (150 mg, 0.35 mmol) in MeOH / DCM (1:1, 3 mL) under RT, followed by the addition of AcOH (10 mg, 0.17 mmol), and the reaction mixture was stirred under RT for 4 h. Then, NaCNBH3 (67 mg, 1.06 mmol) was added to the reaction mixture under RT, and the mixture was stirred for 12 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (4 g silica gel column) using DCM containing 2% to 3% MeOH to provide the title compound (7) (50 mg, 20%) as a colorless, gel-like solid. LC-MS: m / z 678 [M+H] + ;t R = 1.49, LC-MS purity: 47%.

[0880] 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)(oxetane-3-yl)carbamate (9)

[0881] Perkins catalyst (8) (10 mg, 0.02 mmol) was added 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)(oxetane-3-yl)carbamate (7) (7) (50 mg, 0.07 mmol) in EtOH / H2O (5:1, 3 mL), and the reaction mixture was stirred at 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (9) as a grayish-white solid (40 mg, crude, 96%). LC-MS: m / z 640.3 [M-tBu+H] + ;t R = 2.21 min. LC-MS purity: 46.13%.

[0882] Step 6: 2'-Chloro-6-fluoro-5'-(2-(((1r,4r)-4-(4-(hydroxymethyl)-2-oxooxazolidine-3-yl)cyclohexyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 15)

[0883] TFA (0.1 mL) was added 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)(oxetane-3-yl)carbamate (9) (40 mg, 0.05 mmol) in DCM (1 mL) at 0 °C, and the reaction mixture was then stirred at RT for 4 h. 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 x 21.2 x 5 µm); mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 mL / min; gradient: time (min) / %B: 0 / 10, 10 / 50] to provide the trifluoroacetate of the title compound (Example 15) (3 mg, 7%) as a grayish-white solid. LC-MS: m / z 640.3 [M+H] + ;t R= 2.02 min. LC-MS purity: 99.05%; HPLC purity: 98.18%, t R = 7.13 min. 1 H NMR (400 MHz, 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,1H), 5.04 (t, J = 4.8 Hz, 1H), 4.36 (t, J = 6.0 Hz, 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, 1H), 2.07 (m, 2H), 1.83 -1.75 (m, 3H), 1.64-1.60 (m, 1H), 1.44-1.41 (m, 2H).

[0884] Example 16.

[0885] 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

[0886]

[0887] Step 1: (1r,4r)-N1-methylcyclohexane-1,4-diamine (2)

[0888] LiAlH4 (443 mg, 11.6 mmol) was added to a stirred solution of tert-butyl(4-aminocyclohexyl)carbamate (1) (500 mg, 2.33 mmol) in THF (5.0 mL) at 0 °C, and the reaction mixture was then stirred at 70 °C for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to provide the title compound (2) (400 mg, crude, 130%) as an off-white solid. 1H NMR (400 MHz, 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).

[0889] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (4)

[0890] (1r,4r)-N1-methylcyclohexane-1,4-diamine (2) (60 mg,0.47 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (3, prepared according to Example 4, Intermediate 6) (200 mg, 0.47 mmol) in MeOH / DCM (1:1, 4 mL) under RT, followed by the addition of AcOH (2 drops), and the reaction mixture was stirred under RT for 4 h. Then, NaCNBH3 (59 mg, 0.94 mmol) was added, and the reaction mixture was stirred under RT for 20 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (4 g silica gel column) using DCM containing 20% ​​MeOH to provide the title compound (4) (35 mg, 13%) as a brown liquid. LC-MS: m / z 536.3 [MH] + ;t R =1.90 min. LC-MS purity: 92.84%. 1 H NMR (400 MHz, 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 = 4.0 Hz, 2H), 3.36 (m, 6H), 3.31 (s, 3H), 3.11 (s,3H), 1.95-1.91 (m, 3H), 1.23 (m, 4H).

[0891] 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)

[0892] Et3N (23 mg, 0.230 mmol) was added 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-carboxynitrile (4) (25 mg, 0.046 mmol) in THF (1 mL), followed by the addition of (Boc)2O (40 mg, 0.186 mmol), and the reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (2 x 20 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to provide the title compound (5) (19 mg, crude, 55%) as a brown liquid. LC-MS: m / z 536.3 [(M–Boc+H)] + ;t R = 3.37 min. LC-MS purity: 92.84%.

[0893] 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)

[0894] Perkins catalyst (6) (3 mg, 0.007 mmol) was added 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), and the reaction mixture was stirred at 80 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (7) as a yellow liquid (19 mg, crude, 100%). LC-MS: m / z 654.3 [M-Boc+H] + ;t R = 3.10 min. LC-MS purity: 59.23%.

[0895] 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)

[0896] TFA (8 mg, 0.075 mmol) was added 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) at 0 °C, and the reaction mixture was stirred at RT for 3 h. 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 x 21.2 mm; 5.0 μm); mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 mL / min; gradient time (min) / %B: 0 / 10, 2 / 10, 10 / 40] to provide the trifluoroacetate of the title compound (Example 16) (2.5 mg, 12%) as a grayish-white solid. LC-MS: m / z 554.3 [M+H] + ;t R= 1.80 min. LC-MS purity: 97.76%, t R = 6.58 min, HPLC purity: 95.28%, 1 HNMR (400 MHz, 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).

[0897] Example 17.

[0898] Synthesis of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidone-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0899]

[0900] Step 1: 2'-Chloro-6-fluoro-5'-(hydroxy(phenyl)methyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (2)

[0901] NaBH4 (41 mg, 1.09 mmol) was added to a stirred, cooled solution of 5'-benzoyl-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (1, prepared according to Example 4) (150 mg, 0.365 mmol) in MeOH (4 mL) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction was quenched with an aqueous solution of NH4Cl (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product obtained was purified by Combiflash chromatography (4 g silica gel column) using hexane containing 20% ​​EtOAc to provide the title compound (2) (150 mg, 98%) as a colorless liquid. LC-MS: m / z 394.1 [M-OH+H] + ;t R= 2.59 min. 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).

[0902] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrolo-2-yl)methyl)-[1,1'-biphenyl]-2-carboxynitrile (4)

[0903] Add 1H-pyrrole (32 mg, 0.485 mmol) to a stirred solution of 2'-chloro-6-fluoro-5'-(hydroxy(phenyl)methyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxynitrile (2) (100 mg, 0.242 mmol) in a sealed 20 mL tube, followed by the addition of BF3·OEt2 (34 mg, 0.242 mmol). The reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with DCM (2 x 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 (4 g silica gel column) using hexane containing 30% EtOAc to provide the title compound (4) (70 mg, 90%) as a colorless liquid. LC-MS: m / z 461.1 [M+H] + ;t R = 2.78 min. LC-MS purity: 95.53%.

[0904] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrolo-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide (10)

[0905] Perkins catalyst (5) (20 mg, 0.045 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrolo-2-yl)methyl)-[1,1'-biphenyl]-2-carboxynitrile (4) (70 mg, 0.152 mmol) in EtOH / H2O (5:1, 5 mL) under RT, and the reaction mixture was heated to 80 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with 10% MeOH / DCM (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (6) (70 mg, crude, 97%) as a yellow liquid. LC-MS: m / z 479.1, t R = 2.61 min. LC-MS purity: 76.45%.

[0906] Step 4: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidone-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 17)

[0907] One drop of concentrated HCl was added to a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(1H-pyrrolo-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide (6) (70 mg, 0.146 mmol) in EtOH (3.00 mL) under RT, followed by the addition of PtO2 (33 mg, 0.146 mmol). The reaction mixture was stirred under RT for 16 h under hydrogen atmosphere. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with 10% MeOH / DCM (30 mL), filtered through a diatomaceous earth mat, and concentrated under vacuum. The crude compound was purified by Combiflash chromatography (4 g silica gel column) using DCM containing 15% MeOH to provide an impure brown solid (17), which was further purified by HPLC [column: Luna OMEGAC18 (250 x 21.2 mm; 5 μm); mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; gradient time (min) / %B: 0 / 35, 10 / 50; flow rate: 15 mL / min] to provide a trifluoroacetate (Example 17) (7 mg, 11%) of stereoisomer 1 (17a) of the title compound, as a grayish-white solid. LC-MS: m / z 483.1 [M+H] + ;t R= 1.96 min. LC-MS purity: 85.72%, t R = 6.95 min; 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 (17b) of the title compound (Example 17): yield = 7 mg, 11%. LC-MS: m / z 483.1 [M+H] + ;t R = 2.10 min. LC-MS purity: 99.44%, t R = 7.14 min; HPLC purity = 86.43%, 1 H NMR (400 MHz, 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).

[0908] Example 18.

[0909] 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

[0910]

[0911] Step 1: 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)

[0912] DIPEA (1.9 mL, 11.34 mmol) was added to a stirred solution of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (2) (2.4 g, 5.67 mmol) in MeOH / DCM (1:1, 25 mL) under RT, and the reaction mixture was stirred for 1 h. 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-1-phenylethyl)-[1,1'-biphenyl]-2-carboxynitrile (1, prepared according to Example 4, Intermediate 6) (2.4 g, 5.671 mmol) was added to the reaction mixture under RT, followed by AcOH (0.5 mL), and the mixture was stirred for 4 h. NaCNBH3 (0.71 g, 11.34 mmol) was then added to the reaction mixture, and the mixture was stirred under RT for 12 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (24 g silica gel column) using DCM containing 3% to 5% MeOH to provide the title compound (3) (0.6 g, 19%) as a colorless, colloidal liquid. LC-MS: m / z 565.3 [M+H] + ;t R = 2.19 min, LC-MS purity: 85.76%.

[0913] 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)

[0914] Et3N (0.42 mL, 3.189 mmol) was added 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) at 0 °C, followed by the addition of (Boc)2O (348 mg, 1.59 mmol), and the reaction mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude product was purified by Combiflash chromatography (24 g silica gel column) using DCM containing 3% to 5% MeOH to provide the title compound (4) (500 mg, 70%) as a grayish-white solid. 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 (400 MHz, 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).

[0915] 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)

[0916] Perkins catalyst (5) (97 mg, 0.225 mmol) was added 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), and the reaction mixture was stirred at 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The obtained crude product was purified by Combiflash chromatography (12 g silica gel column) using DCM containing 3% to 5% MeOH to provide the title compound (6) as a grayish-white solid (500 mg, 64%) from two batches. LC-MS: m / z 583.3 [M-Boc+H] + ;t R = 2.92 min. 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).

[0917] 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)

[0918] LiOH·H2O (64.5 mg, 1.537 mmol) was added 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), and the reaction mixture was stirred at RT for 5 h. 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, the precipitated solid was filtered, and dried under reduced pressure. The crude product was ground with hexane (20 mL) to provide the title compound (7) (420 mg, 85%) as a grayish-white solid from two batches. LC-MS: m / z 667.3 [MH] + ;t R = 2.66 min. LC-MS purity: 74.87%, HPLC purity: 74.18%. 1 H NMR (400 MHz, 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, 4H), 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).

[0919] 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)

[0920] TFA (185 mg, 1.88 mmol) was added 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) (7) (420 mg, 0.628 mmol) in DCM (5 mL), and the reaction mixture was then stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude product was milled with Et2O (15 mL) to provide the trifluoroacetate of the title compound (Example 18) (365 mg, 67%) as an off-white solid. LC-MS: m / z 569.25; [M+H] + (t R = 1.47 min), LC-MS purity: 96.82%. HPLC purity: t R =7.15 min (78.53%). 1 H NMR (400 MHz, DMSO-d6) = δ ppm 12.23 (bs, 1H), 8.34 (bs,2H), 7.60-7.10 (m, 12H), 4.37 (t, J = 8.0 Hz, 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).

[0921] Synthesis and chiral purification of Example 18

[0922]

[0923] The mixture of 3.0 g stereoisomers of compound (7) was scaled up by performing the same reaction procedure, and 3.0 g of compound (7) was purified by: chiral preparative HPLC (first preparative purification: column: Chiralpak) IG (250 x 10; 5 µm); Mobile phase A: hexane containing 0.1% DEA, Mobile phase B: EtOH (100%); Flow rate: 10 mL / min, Isocratic ratio: 80(A):20(B); Dilution: IPA / DCM (90:10); Second preparative purification: Column: Chiralpak IA (250 x 20; 5 µm); Mobile phase A: hexane containing 0.1% TFA, Mobile phase B: IPA / DCM (90:10); Flow rate: 15 mL / min, Isocratic ratio: 85 (A):15 (B); Dilution: THF (100%) to provide four stereoisomers of compound (7). The first step of chiral preparative purification of compound 7 provided a mixture of 720 mg of compounds 7a and 7b and a mixture of 820 mg of compounds 7c and 7d, respectively. The second step of chiral preparative purification provided 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%.

[0924] By following step 5 in the synthesis of Example 18, the four stereoisomers 7a to 7d of the compound were each independently subjected to Boc deprotection using TFA, so as to provide the four stereoisomers of Examples 18a to 18d with enantiomeric excesses of >90% to 97%. The absolute stereochemistry of the stereoisomers of Examples 18a to 18d has not been determined.

[0925] Example 18a (stereoisomer 1): 155 mg; LC-MS: m / z = 569.3 [M+H] + HPLC purity: 98.25% (210 nm); chiral HPLC purity: 98.03%; optical purity: 96.06% ee. 1 H NMR (400 MHz, DMSO-d6) δppm 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 = 8.0 Hz, 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).

[0926] Example 18b (stereoisomer 2): 50 mg for Boc deprotection; 30 mg; LC-MS: m / z = 569.1 [M+H] +HPLC purity: 96.11% (210 nm); chiral 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 = 8.0 Hz, 1H), 4.29-4.22(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).

[0927] Example 18c (stereoisomer 3): 28 mg; LC-MS: m / z = 569.0 [M+H] + HPLC purity: 98.20% (210 nm); chiral HPLC purity: 95.31%; optical purity: 90.62% ee. 1 H NMR (400 MHz, DMSO-d6) δppm 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 = 8.0 Hz, 1H), 4.28-4.21 (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).

[0928] Example 18d (stereoisomer 4): 54 mg; LC-MS: m / z = 569.1 [M+H] + HPLC purity: 98.25% (210 nm); chiral HPLC purity: 97.07%; optical purity: 94.14% ee. 1H NMR (400 MHz, DMSO-d6) δppm 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 = 8.0 Hz, 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).

[0929] Example 19.

[0930] 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide

[0931]

[0932] Step 1: 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

[0933] K3PO4 (609 mg, 2.745 mmol), N-XantPhos (53 mg, 0.091 mmol), and Pd2(dba)3 (42 mg, 0.045 mmol) were added 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-dioxacyclopentaborane-2-yl)phenyl)-2-phenylethyl)carbamate (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) in toluene / H2O (5:1, 12.0 mL) under RT, and the reaction mixture was degassed with N2 for 5 min. The resulting reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 20% ​​EtOAc to provide the title compound (3) (400 mg, 60%) as a grayish-white solid. LC-MS: m / z 564.2 [M-Boc+H] + ;t R = 3.13 min. LC-MS purity: 96.37%.

[0934] 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)

[0935] Perkins catalyst (4) (20 mg, 0.045 mmol) was added 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), and the reaction mixture was then heated to 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with a saline solution (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (5) (75 mg, 73%) as an off-white solid. LC-MS: m / z 584.2 [M-Boc+H] + ;t R = 2.91 min. LC-MS purity: 95.92%. 1 HNMR (400 MHz, DMSO-d6) = δppm 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).

[0936] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5,6-difluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 19)

[0937] TFA (0.1 mL) was added 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) at 0 °C, and the reaction mixture was then stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was ground with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 x 21.2 mm; 5 μm); mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; flow rate: 15 ml / min; gradient time (min) / %B: 0 / 20, 2 / 20, 10 / 50] to provide the trifluoroacetate of the title compound (Example 19) (55 mg, 92%) as a grayish-white solid. LC-MS: m / z 484.2 [M+H] + ;t R = 1.81 min. LC-MS purity: 99.68%. HPLC: 98.42%, t R = 6.59 min. 1 HNMR (400 MHz, DMSO-d6 ) = δppm 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).

[0938] Example 20.

[0939] Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0940]

[0941] 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)

[0942] NaH (11 mg, 0.30 mmol) was added 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) at 0 °C, and the mixture was stirred at RT for 15 min. 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 intermediate 3, Example 19) (60 mg, 0.150 mmol) was added to the reaction mixture at 0 °C, and the mixture was stirred for 2 h. 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 obtained crude product was ground with hexane (20 mL) to provide the title compound (3) as a grayish-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 (400 MHz, 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, 2H), 7.21-7.17 (m, 2H), 6.64-6.62 (m, 1H), 4.66 (d, J = 3.2 Hz, 1H), 4.46-4.38 (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).

[0943] 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)

[0944] Perkins catalyst (4) (10 mg, 0.022 mmol) was added 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), and the reaction mixture was stirred at 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to provide the title compound (5) (60 mg, 97%) as a grayish-white solid, which was used in the next step without any further purification.

[0945] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-hydroxyethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0946] TFA (0.1 mL) was added 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), and the reaction mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was ground with diethyl ether to provide a trifluoroacetate of the title compound (Example 20) (45 mg, 94%) as an off-white solid. LC-MS: m / z 526.2 [M+H] + ;t R = 1.69 min. LC-MS purity: 99.63%, HPLC purity: 95.51%, t R= 5.35 minutes. 1H NMR (400 MHz, 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).

[0947] Example 21.

[0948] Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-methoxy-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0949]

[0950] Step 1: 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 (3)

[0951] NaOMe (40 mg, 0.751 mmol) was added 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 (1, prepared according to intermediate 3, Example 19) (100 mg, 0.150 mmol) in MeOH (1.0 mL) at 0 °C, and the reaction mixture was stirred at RT for 24 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with H2O (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 20% ​​EtOAc to provide the title compound (3) (60 mg, 59%) as a grayish-white solid. LC-MS: m / z 578.3 [M-Boc+H] + ;tR = 3.23, LC-MS purity: 99.46%. 1H NMR (400 MHz, DMSO-d6) = δ ppm7.86-7.83 (m, 1H), 7.58-7.42 (m, 3H), 7.36-7.34 (m, 2H), 7.31-7.25 (m, 2 H),7.21-7.17 (m, 1H), 4.38 (bs, 1H), 3.98 (d, J = 3.6 Hz, 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).

[0952] 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)

[0953] Perkins catalyst (11 mg, 0.024 mmol) was added 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), and the reaction mixture was heated to 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (5) (60 mg, 98%) as an off-white solid. LC-MS: m / z 596.3 [M-Boc+H] + ;t R = 2.85 min. LC-MS purity: 90.72%. 1H NMR (400 MHz, DMSO-d6) = δ ppm7.62-7.50 (m, 2H), 7.43-7.38 (m, 2H), 7.31-7.13 (m, 9H), 4.45-4.20 (m, 1H),3.90 (d, J = 3.6 Hz, 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).

[0954] 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)

[0955] TFA (0.1 mL) was added 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), and the reaction mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was milled with diethyl ether to provide the trifluoroacetate of the title compound (Example 21) (48 mg, 90%) as an off-white solid. LC-MS: m / z 496.2 [M+H] + ;t R = 1.79 min. LC-MS purity: 99.07%. HPLC: 98.04%, t R =6.55 min. HNMR (400 MHz, 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).

[0956] Example 22.

[0957] Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-3-yloxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[0958]

[0959] Step 1: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyridin-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3)

[0960] NaH (11 mg, 0.30 mmol) was added to a stirred solution of pyridine-3-ol (2) (10.0 mg, 0.105 mmol) in DMF (2.0 mL) at 0 °C, and the reaction mixture was stirred at RT for 15 min. 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 intermediate 3, Example 19) (100 mg, 0.150 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (10 mL), the precipitated solid was filtered through a Buchner funnel, and dried under vacuum. The crude product was ground with hexane containing 10% Et₂O to provide the title compound (3) as a grayish-white solid (60 mg, 54%). LC-MS: m / z 741.3 [MH] + ;t R = 2.06 min, LC-MS purity: 87.01%. 1 HNMR (400 MHz, DMSO-d6 ) = δ ppm 8.57 -8.50 (m, 1H), 7.86 (t, J = 7.2 Hz, 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, 1H), 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).

[0961] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyridin-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5)

[0962] Perkins catalyst (11 mg, 0.024 mmol) was added to a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyridin-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (60 mg, 0.081 mmol) in EtOH / H2O (5:1, 3 mL). The reaction mixture was then heated to 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (5) (60 mg, crude, 98%) as an off-white solid. LC-MS: m / z 759.3 [M+H] + ;t R = 2.97 min. LC-MS purity: 74.63%.

[0963] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-3-yloxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 22)

[0964] TFA (0.1 mL) was added to a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyridin-3-yloxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.079 mmol) in DCM (1 mL) at 0 °C, and the reaction mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was ground with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 x 21.2 mm; 5 μm); dilution: MeCN + H2O + THF; mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10, 10 / 50; flow rate: 15 mL / min] to provide the trifluoroacetate of the title compound (Example 22) (12 mg, 23%) as a grayish-white solid. 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(400 MHz, 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 = 8 Hz, 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).

[0965] Example 23.

[0966] 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

[0967]

[0968] Step 1: 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

[0969] NaH (11 mg, 0.30 mmol) was added to a stirred solution of (R)-(tetrahydrofuran-2-yl)methanol (2) (16.0 mg, 0.105 mmol) in DMF (2.0 mL) at 0 °C, and the reaction mixture was stirred at RT for 15 min. 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 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 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold H2O (10 mL), the precipitated solid was filtered through a Buchner funnel, and dried under vacuum. The crude product was ground with hexane (20 mL) containing 10% Et₂O to provide the title compound (3) (60 mg, 53%) as a grayish-white solid. 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).

[0970] 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)

[0971] Perkins catalyst (4) (11 mg, 0.024 mmol) was added 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) (3) in EtOH / H2O (5:1, 3 mL), and the reaction mixture was heated to 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (5) (60 mg, 97%) as a grayish-white solid. LC-MS: m / z 666.3 [M-Boc+H] + ;t R = 2.90 min. LC-MS purity: 86.84%.

[0972] 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)

[0973] TFA (0.1 mL) was added 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) at 0 °C, and the reaction mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was ground with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 x 21.2 x 5 μm); dilution: MeCN + H2O + THF; mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10, 10 / 50; flow rate: 15 mL / min] to provide the trifluoroacetate of the title compound (Example 23) (32 mg, 53%) as a grayish-white solid. LC-MS: m / z 566.3 [M+H] + ;t R = 1.84 min. LC-MS purity: 99.63%; HPLC purity: 99.65%, t R = 6.61 min. 1 HNMR (400 MHz, 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).

[0974] Example 24.

[0975] 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

[0976]

[0977] Step 1: (S)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzonitrile (3)

[0978] (S)-(tetrahydrofuran-2-yl)methanol (2) (2.108 g, 20.64 mmol) was slowly added to a stirred solution of NaH (60% in mineral oil) (1.00 g, 27.5 mmol) in DMF (40 mL) at 0 °C, and the reaction mixture was stirred for 0.5 h. DMF (10 mL) containing 2-bromo-3,4-difluorobenzonitrile (1) (5.00 g, 22.94 mmol) was added to this reaction mixture at 0 °C, and the reaction mixture was stirred at RT for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (150 mL). The obtained crude product was filtered and dried under vacuum to provide the title compound (3) (4.00 g, 58.1%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (dd, J = 1.6, 8.8 Hz,1H), 7.40 (t, J = 8.0 Hz, 1H), 4.23-4.13 (m, 3H), 3.77 – 3.74 (m, 1H), 3.70 –3.67 (m, 1H), 1.99 (m, 1H), 1.87 – 1.82 (m, 2H), 1.69 – 1.64 (m, 1H).

[0979] Step 2: 5'-benzoyl-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxynitrile (5)

[0980] Under RT, (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-dioxaneborane-2-yl)phenyl)(phenyl)methyl ketone (4, prepared according to a similar reaction procedure for intermediate 3, Example 2) (5.99 g) K3PO4 (7.42 g, 35.0 mmol) was added to a stirred solution of toluene / water (50 mL, 9:1), and the reaction mixture was degassed with N2 for 10 min. N-XantPhos (643 mg, 1.166 mmol) and Pd2(dba)3 (534 mg, 0.583 mmol) were added to this solution at RT, and the mixture was degassed with N2 for 5 min. The resulting reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product obtained was purified by Combiflash chromatography (80 g silica gel column) using hexane containing 0% to 20% EtOAc to provide the title compound (5) (3.00 g, 59%) as a yellow viscous solid. LC-MS: m / z 436.1 [M+H] + . 1 H NMR (400 MHz, 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).

[0981] Step 3: 2'-Chloro-6-fluoro-5'-(2-phenylethyleneoxy-2-yl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxynitrile (6)

[0982] NaH (496 mg, 20.65 mmol) was added to a stirred solution of trimethylsulfonium iodide (2.81 g, 13.77 mmol) in THF / DMSO (40 mL, 1:1) at 0 °C, and the reaction mixture was stirred at RT for 2 h. 5'-benzoyl-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxynitrile (5) (3.00 g, 6.88 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 18 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (150 mL) and extracted with EtOAc (2 x 120 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to provide the title compound (6) (3.00 g, 97%) as a yellow liquid, which was used in the next reaction without further purification.

[0983] Step 4: 2'-Chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxynitrile (7)

[0984] BF3·Et2O (1.26 mL, 10.0 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-phenylethyleneoxy-2-yl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxynitrile (6) (1.50 g, 3.33 mmol) in Et2O (15 mL) at 0 °C, and the resulting reaction mixture was stirred at 0 °C for 10 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with Et2O (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to provide the title compound (7) (1.50 g) as a yellow liquid, which was used in the next reaction without further purification. LC-MS: m / z 448.1 [MH] + .

[0985] Step 5: tert-butyl((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 (9)

[0986] Tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (8) (1.429 g, 6.67 mmol) was added to a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-1-phenylethyl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'-biphenyl]-2-carboxynitrile (7) (1.50 g, 3.33 mmol) in MeOH / DCM (30 mL, 1:1) under RT, followed by the addition of AcOH (0.019 mL, 0.33 mmol). After stirring the reaction mixture under RT for 4 h, NaCNBH3 (629 mg, 10.0 mmol) was added, and the reaction mixture was stirred under RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 120 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 40% EtOAc and then DCM containing 20% ​​MeOH to provide the title compound (9) (1.20 g, 55.5%) as a colorless, gelatinous solid. LC-MS: m / z 648.3 [M+H] + .

[0987] Step 6: tert-butyl((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 (10)

[0988] Et3N (0.77 mL, 5.55 mmol) and (Boc)2O (0.64 mL, 2.78 mmol) were added to a stirred solution of tert-butyl((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 (9) (1.20 g, 1.851 mmol) in DCM (20 mL) at 0 °C, and the resulting reaction mixture was stirred at RT for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (80 mL) and extracted with EtOAc (2 x 90 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Combiflash chromatography (24 g silica gel column) using hexane containing 40% EtOAc to provide the title compound (10) (1.20 g, 86%) as a colorless, colloidal solid. LC-MS: m / z 592.3 [M-Boc-tBu+H] + .

[0989] Step 7: tert-butyl((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 (11)

[0990] Perkins catalyst (275 mg, 0.641 mmol) was added to a stirred solution of tert-butyl((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 (10) (1.20 g, 1.604 mmol) in EtOH / water (20 mL, 4:1) under RT, and the resulting reaction mixture was stirred at 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 0% to 100% EtOAc to provide the title compound (11) (1.10 g, 89%) as a grayish-white gelatinous solid. LC-MS: m / z 766.5 [M+H] + ; 1H NMR (400 MHz, 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, 1H), 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).

[0991] 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)

[0992] TFA (0.016 mL, 0.202 mmol) was added to a stirred solution of tert-butyl((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 (11) (50 mg, 0.067 mmol) in DCM (1 mL), and the resulting reaction mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The obtained crude product was washed with Et2O (10 mL) and pentane (10 mL), dried under vacuum, and lyophilized to provide the title compound (Example 24) (30 mg, 82%) as an off-white solid. LC-MS: m / z 566.5 [M+H] + ; 1H NMR (400 MHz, 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), 4.37 (t, J = 7.6 Hz,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).

[0993] Synthesis and chiral purification of four stereoisomers in Example 24:

[0994]

[0995] The stereoisomer mixture of compound (11, 1.20 g) was purified by the following chiral SFC (column: LuxCellulose-4, 4.4 mm x 250 mm x 21.2 mm; 5 µm; mobile phase A: CO2, and mobile phase B: IPA / MeOH (1:1) containing 0.1% HCOOH; flow rate: 50 mL; isocratic coefficient: 75(A):25(B); diluent: EtOH / DCM (1:1), 18 mL; injection volume: 0.2 mL; run time: 27 min) to provide all four stereoisomers (11a to 11d) of compound 11. Compound 11a: 135 mg; chiral HPLC purity: 99.82%; Compound 11b: 230 mg; chiral HPLC purity: 96.67%; Compound 11c: 200 mg; chiral HPLC purity: 95.11%; Compound 11d: 190 mg; chiral HPLC purity: 95.06%.

[0996] By following step 8 of the process in Example 24, the four stereoisomers 11a to 11d of the compound were each independently subjected to Boc deprotection using TFA, so as to provide the four stereoisomers of Examples 24a to 24d with enantiomeric excesses of >87% to 98%. The absolute stereochemistry of the stereoisomers of Examples 24a to 24d has not been determined.

[0997] 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. 1H NMR (400 MHz, 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 = 7.6 Hz, 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).

[0998] Example 24b (stereoisomer 2): 160 mg; LC-MS: m / z 566.3 [M+H] + HPLC purity: 98.22%; chiral HPLC purity: 98.0%; optical purity: 96% ee. 1 H NMR (400 MHz, 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 = 7.6 Hz, 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).

[0999] Example 24c (stereoisomer 3): 130 mg; LC-MS: m / z 566.3 [M+H] + HPLC purity: 97.1%; chiral HPLC purity: 99.37%; optical purity: 98.74% ee. 1H NMR (400 MHz, 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 = 7.6 Hz, 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).

[1000] Example 24d (stereoisomer 4): 190 mg; LC-MS: m / z 566.3 [M+H] + HPLC purity: 99.08%; chiral HPLC purity: 93.88%; optical purity: 87.76% ee. 1 H NMR (400 MHz, 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 = 7.6 Hz, 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).

[1001] Step 9: (3-Bromo-4-chlorophenyl)(phenyl)methyl ketone (13)

[1002] 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 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The obtained crude product was dissolved in benzene (80 mL), and AlCl3 (13.5 g, 101.91 mmol) was added partically to the reaction mixture at 0 °C. The resulting reaction mixture was stirred at 80 °C for 6 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), alkalized with a saturated aqueous solution of NaHCO3 (50 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The obtained crude product was ground with pentane (100 mL) to provide the title compound (13) (8.78 g, 87%) as a grayish-white solid. 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).

[1003] Step 10: (4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)(phenyl)methyl ketone (4)

[1004] Under RT, (3-bromo-4-chlorophenyl)(phenyl)methyl ketone (13) (9.0) A stirred solution of bis(pinacol)diboron (11.6 g, 45.7 mmol) and KOAc (8.97 g, 91.0 mmol) in 1,4-dioxane (90 mL) was added, followed by degassing with N2 for 10 min. Pd(dppf)Cl2·DCM (2.48 g, 3.05 mmol) was added to the reaction mixture under RT, followed by degassing with N2 for 5 min. The resulting reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (300 mL) and treated with EtOAc. Extraction (2 x 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product obtained was purified by Combiflash chromatography (80 g silica gel column) using hexane containing 0% to 10% EtOAc to provide the title compound (4) (10 g, 96%) as a brown colloidal liquid. LC-MS: m / z = 343.2 [M+H]+ .

[1005] Example 25.

[1006] Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[1007]

[1008] Step 1: 2-Bromo-3-fluoro-4-(pyridin-2-ylmethoxy)benzonitrile (3)

[1009] NaH (0.044 g, 1.100 mmol) was added to a stirred, cooled (0 °C) solution of pyridin-2-ylmethanol (2) (0.080 g, 0.733 mmol) in DMF (8.00 mL) at RT and stirred for 15 min. The mixture was then cooled again to 0 °C, followed by the addition of 2 mL of DMF containing 2-bromo-3,4-difluorobenzonitrile (1) (0.200 g, 0.917 mmol). The reaction mixture was stirred at the same temperature for 2 h. After the reaction was complete (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 provide the title compound (3) (0.22 g, 78%) as a grayish-white solid. LC-MS: No ionization; 1 H NMR (400 MHz, DMSO-d6) = δ ppm 8.60 (s, 1H), 7.89-7.80 (m, 2H), 7.55-7.39 (m, 3H), 5.37 (s, 2H).

[1010] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5)

[1011] K3PO4 (101 mg, 0.456 mmol), n-XantPhos (9 mg, 0.015 mmol) and Pd2(dba)3 (7 mg, 0.0076 mmol) were added 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-dioxacyclopentaborane-2-yl)phenyl)-2-phenylethyl)carbamate (4, prepared according to intermediate 6, Example 10) (100 mg, 0.152 mmol) and 2-bromo-3-fluoro-4-(pyridin-2-ylmethoxy)benzonitrile (56.0 mg, 0.183 mmol) in toluene / H2O (6:1, 3.5 mL) at RT, and the reaction mixture was degassed with argon for 5 min. The reaction mixture was then heated to 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H₂O (30 mL) and the organics were extracted with EtOAc (2 x 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 hexane containing 60% EtOAc to provide the title compound (5) (50 mg, 43%) as a grayish-white solid. LC-MS: m / z 753.4 [MH) + ;t R = 3.23 min. LC-MS purity: 97.25%. 1 H NMR (400 MHz, 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).

[1012] Step 3: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (7)

[1013] Perkins catalyst (6) (9 mg, 0.019 mmol) was added to a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (50 mg, 0.066 mmol) in EtOH / H2O (3 ml), and the reaction mixture was then heated to 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with aqueous brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (7) (50 mg, 97%) as an off-white solid. LC-MS: m / z 773.55 [M+H] + ;t R = 1.88 min. LC-MS purity: 92.80%. 1 H NMR (400 MHz, 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 = 8.0 Hz, 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).

[1014] Step 4: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 25)

[1015] TFA (0.1 mL) was added to a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (7) (50 mg, 0.064 mmol) in DCM (1 mL), and the reaction mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was milled with Et2O to provide the trifluoroacetate of the title compound (Example 25) (45 mg, 99%) as an off-white solid. LC-MS: m / z [M+H] + ;t R = 3.08 min. LC-MS purity: 97.29%, t R = 6.33 min HPLC purity: 96.32%. 1 H NMR(400 MHz, 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).

[1016] Example 26.

[1017] Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[1018]

[1019] Step 1: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3)

[1020] NaH (11 mg, 0.30 mmol) was added to a stirred solution of pyrimidin-2-ylmethanol (2) (16.0 mg, 0.105 mmol) in DMF (1.0 mL) at 0 °C, and stirred at RT for 15 min. 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 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 h. After the reaction was complete (monitored by TLC), the reaction mixture was rinsed with ice-cold H2O (10 mL). The solid was quenched in 20 mL, filtered through a Buchner funnel and dried under vacuum. The crude product was ground with hexane (20 mL) to provide the title compound (3) (60 mg, 53%) as a grayish-white solid. LC-MS: non-ionized. 1 HNMR (400MHz, DMSO-d6) = δ ppm 8.86 (t, J = 4.8 HZ, 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).

[1021] Step 2: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5)

[1022] Perkins catalyst (4) (12 mg, 0.027 mmol) was added to a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (70 mg, 0.092 mmol) in EtOH / H2O (5:1, 3 mL), and the reaction mixture was then heated to 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (5) (60 mg, crude, 84%) as an off-white solid. LC-MS: m / z 674.3 [M-Boc+H] + ;t R = 2.89 min. LC-MS purity: 59.2%. 1 HNMR (400 MHz, DMSO-d6) = δppm 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).

[1023] Step 3: 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 26)

[1024] TFA (0.1 mL) was added to a stirred solution of tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.077 mmol) in DCM (1 mL) at 0 °C, and the reaction mixture was then stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was ground with diethyl ether and purified by preparative HPLC [column: Kinetex C18 (250 x 21.2; 5 μm); dilution: MeCN + H2O + THF; mobile phase A: H2O containing 0.1% TFA, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10, 10 / 50; flow rate: 15 mL / min] to provide the trifluoroacetate of the title compound (Example 26) (16 mg, 32%) as a grayish-white solid. LC-MS: m / z 574.2 [M+H] + ;t R = 1.78 min. 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 = 4.8 Hz, 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 = 7.6 Hz, 1H), 3.79-3.68 (bs, 2H), 3.07-2.93 (m, 2H), 2.08 (s, 3H), 1.96 -1.94 (bs, 2H), 1.43-1.23 (m, 4H).

[1025] Example 27.

[1026] Synthesis of 5-(2-((1-acetylazetane-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[1027]

[1028] Step 1: Benzyl 3-(2-ethoxy-2-oxoethoxy)azacyclobutane-1-carboxylate (3)

[1029] NaH (0.21 g, 5.314 mmol) was added to a stirred solution of benzyl 3-hydroxyazacyclobutane-1-carboxylate (1) (1 g, 4.83 mmol) in THF (10 mL) at 0 °C and stirred for 30 min at the same temperature. Then, ethyl bromoacetate (2) (0.8 g, 4.830 mmol) was added at 0 °C and stirred at RT for 1.5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with aqueous brine, dried over anhydrous Na2SO4, and concentrated under vacuum to provide the title compound (3) (0.8 g, 57%) as an off-white solid. 1 H NMR (400 MHz, 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 = 7.2 Hz, 3H).

[1030] Step 2: Benzyl 3-(2-hydroxyethoxy)azacyclobutane-1-carboxylate (4)

[1031] LiAlH4 (124 mg, 3.275 mmol) was added to a stirred solution of benzyl 3-(2-ethoxy-2-oxoethoxy)azacyclobutane-1-carboxylate (3) (800 mg, 2.729 mmol) in THF (10 mL) at 0 °C, and the mixture was stirred at RT for 3 h. After the reaction was complete (monitored by TLC), the solution was diluted with saturated NH4Cl aqueous solution (10 mL) and treated with EtOAc. Extraction (50 mL). The combined organic layers were washed with aqueous brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 50% EtOAc to provide the title compound (4) (600 mg, 88%) as a grayish-white solid. LC-MS: m / z 252.2 [M+H] + tR = 2.04, LC-MS purity: 98.80%.

[1032] Step 3: Benzyl 3-(2-(3-bromo-4-cyano-2-fluorophenoxy)ethoxy)azacyclobutane-1-carboxylate (6)

[1033] NaH (143 mg, 3.585 mmol) was added to a stirred solution of benzyl 3-(2-hydroxyethoxy)azacyclobutane-1-carboxylate (4) (600 mg, 2.390 mmol) in DMF (15 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 min. Subsequently, DMF (5 mL) containing 2-bromo-3,4-difluorobenzonitrile (5) (622 mg, 2.868 mmol) was added at 0 °C, and the mixture was stirred at the same temperature for 1.5 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with aqueous brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude compound was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 50% EtOAc to provide the title compound (6) (600 mg, 66%) as a brown liquid. LC-MS: m / z 490.0 [M+MeCN+H] + ;t R = 2.74, LC-MS purity: 88.22%. 1 H NMR (400 MHz, 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).

[1034] 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)azacyclobutane-1-carboxylate (8)

[1035] K3PO4 (850 mg, 4.017 mmol) and Pd2dba3 (62 mg, 0.066 mmol) and N-XantPhos (73 mg, 73 mmol) were added to a stirred solution of benzyl 3-(2-(3-bromo-4-cyano-2-fluorophenoxy)ethoxy)azacyclobutane-1-carbamate (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-dioxacyclopentaborane-2-yl)phenyl)-2-phenylethyl)carbamate (7, prepared according to Example 10) (800 mg, 1.339 mmol) in toluene / H2O (9:1, 12 mL) under an argon atmosphere. The reaction mixture was heated to 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 90% EtOAc to provide the title compound (8) (400 mg, 33%) as a viscous brown liquid. LC-MS: m / z 797.3 [M-Boc+H] + ;t R =3.25, LC-MS purity: 48.66%.

[1036] 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)azacyclobutane-1-carboxylate (10)

[1037] Perkins catalyst (9) (76 mg, 0.178 mmol) was added 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)azacyclobutane-1-carboxylate (8) (400 mg, 0.446 mmol) in EtOH / H2O (9:1, 8 mL), and the reaction was heated to 90 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with aqueous brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (12 g silica gel column) using hexane containing 90% EtOAc to provide the title compound (10) (300 mg, 75%) as a yellow liquid. LC-MS: m / z 815.3 [M-Boc+H] + ;t R = 3.08, LC-MS purity: 92.31%. 1 H NMR (400 MHz, DMSO-d6) = δppm 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 = 8.0 Hz, 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).

[1038] Step 6: tert-butyl(2-(3'-(2-(azacyclobutane-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)

[1039] 10% Pd / C (10 mg) was added to a stirred solution of 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)azacyclobutane-1-carboxylate (10) (40 mg, 0.043 mmol) in THF / MeOH (1:1, 1 mL), and the mixture was stirred at RT for 3 h under H2 atmosphere. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth filter bed, and the filtrate was concentrated under vacuum to provide the title compound (11) (40 mg, crude, 110%) as an off-white solid. LC-MS: m / z 781.3; [M+H] + , t R = 2.30 min. LC-MS purity: 46.17%.

[1040] Step 7: tert-butyl(2-(3'-(2-((1-acetylazetane-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)

[1041] Et3N (0.1 mL, 0.102 mmol) and (Ac)2O (0.1 mL, 0.328 mmol) were added to a stirred solution of tert-butyl(2-(3'-(2-(azacyclobutan-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), and the reaction was stirred at RT for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with aqueous brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Combiflash chromatography (4 g silica gel column) using hexane containing 90% EtOAc to provide the title compound (12) (30 mg, 71%) as a grayish-white solid. LC-MS: m / z 723.3; [M-Boc+H] + ;t R = 2.76 min; LC-MS purity: 99.86%.

[1042] Step 8: 5-(2-((1-acetylazetane-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)

[1043] TFA (0.1 mL) was added to a stirred solution of tert-butyl(2-(3'-(2-((1-acetylazetane-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) under a nitrogen atmosphere and the reaction was stirred at the same temperature for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was milled with pentane and lyophilized for 2 days to provide the trifluoroacetate of the title compound (Example 27) (15 mg, 68%) as an off-white solid. LC-MS: m / z 623.3 [M+H] + ;(t R = 1.76 min). LC-MS purity: 98.42%, HPLC purity: 98.81%, t R = 6.41 min, 1 H NMR (400 MHz, DMSO-d6) = δppm 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).

[1044] Example 28.

[1045] Synthesis of 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate

[1046]

[1047] Step 1: N,N-Dimethyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)acetamide (3)

[1048] Add 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), cool the reaction mixture to 0 °C, add NaH (0.164 g, 4.104 mmol) and stir at RT for 15 min, then add 5 mL (THF) containing 2-bromo-N,N-dimethylacetamide (1) (0.681 g, 4.104 mmol) at 0 °C, and stir the reaction mixture at RT for 2 h. After the reaction is complete (monitored by TLC), quench the reaction mixture with H2O (100 mL) and extract with DCM (2 x 100 mL) containing 10% MeOH. The combined organic layers were washed with a saline solution (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (3) (0.7 g, 88%) as a colorless colloidal liquid. LC-MS: non-ionized; 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).

[1049] Step 2: 2-(2-hydroxyethoxy)-N,N-dimethylacetamide (4)

[1050] 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) was added to PTSA monohydrate (0.032 g, 0.172 mmol) under RT, and the reaction mixture was stirred under RT for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum to provide the title compound (4) (0.2 g, 78%) as a colorless gel-like liquid. LC-MS: m / z 148.30 [M+H] + ;t R = 0.35 min; LC-MS purity: 88.07%. 1H NMR (400 MHz, 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).

[1051] 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)

[1052] To a stirred 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 RT for 15 min. 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 intermediate 3, Example 19) (100 mg, 0.150 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saline 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 DCM containing 3% to 6% MeOH to provide the title compound (6) (60 mg, 50%) as a grayish-white solid. LC-MS: m / z 693.3 [M-Boc+H] + ;t R = 3.01 min. 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), 1.67-1.50 (m, 5H), 1.34-1.33 (m, 18H), 1.23(bs, 3H), 1.13-1.09 (m, 4H), 0.86-0.81 (m, 2H).

[1053] Step 4: tert-butyl((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-ca...

Claims

1. A compound comprising or substantially consisting of (Formula I). in: X is selected from: CH; CF; N; or CR 1d ; A1 is selected from the group consisting of: phenyl, wherein the phenyl is optionally substituted with fluorine; and a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, S and O; A2 can choose from the following groups: Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens; C1-C3 alkoxy groups; C1-C3 alkyl groups; C 1-3 - Haloalkyl groups, such as CF3; and A 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from the group consisting of N, S and O, preferably S, wherein the heteroaromatic ring is optionally substituted by one or more substituents, the one or more substituents being independently selected from halogens, C1-C3 alkoxy groups, C1-C3 alkyl groups, preferably Cl; R 1 Choose the group consisting of: hydrogen; halogens; C1-C6 haloalkoxy groups; O(CH2). n O(CH2) m R 1a NR 1b (CH2) n O(CH2) m ;C1-C6 alkoxy group, optionally substituted with: C3-C6 cycloalkyl group; COOH group; (O-CH2 group) 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 5- 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 heteroatom; And 5- or 6-membered heteroaryloxy groups; R 1a Choose from the group consisting of: hydrogen, C1-C2 alkyl groups, or 4-membered heterocycles containing NCOCH3; R 1b and R 1c Independently selected from the group consisting of hydrogen, C1-C6 alkyl groups, or R 1b and R 1c Together with the nitrogen atom it is attached to, it forms a 5- or 6-membered saturated heterocycle; R 1d and R 1 Together with the carbon atoms they are attached to, they form 5- or 6-membered aromatic rings, heteroaromatic rings, cyclic rings, or heterocycles; R 2 Choose from the group consisting of hydrogen, C1-C3 alkyl groups, and halogens; R 3 Choose from the group consisting of: hydrogen; hydroxyl C1-C3 alkyl; (CH2) n OCH2CONR 9 R 9 ;C1-C3 alkyl groups, optionally substituted with a 4-membered heterocycle containing NCOCH3; R 4 Choose from the group consisting of: hydrogen; C1-C5 alkyl groups optionally substituted with OH or C1-C4 alkyl groups optionally substituted with OH; 4-, 5-, 6-, or 7-membered saturated cyclic rings or heterocycles optionally substituted with: C1-C3 alkyl groups, NHR 9 CONR 9 R 9 NHCO (C1-C3-alkyl), CONR 6 R 6 NH-CH2-R 7 、COOH, CHO, CO (C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O; Or NH-R 4 With NH-R 4 The attached carbon atoms form 5- or 6-membered saturated heterocycles; R 5 Selected from hydrogen, OH, and fluorine; R 6 Independently selected from the group consisting of hydrogen, C1-C3 alkyl groups, or R 6 R 6 Together with the nitrogen to which it is attached, it forms a 5- or 6-membered ring, optionally wherein the 5- or 6-membered ring further comprises oxygen. R 7 For containing at least one NR 8 The 5 or 6 yuan Fangzu ring; R 8 Choose free hydrogen and CH2CONR 9 The group formed; R 9 Independently selected from the group consisting of hydrogen and methyl groups; Each n is individually 1, 2, or 3; Each m is individually 0 or 1; Or its pharmaceutically acceptable salt, tautomer or stereoisomer.

2. The compound according to claim 1, wherein A2, R 1 and / or R 2 The halogens mentioned are selected from the group consisting of chlorine and fluorine.

3. The compound according to any one of claims 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: a phenyl group substituted with at least one halogen and a 5-membered heteroaromatic ring; such as wherein A2 is a phenyl group substituted with at least one halogen.

8. The compound according to any one of claims 1 to 7, wherein R 1 Choose the group consisting of: hydrogen; halogens; C1-C6 haloalkoxy groups; O(CH2). n O(CH2) m R 1a NR 1b (CH2) n O(CH2) m ;C1-C6 alkoxy groups, optionally substituted with: C3-C6 cycloalkyl groups; (O-CH2) m -CONR 1b R 1c ; a 6-membered heteroaromatic ring containing at least one N; or a 5-membered saturated heterocycle containing a heteroatom selected from N and O; a 5-membered aromatic heterocycle containing at least one N; and a 5- or 6-membered heteroaryloxy group; R 1a Choose from the group consisting of: hydrogen, C1-C2 alkyl groups, and 4-membered heterocycles containing NCOCH3; R 1b and R 1c The group consisting of hydrogen and C1-C3 alkyl groups is selected independently.

9. The compound according to any one of claims 1 to 8, wherein R 1 Choose from the following groups:

10. The compound according to any one of claims 1 to 9, wherein R 2 Choose the group composed of hydrogen and F.

11. The compound according to any one of claims 1 to 10, wherein R 3 Choose from the group consisting of: hydrogen, (CH2)2OCH2CON(CH3)2, C2-alkyl groups substituted with a 4-membered heterocycle containing NCOCH3, such as R 3 It is hydrogen.

12. The compound according to any one of claims 1 to 11, wherein R 4 Choose from the group consisting of: hydrogen; C1-C4 alkyl; C2-C4 alkyl substituted with OH; 4-, 5-, 6-, or 7-membered saturated cyclic rings or heterocycles; 6-membered saturated cyclic rings or heterocycles substituted with: 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 C1-C3 alkyl and OH, or CH2OH and =O; or NH-R 4 With NH-R 4 The attached carbon atoms form a 5-membered saturated heterocycle.

13. The compound according to any one of claims 1 to 12, wherein R 4 Choose from the following groups: hydrogen; and a 6-membered saturated ring, which is bonded by CHO, COOH, and CONHR. 6 Or NH2 can be substituted.

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

15. The compound according to any one of claims 1 to 14, wherein A2 is bonded in formula I such that the ring with X and the carbon connected to A1 are positioned 1,3 to each other.

16. The compound of claim 1, wherein the compound is selected from the group consisting of: 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((R)-azacycloheptane-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((S)-azacycloheptane-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)-azacycloheptane-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-pyrazol-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-oxooxazolidin-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(pyrrolidone-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-(pyridin-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-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(pyrimidin-2-ylmethoxy)-[1,1'-biphenyl]-2-carboxamide; 5-(2-((1-acetylazetane-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-carboxynitrile; 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-pyrazol-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-acetylazacyclobutane-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; and / or selected from the group consisting of: 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-(morpholin-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-[(propane-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-acetylpiperidin-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((R)-1-acetylpiperidin-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)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-acetamidocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(methylcarbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(piperidine-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

17. A conjugate comprising or substantially consisting of formula II: ABC (Form II) Wherein A is a compound of formula I according to any one of claims 1 to 16; provided that R in formula I is... 1 R 3 Or R 4 One of them is a bond with B or contains a bond with B, or wherein AB is a condensation product formed from the compound of formula I according to any one of claims 1 to 16 and B; B is the connector that covalently connects A and C, and C is the ligase binding agent.

18. The conjugate according to claim 17, wherein the connector B has the following formula: -L1-X1-L2-X2-L3- (B), and wherein the conjugate has the following formula: A-L1-X1-L2-X2-L3-C, where L1 is selected from the group consisting of the following: 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 cyclohexyl; where * represents the bond between L1 and X1; L1a is selected from the group consisting of the following: C(O), *NH-C(O) and *C1-C6 alkylene-NH-C(O), where * represents the bond between L1a and X1; X1 and X2 are each independently selected from the group consisting of: bonds; C4-C7 cycloalkylene groups; 4- to 7-membered heterocyclic groups containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; and 5- or 6-membered heteroarylene groups containing 1 to 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 * represents the bond between L2 and X2; or X1-L2-X2 forms a 7- to 13-membered spiroheterocyclic subcyclic group, wherein the 7- to 13-membered spiroheterocyclic subcyclic group contains one to four heteroatoms independently selected from the group consisting of N, O and S; L3 is selected from the group consisting of: bond, C1-C5 alkylene, C2-C5 alkenylene, C1-C6 alkyneene, 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 * denotes the bond between L3 and X2; and each R' is independently hydrogen or C1-C6 alkyl, preferably where each R' is hydrogen.

19. The conjugate according to claim 17, wherein the connector B has the following formula: -L1-X1-L2-X2-L3-X3-L4- (B), And the conjugate described therein has the following formula: A-L1-X1-L2-X2-L3-X3-L4-C, where X1, X2, and X3 are each independently selected from the group consisting of the following: bond, -O-, -CH2-, and -NH-; and L1, L2, L3, and L4 are each individually selected from the group consisting of the following: key; Heterocyclic or spirocyclic rings having 7 to 11 ring atoms; Cyclic or heterocyclic rings; Bicyclic or biheterocyclic, or two rings or heterocycles bonded together by carbon, nitrogen or oxygen; 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 connector is a bond between A and C in formula II, wherein R 1a Select from the group consisting of hydrogen and C1-C2 alkyl groups; or An aromatic ring or heteroaromatic ring having 5 to 6 ring atoms; optionally, the heteroaromatic ring contains one or two nitrogen atoms; and the linker is optionally substituted with F, Me and / or OH.

20. The conjugate according to any one of claims 17 or 19, wherein L1, L2, L3 and L4 are each individually selected from the group consisting of: Bond, -CH2-, -C(=O)-, -O-, -NH-, -NH-C1-C3 alkyl, -NH-hydroxyC1-C3 alkyl, Each of them For the connection point with A, X1, X2, X3 or C, and wherein L1, L2, L3 and / or L4 are optionally replaced by F, Me and / or OH.

21. The conjugate according to any one of claims 17 and 19 to 20, wherein the connector is selected from the group consisting of: Wherein A is a compound of formula I, and C is a ligase binding agent.

22. The conjugate according to any one of claims 17 and 19 to 21, wherein the connector is selected from the group consisting of: Wherein A is a compound of formula I, and C is a ligase binding agent.

23. The conjugate according to any one of claims 17 and 19 to 20, wherein the connector is selected from the group consisting of: Each of them This is the connection point with A or C.

24. The conjugate according to any one of claims 17 to 23, having: about 2 to about 50 bonds between A and C, such as 3 to about 45 bonds, such as 3 to about 40 bonds, such as 3 to about 35 bonds, such as 3 to about 30 bonds, such as 4 to about 23 bonds, such as 4 to 23 bonds; or such as 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 5- or 6-membered cyclic rings or heterocycles, wherein 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 6-membered heterocyclic group, the 6-membered heterocyclic group comprising one or two nitrogen atoms and / or two oxo substituents in the ring.

27. The conjugate according to any one of claims 17 to 26, wherein the ligase binding agent is selected from the group consisting of: in It is the connection point with the connector or the bond with the connector, and R is H, F, Cl, methyl or methoxy.

28. The conjugate according to any one of claims 17 to 27, wherein the ligase binding agent is selected from the group consisting of: in This is the connection point with the connector.

29. The conjugate according to any one of claims 17 to 28, wherein the ligase binding agent is selected from the group consisting of: in This is the connection point with the connector.

30. The conjugate according to any one of claims 17 to 29, wherein the ligase binding agent is selected from the group consisting of: in This is the connection point with connector (B).

31. The conjugate according to claim 17, wherein the conjugate is selected from the group consisting of: 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetamido)cyclohexyl]amino}ethyl)-5-[(pyridin-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-5-[(pyridin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}octamido)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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}propamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-N-[(1r,4r)-4-[(2-{6'-carbamoyl-6-chloro-2'-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl}-2-phenylethyl)amino]cyclohexyl]piperidin-4-carboxamide; 2'-Chloro-6-fluoro-5-methoxy-5'-(1-phenyl-2-{[(1r,4r)-4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propamido]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-diazin-1-yl)-4-methoxyphenyl]formamido}ethoxy)ethoxy]ethoxy}propamido)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-diazinyl-1-yl)-4-methoxybenzoyl]piperazin-1-yl}acetamido)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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-[4,4'-bipiperidin]-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]oxy}piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}-2-oxoethyl)-1H-pyrazol-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}methyl)amino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-N-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetyl)azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propionyl]azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetyl]azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-carbonyl}azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)azacyclobutane-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and / or selected from the group consisting of: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[4-(2,4-dioxo-1,3-diazinyl-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-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}oxy)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-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-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-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-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)piperidin-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-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-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-diazin-1-yl)-4-methoxybenzoyl]piperidin-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-diazin-1-yl)-4-methoxyphenyl]formamido}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-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-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-diazinyl-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-diazinyl-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-diazinyl-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-diazinyl-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-diazin-1-yl)benzoyl]piperidin-4-yl}methyl)piperidin-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-diazinyl-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-diazin-1-yl)-4-methoxybenzoyl]piperidin-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-diazinyl-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-[4,4'-bipiperidin]-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(2-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-({4-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperazin-1-yl}methyl)cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzamido]piperidin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxyphenyl]formamido}methyl)piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3S)-3-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzamido]piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[(3R)-3-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzamido]piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1-{1-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(4-{4-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperazine-1-carbonyl}phenyl)methyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[4-({4-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperazin-1-yl}methyl)phenyl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[2-(1-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)ethyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-carbonyl)piperidin-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-({[1-(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-carbonyl)piperidin-4-yl]methyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[1-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-carbonyl)piperidin-4-yl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]phenyl}methyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{[(1r,3r)-3-[(4-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]cyclobutyl]carbamoyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)ethyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}piperidin-1-yl)methyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[4-({2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}methyl)piperidin-1-yl]methyl}piperidin-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-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)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]piperidine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diazin-1-yl)-3-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{4-[(1-{2-[4-(2,4-dioxo-1,3-diazin-1-yl)-3-methylphenoxy]acetyl}piperidin-4-yl)oxy]piperidin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(1'-{2-[4-(2,4-dioxo-1,3-diazinyl)-3-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[4-chloro-3-(2,4-dioxo-1,3-diazinyl-1-yl)benzoyl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{1'-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]-[4,4'-bipiperidine]-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{9-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]-3,9-diazaspiro[5;5]undecane-3-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(2-{1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{1-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperidin-4-yl}piperazin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methoxybenzoyl]piperidine-4- [1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-({1-[4-chloro-3-(2,4-dioxo-1,3-diazinyl-1-yl)benzoyl]piperidin-4-yl}oxy)cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-{4-[4-chloro-3-(2,4-dioxo-1,3-diazinyl)benzoyl]piperidin-1-yl}cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 1-{1-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}-N-[(1r,4r)-4-{[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxacyclopentan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1-{1-[3-(2,4-dioxo-1,3-diazinyl)-4-methoxybenzoyl]piperidin-4-carbonyl}piperidin-4-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(9-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}-3,9-diazaspiro[5;5]undecane-3-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[2-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)ethyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetamido}piperidin-1-yl)methyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)piperazin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(4-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperazin-1-yl)methyl]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{4-[(1-{2-[3-(2,4-dioxo-1,3-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]piperidin-1-yl}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-(4-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperazinyl)cyclohexanylamino]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 1-(1-{2-[3-(2,4-dioxo-1,3-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)-N-[(1r,4r)-4-{[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxacyclopentan-2-yl]methoxy}-[1,1'-biphenyl]-3-yl)-2-phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(1'-{2-[4-(2,4-dioxo-1,3-diazinyl)-3-methylphenoxy]acetyl}-[4,4'-bipiperidine]-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiridine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[(1r,4r)-4-[(1-{2-[3-(2,4-dioxo-1,3-diazinyl)-4-methylphenoxy]acetyl}piperidin-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-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-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-diazin-1-yl)-4-methylphenoxy]acetyl}piperidin-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-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-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-diazinyl-1-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamide]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[3-(2,6-dioxopiperidin-3-yl)benzoyl]piperidin-4-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; as well as 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]piperidin-1-yl}methyl)piperidin-1-carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

32. The conjugate according to claim 17, wherein the conjugate is selected from the group consisting of: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}-2-oxoethyl)-1H-pyrazol-4-yl]methyl}amino)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetamido)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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azacyclobutane-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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-5-(2-{[1-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}acetyl)azacyclobutane-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide 2'-Chloro-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}cyclohexyl]amino}ethyl)-5-[(pyridin-2-yl)methoxy]-[1,1'-biphenyl]-2-carboxamide.

33. The conjugate according to claim 17, wherein the conjugate is selected from the group consisting of: 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-carbonyl}piperidin-1-yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetamido}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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethyl}carbamoyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; and 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide.

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

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

36. 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 as a medicine.

37. The compound of any one of claims 1 to 16, or the conjugate of any one of claims 17 to 34, or the pharmaceutical composition of claim 35, for treating a disease or condition, wherein the Hippo pathway is hyperactivated; optionally, wherein the Hippo pathway is hyperactivated due to overexpression of YAP, mutation or deletion of LATS2, or neurofibromatosis type 2 (NF2), or hypermethylation of the LATS2 promoter.

38. 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 treating cancer by administering the compound, conjugate, or composition to a patient in need.

39. 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, wherein 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.

40. 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 according to any one of claims 36 or 39, wherein said administration is in combination with at least one compound selected from the group consisting of: AKT inhibitors, such as afluctinib, capipecetide, partacetide, miracetide, perifocin, and euprocetide; CDK4 / 6 inhibitors, such as abecilide, palbociclib, and reboxilide; EGRF inhibitors, such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; MAP2K inhibitors, such as bemettinib, colmettinib, and trametinib; FGFR inhibitors; mTOR inhibitors; MEK1 inhibitors; ALK inhibitors; HSP90 inhibitors; CDK8 inhibitors; PI3K-α inhibitors; ABL1 inhibitors; and XPO1 inhibitors.

41. 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 treating fibrosis by administering the compound, conjugate, or composition to a patient in need.

42. The compound of any one of claims 1 to 16, or the conjugate of any one of claims 17 to 34, or the pharmaceutical composition of claim 35, for use as described in claim 41, 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 / or kidneys.

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 any one of claims 41 to 42, wherein the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

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

45. The method of 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 any one of claims 44 or 45, wherein the administration is a combination of at least one compound selected from the group consisting of: AKT inhibitors, such as afluctinib, capipecetib, partacetib, miracetib, perifoxetine, and ouprecetib; CDK4 / 6 inhibitors, such as abeciclib, palbociclib, and reboxil; EGRF inhibitors, such as afatinib, brigatinib, erlotinib, gefitinib, and osimertinib; MAP2K inhibitors, such as bemettinib, cmettinib, and trametinib; FGFR inhibitors; mTOR inhibitors; MEK1 inhibitors; ALK inhibitors; HSP90 inhibitors; CDK8 inhibitors; PI3K-α inhibitors; ABL1 inhibitors; and XPO1 inhibitors.

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

48. The method of 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 any one of claims 47 to 48, wherein the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

50. Use of 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, in the manufacture of a medicament for treating 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, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma.

52. Use of 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, in the manufacture of a medicament for treating 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; preferably selected from the group consisting of: idiopathic pulmonary fibrosis and scleroderma.

54. A method for preparing a conjugate according to formula II, the method comprising: - React the ligase conjugate according to any one of claims 25 to 30 with the linker according to any one of claims 18 to 24 to form an intermediate; - React 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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