Aromatic amides and conjugates thereof as binders to tead

Abstract

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

Description

[0001] AROMATIC AMIDES AND CONJUGATES THEREOF AS BINDERS TO TEAD

[0002] Field of the Invention

[0003] The present invention provides novel compounds and conjugates comprising said compounds. The compounds may be binders to TEA domain transcription factor (TEAD). The conjugates may comprise a ligase binding moiety. The present invention further provides pharmaceutical compositions containing such compounds and / or conjugates, and methods for using such pharmaceutical compositions in treating diseases, such as cancer and fibrosis.

[0004] Bifunctional Degraders

[0005] Numerous diseases, including cancer, are caused by the excessive activation of proteins within signal transduction networks [1], This over activation leads to abnormal growth, metabolism, or has other pathological consequences. Traditional small molecule drugs can inhibit, antagonize, or block these over activated proteins by binding to ortho- or allosteric sites on the protein. By doing so, they can restore normal cellular homeostasis and alleviate the pathological consequences caused by these dysregulated proteins [2],

[0006] As an alternative to small molecule drugs that block the function of proteins, bifunctional molecules that bind both to the dysregulated protein and an E3 ligase can facilitate ubiquitination of the protein by the ligase, and thus target the protein for proteasomal degradation [3], Instead of inhibiting the protein, the levels of the protein within the cell are decreased by the bifunctional molecule [4] . Degraders may have good biochemical efficiency[5] and long duration of action that can persist after the drug is eliminated from the body[6].

[0007] Hippo Signaling Pathway

[0008] The growth of normal tissue, as well as its repair and remodeling, requires careful control of transcriptional activity. This is achieved through the coordinated activity of several signaling transduction pathways, including the Hippo pathway. The Hippo signaling network is composed of the Mstl / 2 and Eats 1 / 2 kinases that when activated, phosphorylate the yes associated protein (YAP) and transcriptional co-activator with PDZ -binding motif (TAZ), resulting in their retention in the cytosol and proteasomal degradation. When the Hippo pathway is de-activated, YAP and TAZ remain unphosphorylated. This allows them to move into the nucleus where they can co-activate TEAD-mediated transcription [7],

[0009] Through controlling TEAD-mediated transcription, the Hippo pathway plays a key role in regulating cellular proliferation and apoptosis. The Hippo pathway also controls stem cell self-renewal and differentiation[8]. Finally, the Hippo pathway regulates 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 an immunosuppressive tumor microenvironment by recruiting tumor associated M2 macrophages

[0010] and myeloid-derived suppressor cells (MDSCs) to the tumor

[0011] Hence blocking of TEAD regulated gene expression in tumors has a triple mode of action. Blockers have a direct antiproliferative effect on the cancer cells, promote terminal differentiation of cancer stem cells, and reduce the immunosuppressive tumor microenvironment so that the immune system has a better chance of recognizing and clearing the tumor. The Hippo signalling pathway plays a role in regulating wound healing. When this pathway is disrupted, it can lead to fibrosis. TEAD Transcription Factors The TEA domain transcription factor (TEAD) is a family of transcription factors that regulate gene transcription by binding to upstream response elements of TEAD regulated genes

[0014] . In humans, there are four TEAD orthologs designated TEAD1, TEAD2, TEAD3, and TEAD4. Co-regulators of the TEAD transcription factor include the yes associated protein (YAP), transcriptional co-activator with PDZ- binding motif (TAZ), and the vestigial-like family members (VGLL1-4)

[0015] . TEAD regulated gene expression is the penultimate step in the Hippo signaling pathway. Hence inhibiting or degrading TEAD will have therapeutic effect in the treatment of diseases such as cancer and fibrosis where the Hippo pathway is aberrantly activated.

[0013] YAP and TAZ interact with the C-terminal transactivation domain of TEAD through three surface - -strands. At interface -helix that fits into a groove in a TEAD helix turn helix motif. At interface 3, YAP / TAZ adopt a loop-like structure that interacts with TEAD. In addition, TEAD contains an internal hydrophobic cavity that is occupied by palmitate as a result of auto-palmitoylation. Only palmitoylated TEAD is able to bind with high affinity to YAP.

[0016] A number of small molecules have been reported in the literature that are able to prevent YAP binding to TEAD and hence block the transcription of TEAD-regulated genes. The most common target of these small molecules to date is the internal lipophilic binding pocket.

[0016] A fewer number of inhibitors that bind to the external interface #2 or #3 have also been reported.

[0016] WO 2023 / 031801 describes bifunctional degraders comprising a TEAD binder, synthesized over 13 steps. Summary of the invention It is an object of the invention to provide novel compounds that may be used for treating disease, such as cancer and / or fibrosis. Another object of the invention is to provide novel compounds that bind TEAD1, TEAD2, TEAD3 and / or TEAD4 and that may be used for treating disease, such as cancer and / or fibrosis. The novel compounds may bind TEAD1, TEAD2, TEAD3 and / or TEAD4 (TEADx) with high affinity. Another object of the invention is to provide novel compounds that bind to both TEADx and an E3 ligase to form a stable ternary complex composed of TEADx, an E3 ligase, and the novel compound. An additional object is to provide conjugates comprising novel compounds that bind TEAD1, TEAD2, TEAD3 and / or TEAD4, which conjugates may be able to at least partly degrade TEAD1, TEAD2, TEAD3 and / or TEAD4. Thus, according to a first aspect of the invention, there is provided a compound, which comprises, essentially consists of or is (Formula I) wherein: X is selected from CH; CF; and N, or X is C-R1d; A1 is selected from the group consisting of phenyl, wherein said phenyl is optionally substituted with fluoro; and a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N, S, and O; A2 is selected from the group consisting of phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; C1-C3alkoxy; C1-C3alkyl; C1-3-haloalkyl, 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 said heteroaromatic ring is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkoxy, C1-C3alkyl, preferably Cl; R1is selected from the group consisting of hydrogen; halogen; C1-C6 haloalkoxy; O(CH2)nO(CH2)mR1a; NR1b(CH2)nO(CH2)m; C1-C6 alkoxy optionally substituted with C3-C6 cycloalkyl, COOH, (O-CH2)m-CONR1bR1c, a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, or a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and a 5- or 6-membered heteroaryloxy; R1ais selected from the group consisting of hydrogen, C1-C2 alkyl, or a 4-membered heterocyclic ring comprising NCOCH3; R1band R1care independently selected from the group consisting of hydrogen, C 1b 1-C6 alkyl or R and R1ctogether with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring; R1dand R1taken together with the carbon atom to which they are each attached form a 5- or 6- membered aromatic, heteroaromatic, cyclic or heterocyclic ring; R2is selected from the group consisting of hydrogen, C1-C3alkyl, and halogen; R3is selected hydroxyC1-C3 alkyl; (CH2)nOCH2CONR9R h a 4-membered heterocyclic ring comprising NCOCH3; R4is selected from the group consisting of hydrogen, C1-C5alkyl optionally substituted with OH or C1-C4alkyl optionally substituted with OH; a 4-, 5-, 6- or 7-membered saturated cyclic or heterocyclic ring optionally substituted with C1-C3 alkyl, NHR9, CONR9R9, NHCO(C1-C3-alkyl), CONR6R6, NH- CH2-R7COOH, CHO, CO(C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O; or NH-R4forms a 5- or 6-membered saturated heterocyclic ring to the carbon to which NH-R4is attached; R5is selected from hydrogen, OH and fluoro; R6is independently selected from the group consisting of hydrogen, C1-C3 alkyl, or R6R6together form a 5- to 6-membered ring with the nitrogen to which they are attached optionally wherein said 5- to 6-membered ring further comprises oxygen, R7is a 5- or 6-membered aromatic ring comprising at least one NR8; R8is selected from the group consisting of hydrogen and CH2CONR9; R9is independently selected from the group consisting of hydrogen and methyl; each n is individually 1, 2 or 3; each m is individually 0 or 1; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. The skilled person appreciates that when R1dand R1taken together with the carbon atom to which they are each attached form a 5- or 6-membered aromatic, heteroaromatic, cyclic or heterocyclic ring, means that the resulting ring comprises X, the carbon to which R1 is attached as well as the required atoms to form the 5- or 6-membered aromatic, heteroaromatic, cyclic or heterocyclic ring. In some embodiments X is selected from CH; CF; and N; A1 is selected from the group consisting of phenyl, wherein said phenyl is optionally substituted with fluoro; and a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N, S, and O; A2 is selected from the group consisting of phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; C1-C3alkoxy; C1-C3alkyl; C1-3-haloalkyl, 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 said heteroaromatic ring is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkoxy, C1-C3alkyl, preferably Cl; R1is selected from the group consisting of hydrogen; halogen; C1-C6 haloalkoxy; O(CH2)nO(CH2)mR1a; NR1b(CH2)nO(CH2)m; C1-C6 alkoxy optionally substituted with C3-C6 cycloalkyl, COOH, (O-CH2)m-CONR1bR1c, a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N O and S preferably at least one N heteroatom or a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and a 5- or 6-membered heteroaryloxy; R1ais selected from the group consisting of hydrogen, C1-C2 alkyl, or a 4-membered heterocyclic ring comprising NCOCH3; R1band R1care independently selected from the group consisting of hydrogen, C 1b 1-C6 alkyl or R and R1ctogether with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring; R2is selected from the group consisting of hydrogen, C1-C3 alkyl, and halogen; R3is selected from the group consisting of hydrogen, hydroxyC1-C3 alkyl; (CH2)nOCH2CONR9R9, C1-C3alkyl optionally substituted with a 4-membered heterocyclic ring comprising NCOCH3; R4is selected from the group consisting of hydrogen, C1-C5alkyl optionally substituted with OH or C1-C4alkyl optionally substituted with OH; a 4-, 5-, 6- or 7-membered saturated cyclic or heterocyclic ring optionally substituted with C1-C3 alkyl, NHR9, CONR9R9, NHCO(C1-C3-alkyl), CONR6R6, NH- CH2-R7COOH, CHO, CO(C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O; or NH-R4forms a 5- or 6-membered saturated heterocyclic ring to the carbon to which NH-R4is attached; R5is selected from hydrogen, OH and fluoro; R6is independently selected from the group consisting of hydrogen, C1-C3alkyl, or R6R6together form a 5- to 6-membered ring with the nitrogen to which they are attached optionally wherein said 5- to 6-membered ring further comprises oxygen, R7is a 5- or 6-membered aromatic ring comprising at least one NR8; R8is selected from the group consisting of hydrogen and CH2CONR9; R9is independently selected from the group consisting of hydrogen and methyl; each n is individually 1, 2 or 3; each m is individually 0 or 1; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. In some embodiments X is selected from CH; and N; A1 is selected from the group consisting of phenyl, wherein said phenyl is optionally substituted with fluoro; and a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N, S, and O; A2 is selected from the group consisting of phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; C1-C3alkoxy; C1-C3alkyl; 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 said heteroaromatic ring is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkoxy, C1-C3alkyl, preferably Cl; R1is selected from the group consisting of hydrogen; halogen; C1-C6 haloalkoxy; O(CH2)nO(CH2)mR1a; C1-C6 alkoxy optionally substituted with C3-C6 cycloalkyl, COOH, (O-CH2)m- CONR1bR1c, a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, or a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and a 5- or 6-membered heteroaryloxy; R1ais selected from the group consisting of hydrogen, C1-C2 alkyl, or a 4-membered heteroaliphatic ring comprising NCOCH3; R1band R1care independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C3alkyl or R1band R1ctogether with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring; R2is selected from the group consisting of hydrogen, C1-C3 alkyl, and halogen; R3is selected from the group consisting of hydrogen, hydroxyC1-C3 alkyl; (CH2)nOCH2CONR9R9, C1-C3 alkyl optionally substituted with a 4-membered heteroaliphatic ring comprising NCOCH3; R4is selected from the group consisting of hydrogen, C1-C4alkyl (a linear C1-C4alkyl or in some embodiments when the alkyl is a C3-C4alkyl a branched) optionally substituted with OH; a 4-, 5-, 6- or 7- membered saturated cyclic or heterocyclic ring optionally substituted with C1-C3alkyl, NHR9, CONR9R9, NHCO(C1-C3-alkyl), CONR6R6, NH-CH2-R7COOH, or OH, or C1-C3alkyl and OH, or CH2OH and =O; or NH-R4forms a 5- or 6-membered saturated heterocyclic ring to the carbon to which NH-R4is attached; R5is selected from hydrogen, OH and fluoro; R6is independently selected from the group consisting of hydrogen, C1-C3alkyl, or R6R6together form a 5- to 6-membered ring with the nitrogen to which they are attached optionally wherein said 5- to 6- membered ring further comprises oxygen, R7is a 5- or 6-membered aromatic ring comprising at least one NR8; R8is selected from the group consisting of hydrogen and CH2CONR9; R9is independently selected from the group consisting of hydrogen and methyl; each n is individually 1, 2 or 3; each m is individually 0 or 1; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. The compounds according to formula I may serve as a TEAD binders. This is shown in Example 202, which shows an SPR assay for determination of binding affinities towards TEAD1-4 for exemplified compounds 1-46 to 84-110. According to the present disclosure, the compound of formula I may further comprise a second compound having bindig affinity for another target present in the body of a mammal Such compound may be attached directly or via a suitable linker, optionally wherein R1, R3or R4in formula I is or contains a point of attachment to the linker or the second compound. In some embodiments, said halogen is selected from the group consisting of chloro and fluoro. In some embodiments, X is CF, CH or N. In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, A1 is phenyl or a 6-membered heteroaromatic. In some embodiments, A1 is phenyl or pyridine. In some embodiments, A1 is phenyl. In some embodiments, A2 is phenyl substituted with at least one halogen. In some embodiments, A2 is phenyl substituted with one or two chlorine(s) and / or at one or two flourine(s). In some embodiments, A2 is selected from the group consisting of phenyl substituted with at least one halogen and a 5-membered heteroaromatic ring. As apparent to a person of skill in the art, according to Formula I A2 binds the remaining part of the molecule orto, meta, or para. The skilled person understands that this describes how A2 is bound to the ring bearing X and the carbon to which A1 is attached. In other words, A2 is bound in Formula I such that the ring bearing X and the carbon to which A1 is attached are positioned orto, meta, or para to each other. In one embodiment, A2 binds the remaining general part of the molecule orto. In one embodiment, A2 binds the remaining general part of the molecule meta. In one embodiment, A2 binds the remaining general part of the molecule para. In some embodiments, R1is selected from the group consisting of hydrogen; halogen; C1-C6haloalkoxy, O(CH2)nO(CH2)mR1a; NR1b(CH2)nO(CH2)m;C1-C6alkoxy optionally substituted with C3-C6cycloalkyl, (O-CH2)m-CONR1bR1c, a 6-membered heteroaromatic ring comprising at least one N, or a 5- membered saturated heterocyclic ring comprising one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring comprising at least one N; and a 5- or 6-membered heteroaryloxy; R1ais selected from the group consisting of hydrogen, C1-C2alkyl, and a 4-membered heteroaliphatic ring comprising NCOCH3;R1band R1care independently selected from the group consisting of hydrogen, C1-C3alkyl. In some embodiments, R1is selected from the group consisting of hydrogen; halogen; C1-C6haloalkoxy, O(CH2)nO(CH2)mR1a; C1-C6alkoxy optionally substituted with C3-C6cycloalkyl, (O-CH2)m- CONR1bR1c, a 6-membered heteroaromatic ring comprising at least one N, or a 5-membered saturated heterocyclic ring comprising one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring comprising at least one N; and a 5- or 6-membered heteroaryloxy; R1ais selected from the group consisting of hydrogen, C1-C2alkyl, and a 4-membered heteroaliphatic ring comprising NCOCH3;R1band R1care independently selected from the group consisting of hydrogen, C1-C3alkyl. In some embodiments, R1 is selected from the group consisting of:

[0010] In some embodiments, R1is selected from the group consisting of: As apparent to a person of skill in the art, illustrates where the bond to R1 is and can be seen is an attachment point to R1. As apparent to a person of skill in the art, a bond can also be called an attachment point. In some embodiments, R2is selected from the group consisting of hydrogen and F. In some embodiments, R3is selected from the group consisting of hydrogen, (CH2)2OCH2CON(CH3)2, C2alkyl substituted with a 4-membered heteroaliphatic ring comprising NCOCH3. In some embodiments, R3is hydrogen. In some embodiments, R4is selected from the group consisting of hydrogen, C1-C4alkyl, C2- C4alkyl substituted with OH; a 4-, 5-, 6- or 7-membered saturated cyclic or heterocyclic ring; 6-membered saturated cyclic or heterocyclic ring substituted with C1-C3alkyl, NHR9, CONR9R9, NHCO(C1-C3-alkyl), CONR6R6, NH-CH2-R7, COOH, or OH, or C1-C3 alkyl and OH, or CH2OH and =O; or NH-R4forms a 5- membered saturated heterocyclic ring to the carbon to which NH-R4is attached. As an alternative, NH-R4forms a 6-membered saturated heterocyclic ring to the carbon to which NH-R4is attached. In some embodiments, R4is selected from the group consisting of hydrogen; C1-C4alkyl; C2- C4alkyl substituted with OH; a 4-, 5-, 6- or 7-membered saturated cyclic or heterocyclic ring; 6-membered saturated cyclic or heterocyclic ring substituted with C1-C3 alkyl, NHR9, CONR9R9, NHCO(C1-C3-alkyl), CONR6R6, NH-CH2-R7, COOH, OH, C1-C3 alkyl and OH, or CH2OH and =O; or NH-R4forms a 5- membered saturated heterocyclic ring to the carbon to which NH-R4is attached. As an alternative, NH-R4forms a 6-membered saturated heterocyclic ring to the carbon to which NH-R4is attached. In some embodiments, R4is selected from the group consisting of hydrogen and a 6-membered saturated ring substituted with CHO, COOH, CONHR6, or NH2. In some preferred embodiments, R4is selected from the group consisting of hydrogen and a 6- membered saturated ring substituted with NH2. In some embodiments, R5is hydrogen. In some embodiments, A2 is bound in Formula I such that the ring bearing X and the carbon to which A1 is attached are positioned orto, meta, or para to each other. In one embodiment, the compound of formula I is selected from the list consisting of 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl] -2-carboxamide; 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2- carboxamide; 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide; 2'-chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]- 2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]- 2-carboxamide; 5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-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(pyrrolidin-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-acetylazetidin-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1- phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2- oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-3',6-difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5- (2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2- oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- (methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5- (2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1- phenylethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H- 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-acetylazetidin-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-(morpholine-4- carbonyl)cyclohexyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2-carboxamide ; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(((1r,4r)-4-(piperidine-1- carbonyl)cyclohexyl)amino)ethyl)-[1,1'-biphenyl]-2-carboxamide ; 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide ; 2'-chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide ; 2'-chloro-4',6-difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide ; 2'-chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide ; 3'-(2-Amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide ; 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2- methoxyethoxy)nicotinamide ; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'- (trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide ; (1r,4r)-4-((2-(6'-carbamoyl-4,6-dichloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and stereoisomers thereof; (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 stereoisomers thereof; 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 trifluoracetate; 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; In some embodiments, said compound is selected from the list consisting of 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl] -2- carboxamide; 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2- carboxamide; 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide; 2'-chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]- 2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]- 2-carboxamide; 5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-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(pyrrolidin-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-acetylazetidin-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1- phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2- oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-3',6-difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5- (2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2- oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- (methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5- (2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1- phenylethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H- 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-acetylazetidin-3-yl)methyl)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'- chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2-(5-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)benzamide; 2-(5-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2-chlorothiophen-3-yl)-3- fluorobenzamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-3'-methoxy-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(2-((3-hydroxy-3-methylbutyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide ; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)amino)-1- phenylethyl)-[1,1'-biphenyl]-2-carboxamide ; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((1r,4r)-4-(morpholine-4-carbonyl)cyclohexyl)amino)-1- phenylethyl)-[1,1'-biphenyl]-2-carboxamide ; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(((1r,4r)-4-(piperidine-1- carbonyl)cyclohexyl)amino)ethyl)-[1,1'-biphenyl]-2-carboxamide ; 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide ; 2'-chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide ; 2'-chloro-4',6-difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide ; 2'-chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide ; 3'-(2-Amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide ; 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2- methoxyethoxy)nicotinamide ; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'- (trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide ; (1r,4r)-4-((2-(6'-carbamoyl-4,6-dichloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane 1 carboxylic acid and stereoisomers thereof; (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 stereoisomers thereof; 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 trifluoracetate; (1r,4r) 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; (1r,4r) (1r,4r) (1r,4r) The disclosure provides compounds of formula I according to the first aspect of the invention that target TEAD. A conjugate that comprises a compound of formula I and a ligase binder may recruit TEAD to E3 Ubiquitin ligase for degradation. Thus, according to a second aspect of the invention, there is provided a conjugate, which is, comprises or essentially consists formula II: A-B-C (formula II) wherein A is a compound of formula I according to any one of the embodiments of the first aspect, with the proviso that one of R1, R3or R4in formula I is or contains a bond to B. In other words, the proviso includes that one of R1, R3or R4in formula I is or contains a point of attachment to B. Alternatively, A-B is a condensation product formed from a compound of formula I according to the first aspect and the linker B. As apparent to a person of skill in the art, a condensation product requires the removal of water in the reaction forming said product. As such, the condensation product A-B may be formed from a carboxylic acid (-COOH) and an amine (-NHR or -NH2), forming a amide bond (-CONR- or -CONH-) and water (H2O). As such, when formula I is attached to the linker B via -COOH, the resulting conjugate lacks OH previously present in the carboxylic acid of formula I, as apparent to a skilled person. B is a linker. B may be a linker that covalently links A to C. C is a ligase binder.The conjugates according to formula II may serve as TEAD binders. This is shown in Example 202, which shows an SPR assay for determination of binding affinities towards TEAD1- 4 for examplified compounds 1-46 and 84-110 and exemplified conjugates 47-83 and 111-200. Without being bound by to any particular theory, the conjugates according to formula II may induce the formation of a ternary complex comprising the conjugate of formula II, TEAD and an E3 ligase; or a ternary complex comprising the conjugate of formula II, TEAD and Cereblon. The conjugates according to formula II may serve as a TEAD degrader. This is exemplified for some of the conjugates according to the second aspect, see Example 204. This is evident from figure 1 and / or figure 2, which shows amount of TEAD after incubation with a conjugate according to the second aspect of the invention. As apparent for a person of skill in the art, the linker is group that covalently links the compound of Formula I (A) to the ligase binder (C). The skilled person understands which linkers are suitable for the conjugate according to the second aspect of the invention. For example, the linker may have a number of rotatable bonds between 1 and 13, preferably below 10. In addition, the linker may have a number of non- hydrogen atoms between 5 and 30, preferably below 26. In addition, the linker may have a number of hydrogen bond donors, preferably at most 2 hydrogen bond donors. The skilled person is well aware of the meaning of a rotatable bond, as well as the meaning of non-hydrogen atoms and hydrogen bond donors. The linker according to the present invention may be a diamine linker, a spirocyclic or heterospirocyclic linker, a cyclic or heterocyclic linker, a linear or branced C1-C10 alkyl linker, an ether linker, an amino acid linker, e.i., the linker may comprise any of these groups or a combination of these groups. The ligase binder is a group that is capable of binding to a ligase, such as a Ubiquitin ligase, such as Cereblon E3 Ubiquitin ligase. Other ligase binders suitable for the conjugate of formula II are also part of the present disclosure. As discussed above, the skilled person understands what linkers are suitable to be part of the conjugate according to formula II. In some embodiments, said linker B has the fomula -L1-X1-L2-X2-L3- (B), and wherein the conjugate has the formula: A-L1-X1-L2-X2-L3-C, and wherein L1 is selected from the group consisting of a bond, -O-, -NR'-, -C(O)-, C1-C9alkylene, C1- C9heteroalkylene, *C(O)-C1-C6alkylene, *C(O)-C1-C6heteroalkylene, *C1-C6alkylene-C(O), *C1-C6 heteroalkylene-C(O), and *L1a-C4-C7cycloalkylene, wherein * denotes the bond of L1 to X1; wherein L1a is selected from the group consisting of C(O), *N H-C(O) and *C1-C6alkylene-NH- C(O) wherein* denotes the bond of L1a to X1; X1 and X2 are each independently selected from the group consisting of a bond, C4- C7cycloalkylene, 4 to 7 membered heterocyclylene comprising 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, and 5 or 6 membered heteroarylene comprising 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; L2 is selected from the group consisting of a bond, -O-, -NR'-, -C(O)-, C1-C6alkylene, -NR'-C1- C9alkylene-NR'-, *C1-C9alkylene-N R'-,*NR'-C1-C9alkylene, *C(O)NR'-C1-C5alkylene, polyethylene glycol , -NR'-polyethylene glycol-NR'-, polyethylene glycol, *NR'-polyethylene glycol and *polyethylene glycol-NR', wherein * denotes the bond of L2 to X2; or X1-L2-X2 form a 7 to 13 membered spiroheterocyclylene comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; L3 is selected from the group consisting of a bond, C1-C5alkylene, C2- C5alkenylene, C1-C6alkynylene, C1C6heteroalkylene, -C(O)-, -S(O)r, -O-, *C(O)-C1- C6alkylene, *C(O)-C1-C5alkylene-O, *C(O)-C1-C6heteroalkylene, ,*C1-C5alkylene-NH and *NH-C1- C5alkylene; wherein* denotes the bond of L3 to X2; and wherein each R' is independently hydrogen or C1-C6alkyl, preferably wherein each R' is hydrogen. In some embodiments, L1 is *L1a-C4-C1cycloalkylene**, and L1a is selected from the group consisting of a bond, C(O), *NH-C(O) and *C1-C5alkylene-NH-C(O).* denotes the bond to X1, and ** denotes the bond to A. In some embodiments, L1 is *L1a-C6cycloalkylene** and L1a is selected from the group consisting of C(O), *NH-C(O) and *C1-C5alkylene-NH-C(O) (e.g. *C2alkylene-NHC(O)) ).* denotes the bond to X1. In some embodiments, said linker B has the formula -L1-X1-L2-X2-L3-or L1-X1-L2-X2-L3-X3- L4- (B), and said conjugate has a formula: A-L1-X1-L2-X2-L3-C or A-L1-X1-L2-X2-L3-X3-L4-C, wherein X1 and X2 are each independently selected from the group consisting of a bond, -O-, -CH2-, and -NH-, and wherein L1, L2 and L3 or L1, L2, L3 and L4 are each individually selected from the group consisting of: a bond; a heterospirocycle or spirocycle having 7-11 ring atoms; a cycle or heterocycle; a bicycle or a biheterocycle, or two cycles or heterocycles being bound to each other via a carbon, a nitrogen or an 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 linker is a bond between A and C in formula II, wherein R1ais selected from the group consisting of hydrogen, C1-C2 alkyl; or an aromatic or heteroaromatic ring having 5 to 6 ring atoms. Optionally said heteroaromatic ring comprises one or two nitrogen atoms. According to this embodiment, said linker is optionally substituted with F, Me, OH. The skilled person understands which positions are suitable for such substitutions. In some embodiments, L1, L2 and L3 or L1, L2, L3 and L4 are each individually selected from the group consisting of: a bond, -CH2-, -C(=O)-, -O-, -NH-, -NH-C1-C3alkyl, -NH-hydroxyC1-C3alkyl, . As apparent to a person of skill in the art, each is an attachment point to A, X1, X2, or C. Additionally, said linker may be substituted with F, Me, OH at any suitable position of L1, L2 and / or L3 or L1, L2, L3 and / or L4. The skilled person appreciates that such substituents can be at any position of L1, L2 and / or L3 or at L1, L2, L4 and / or L4 apart from the position of the attachment point. In some embodiments, said linker is selected from the group consisting of

[0011] wherein A is a compound of formula I and wherein C is a ligase binder.

[0012] In some embodiments, said linker is selected from the group consisting of: wherein A is a compound of formula I and wherein C is a ligase binder. In this embodiment, it is specifically preferred that R4in formula I is the part of A that is or contains a bond to B. In order words, this group of linkers is particularly suitable for attachment at a position in R4in formula I.

[0013] In some embodiments, said linker is selected from the group consisting of:

[0014] wherein A is a compound of formula I and wherein C is a ligase binder. In this embodiment, it is specifically preferred that R4in formula I is the part of A that is or contains a bond to B. In order words, this group of linkers is particularly suitable for attachment at a position in R4in formula I.

[0015] In some embodiments, said linker is selected from the group consisting of:

[0016] wherein A is a compound of formula I and wherein C is a ligase binder. In this embodiment, it is specifically preferred that R1or R3in formula I is the part of A that is or contains a bond to B. In other words, this group of linkers is particularly suitable for attachment at a position in R1or R3in formula I.

[0017] In some embodiments, said linker is selected from the group consisting of:

[0018]

[0019] As apparent to a person of skill in the art, each > is an attachment point to A or C. Additionally, said linker may be substituted with F, Me, OH at any suitable position of LI, L2, L3 and / or L4 or at any position of LI, L2 and / or L3. The skilled person appreciates that such substituents can be at any position of LI, L2, L3 and / or L4 or at any position of LI, L2 and / or L3 apart from the position of the attachment point. In this embodiment, it is specifically preferred that R4formula I is the part of A that is or contains a bond to B. In other words, this group of linkers is particularly suitable for attachment at a position in R4in formula I. According to this embodiment, most preferred is that R4in formula I is cyclohexyl-4-amine or cyclohexyl -4-formyl .

[0020] In some embodiments, said linker is selected from the group consisting of:

[0021] In some embodiments, said linker is selected from the group consisting of:

[0022] In some embodiments, said linker is selected from the group consisting of:

[0023] In some embodiments, said linker is selected from the group consisting of:

[0024] In some embodiments, said linker is selected from the group consisting of:

[0025] In some embodiments, said linker is selected from the group consisting of:

[0026] In some embodiments, said linker is selected from the group consisting of: In some embodiments, said linker is selected from the group consisting of:

[0027] In some embodiments, said linker is selected from the group consisting of:

[0028] In some embodiments, said linker is selected from the group consisting of:

[0029] In some embodiments, said linker is selected from the group consisting of:

[0030] In some embodiments, said linker is selected from the group consisting of:

[0031] The conjugate according to the second aspect of the present inventions comprises a linker of a certain length. Such length may be calculated as the shortest length between A and C in the conjugate. In some embodiments, the length of the linker is from 2 to about 50 bonds, such as from 3 to about 45 bonds, such as from 3 to about 40 bonds, such as from 3 to about 35 bonds, such as from 3 to about 30 bonds, such as from 4 to about 23 bonds, such as 4 to 23 bonds between A and C, 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.

[0032] A ligase binder according to the present disclosure may comprise two or three 5- or 6-membered cyclic or heterocyclic rings, wherein at least one of the two or three heterocyclic rings is aromatic. When the ligase binder includes two rings, one of the rings may be phenyl, or phenyl substituted with alkoxy such as methoxy. In some embodiments, the second ring is glutarimide or dihydrouracil.

[0033] When the ligase binder includes three rings, two of the rings may together form a bicycle, such as a phthalimide. In some embodiments, the third ring is glutarimide or dihydrouracil.

[0034] The ligase binder may comprise a 6-membered heterocyclic group comprising one or two nitrogen atoms in the ring and / or and two oxo substituents. In preferred embodiments, the ligase binder comprises a glutarimide or a dihydrouracil group, or a similar group.

[0035] In some embodiments, said ligase binder is selected from the group consisting of:

[0036] In some embodiments, said ligase binder is selected from the group consisting of:

[0037] wherein > is an atachment point to a linker or is a bond to a linker, such as the linker B in accordance with the present disclosure, 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. The skilled person appreciates that R can be at any available position in the phenyl ring. In other words, when R is not H, R may replace an H of the phenyl ring.

[0038] In some embodiments, said ligase binder is selected from the group consisting of: wherein f is a bond of an attachment point to a linker or is a bond to a linker, such as the linker B in accordance with the present disclosure.

[0039] In some embodiments, said ligase binder is selected from the group consisting of wherein > is a bond of an attachment point to a linker or is a bond to a linker, such as the linker B in accordance with the present disclosure.

[0040] The conjugate according to the present disclosure can prepared as laid out in the examples. In embodiments, the conjugate comprises a compound A of formula I according to the first aspect of the present invention, which conjugate is prepared by reacting said compound with an intermediate formed from a ligase binder C and a linker B according to the present disclosure. As such, the intermediate may be represented by B-C. In some embodiments, said intermediate is selected from the group consisting of: l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidine-4-carboxylic acid;

[0041] 1-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]piperidine-4-carboxylic acid;

[0042] 2-{ l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]piperidin-4-yl}acetic acid;

[0043] 3-{2-[2-(2-{[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl] amino } ethoxy jethoxy] ethoxy } propanoic acid;

[0044] 3-(2-{[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl] amino} ethoxy jpropanoic acid; 2-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperazin-l- yl}methyl)piperidin-l-yl] acetic acid ;

[0045] 2-[4-({l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4- yl } oxy)piperidin- 1 -yl] acetic acid;

[0046] 2-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]piperazin-l- yl}methyl)piperidin- 1 -yl] acetic acid;

[0047] 2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperazine-l- carbonyl}piperidin- 1 -yl)acetic acid;

[0048] 3-{2-[2-(2-{[3-(2,4-dioxo-l,3-diazinan-l-yl)-4- methoxyphenyl] formamido } ethoxy)ethoxy] ethoxy } propanoic acid;

[0049] 2- { 4 - [3 -(2,4-Dioxo- 1 ,3 -diazinan- 1 -yl)-4-methoxybenzoyl]piperazin- 1 -yl } acetic acid ;

[0050] 2-{[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetic acid;

[0051] 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin- 1 -yl)-2,3 -dihydro- IH-isoindole- 1 ,3 -dione;

[0052] 4-({2-[2-(2-Aminoethoxy)ethoxy]ethyl}amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-lH- isoindole- 1 ,3 -dione;

[0053] 4-[4-(2-Aminoethyl)piperidin-l-yl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole-l,3- dione;

[0054] 4- { [4,4'-Bipiperidin] - 1 -yl } -2-(2,6-dioxopiperidin-3 -yl)-2, 3 -dihydro- IH-isoindole- 1 ,3 -dione;

[0055] 2-(2,6-Dioxopiperidin-3-yl)-4-[4-(piperidin-4-yloxy)piperidin-l-yl]-2,3-dihydro-lH-isoindole- 1, 3-dione;

[0056] 4-[4-(Aminomethyl)piperidin- 1 -yl]-2-(2,6-dioxopiperidin-3-yl)-2,3 -dihydro- IH-isoindole- 1,3- dione;

[0057] 5 -(3 -Aminoazetidin- 1 -yl)-2-(2,6-dioxopiperidin-3 -yl)-2, 3 -dihydro- IH-isoindole- 1 ,3 -dione;

[0058] 5-[3 -(Aminomethyl)azetidin- 1 -yl] -2-(2,6-dioxopiperidin-3-yl)-2,3 -dihydro- IH-isoindole- 1,3- dione;

[0059] 2-(2,6-dioxopiperidin-3-yl)-4-{4-[(piperidin-4-yl)methyl]piperazin-l-yl}-2,3-dihydro-lH- isoindole- 1,3 -dione ;

[0060] 2-(2,6-dioxopiperidin-3-yl)-4-[4-(piperidine-4-carbonyl)piperazin-l-yl]-2,3-dihydro-lH- isoindole- 1,3 -dione ;

[0061] 2-(2,6-dioxopiperidin-3-yl)-5-{2-oxo-2-[4-(piperidin-4-yloxy)piperidin-l-yl]ethoxy}-2,3- dihydro- IH-isoindole- 1, 3-dione ; and

[0062] 5-{2-[4-(2-Aminoethyl)piperidin-l-yl]-2-oxoethoxy}-2-(2,6-dioxo piperidin-3-yl)-2,3-dihydro- IH-isoindole-l, 3-dione; in order to form said conjugate of Formula II.

[0063] In one embodiment, said conjugate is selected from the group consisting of:

[0064] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazin- 1 -yl }methyl)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ; 2'-Chloro-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{ l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro- lH-isoindol-5 -yl]piperidin-4-yl } acetam ) y exyl] amino } ethyl)-5 -[(pyridin-2-yl)methoxy] - [1, l'-biphenyl]-2 -carboxamide;

[0065] 2'-Chloro-6-fluoro-5 - { [(2S)-oxolan-2-yl]methoxy } -5 '-( 1 -phenyl -2- { [( 1 r,4r)-4-(2- { [2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0066] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(4-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl }piperidin- 1 - yl)acetamido] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0067] 2'-chloro-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-

[0068] 2.3-dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l-yl]acetamido}cyclohexyl]amino}ethyl)- 5-[(pyridin-2-yl)methoxy] -[ 1 , 1' -biphenyl] -2 -carboxamide;

[0069] 2'-Chloro-6-fluoro-5-methoxy-5'-(l-phenyl-2-{[(lr,4r)-4-(8-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-4-yl]oxy}octanamido)cyclohexyl]amino}ethyl)-[l,r-biphenyl]-2- carboxamide;

[0070] 2'-Chloro-6-fluoro-5-methoxy-5'-(l-phenyl-2-{[(lr,4r)-4-(3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4- yl] amino } ethoxy)ethoxy] ethoxy } propanamido)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ; l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]-JV-[(lr,4r)-4-[(2-{6'- carbamoyl-6-chloro-2'-fluoro-3 '-methoxy-[ 1 , 1 '-biphenyl] -3 -yl } -2- phenylethyl)amino] cyclohexyl] piperidine -4-carboxamide ;

[0071] 2'-Chloro-6-fluoro-5-methoxy-5'-(l-phenyl-2-{[(lr,4r)-4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-

[0072] 1.3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}ethoxy)propanamido]cyclohexyl]amino}ethyl)-[l,l'- biphenyl] -2-carboxamide;

[0073] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(3-{2-[2-(2-{[3-(2,4-dioxo-

[0074] 1 ,3 -diazinan- 1 -yl)-4- methoxyphenyl] formamido } ethoxy)ethoxy] ethoxy } propanamido)cyclohexyl] amino } ethyl) -[1,1'- biphenyl] -2-carboxamide;

[0075] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{4-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methoxybenzoyl]piperazin- 1 -yl } acetamido)cyclohexyl] amino } ethyl)-[ 1 , 1 '-biphenyl] -2- carboxamide;

[0076] 2'-Chloro-5,6-difluoro-5'-[(lR)-l-phenyl-2-{[(lr,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]-[l,l'-biphenyl]-2- carboxamide;

[0077] 2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(lR)-l-phenyl-2-{[(lr,4r)-4-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]- [1, l'-biphenyl]-2 -carboxamide; 2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(lR)-l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH- yl]piperidin-4-yl } oxy)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl] -[1,1 '-biphenyl] -2-carboxamide ;

[0078] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-JV-methyl-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4-yl } oxy)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0079] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazin- 1 -yl }methyl)piperidine- 1 - carbonyl] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0080] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl [ piperidine- 1 - carbonyl)cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2 -carboxamide;

[0081] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({2-[2-(2-{[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4- yl] amino } ethoxy)ethoxy] ethyl } carbamoyl) cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0082] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[(2-{l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4- yl } ethyl)carbamoyl] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0083] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{l'-[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl] -[4,4'-bipiperidine] - 1 -carbonyl } cyclohexyl] amino } ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0084] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4-yl } oxy)piperidine- 1 - carbonyl] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0085] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{[l-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]oxy}piperidine- 1 -carbonyl)cyclohexyl] amino } ethyl)- [ 1,1' -biphenyl] -2-carboxamide ;

[0086] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({2-[l-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetyl)piperidin-4- yl] ethyl } carbamoyl)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0087] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazine- 1 -carbonyl}cyclohexyl]amino}ethyl)-[ 1 , 1 '- biphenyl] -2-carboxamide;

[0088] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(2,6-dioxopiperidin- 3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4- yl } methyl)carbamoyl] cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({l-[2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]az y }carbamoyl)cyclohexyl]amino}ethyl)-[l,r- biphenyl] -2 -carboxamide;

[0089] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]azetidin-3-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0090] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({[l-(2-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4-yl]piperazin- 1 -yl} -2 -oxoethyl)- lH-pyrazol-4- yl]methyl } amino)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0091] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(4-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl [pipcridin- 1 -yl)-2- oxoethyl] - lH-pyrazol-4-yl}methyl)amino]cyclohexyl]amino} ethyl)-[ 1 , 1 '-biphenyl]-2 -carboxamide;

[0092] 2'-Chloro-JV-(2-{ 1 -[2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4- yl]piperidin-4-yl}ethyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0093] 2'-Chloro-JV-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]amino}ethoxy)ethoxy]ethyl}-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0094] 2'-Chloro-JV-({l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]azetidin-3- yl}methyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-aminocyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0095] 2'-Chloro-5 -(2- { [ 1 -(2- { 1 -[2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-5 - yl]piperidin-4-yl } acetyl)azetidin-3 -yl]oxy } ethoxy)-6-fluoro-5 '-( 1 -phenyl -2- { [( 1 r,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0096] 2'-Chloro-5-[2-( { 1 -[3 -(2-{ [2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxo-2,3 -dihydro- lH-isoindol-4- yl]amino } ethoxy )propanoyl]azetidin-3 -yl } oxy)ethoxy] -6-fluoro-5 '-( 1 -phenyl -2- { [( 1 r,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0097] 2'-Chloro-5-[2-({l-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]piperazine- 1 -carbonyl [pi pcridin- 1 -yl)acetyl]azetidin-3 -yl } oxy)ethoxy] -6-fluoro-5 '-( 1 -phenyl -2- { [( lr,4r)-4-aminocyclohexyl]amino}ethyl)-[ 1 , l'-biphenyl] -2 -carboxamide;

[0098] 2'-Chloro-5-{2-[(l-{l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5- yl]piperidine-4-carbonyl}azetidin-3-yl)oxy]ethoxy}-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ; and

[0099] 2'-Chloro-5 -(2- { [ 1 -(2- { [2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-5 - yl]oxy}acetyl)azetidin-3-yl]oxy}ethoxy)-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ; and

[0100] 2-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-4-methylphenoxy) acetic acid;

[0101] 4-chloro-3-(2,4 dioxotetrahydropyrimidin l(2H) yl)benzoic acid; 3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methoxybenzoic acid;

[0102] ( lr,4r)-4-(( 1 -(4-chloro-3-(2,4-dioxotetra y py midin- 1 (2H)-yl)benzoyl) piperidin-4- yl)oxy)cyclohexane- 1 -carboxylic acid; lr,4r)-4-((l-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methylphenoxy)acetyl)piperidin-4- yl)oxy)cyclohexane- 1 -carboxylic acid;

[0103] ( lr,4r)-4-(4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)benzoyl)piperazin- 1 - yl)cyclohexane-l -carboxylic acid— 2,2, 2-trifluoroacetic acid ;

[0104] ( lr,4r)-4-(4-(2-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-4-methylphenoxy)acetyl)piperazin- l-yl)cyclohexane-l -carboxylic acid ;

[0105] 4-[[ 1 -[3 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl] -4- piperidyl] oxy] cyclohexanecarboxylic acid;

[0106] 1 -[3 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl]piperidine-4-carboxylic acid;

[0107] 2-[ 1 -[3-(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl] -4-piperidyl]acetic acid;

[0108] 1 -[ 1 -[3-(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl]piperidine-4- carbonyl]piperidine-4-carboxylic acid;

[0109] 2-[ 1 -[ 1 -[3 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl]piperidine-4-carbonyl] -4- piperidyl] acetic acid;

[0110] 1 -[ 1 - [2- [3 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methyl-phenoxy]acetyl]piperidine-4- carbonyl]piperidine-4-carboxylic acid;

[0111] 2-[4-[[ 1 -[3-(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl]-4-piperidyl]methyl] - 1 - piperidyl] acetic acid ;

[0112] 2-[3-[3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methoxy-benzoyl]-3,9-diazaspiro[5.5]undecan- 9-yl]acetic acid ;

[0113] 2-[4-[ 1 -[3 -(2,4-Dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl] -4-piperidyl]- 1 - piperidyl] acetic acid ;

[0114] 2-[4-[[ 1 -[4-chloro-3-(2,4-Dioxohexahydropyrimidin- 1 -yl)benzoyl] -4-piperidyl]methyl] - 1 - piperidyl] acetic acid ;

[0115] 2-[4-[[ 1 -[3-(2,4-Dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl]-4-piperidyl]oxy] - 1 - piperidyl] acetic acid ;

[0116] 2-[4-[2-[ 1 -[3-(2,4-Dioxohexahydropyrimidin- 1 -yl)-4-methoxy-benzoyl] -4-piperidyl]ethyl]- 1 - piperidyl] acetic acid ;

[0117] 2-(4-{l-[3-(2,4-Dioxo-l,3-diazinan-l-yl)-4-methoxybenzoyl]piperidin-4-yl}piperazin-l-yl)acetic acid;

[0118] 2-[4-[[ 1 -[2-[3-(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methyl-phenoxy]acetyl] -4- piperidyl] methyl] -1 -piperidyl] acetic acid ;

[0119] 2-[4-[ 1 -[2-[3-(2,4-Dioxohexahydropyrimidin- 1 -yl)-4-methyl-phenoxy]acetyl] -4-piperidyl] - 1 - piperidyl] acetic acid ; 2-[3 - [2- [3 -(2,4-Dioxohexahydropyrimidin- 1 -yl)-4-methyl-phenoxy]acetyl] -3,9- diazaspiro[5.5]undecan-9-yl]acetic acid ;

[0120] 2-[4-[2-[l-[2-[3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methyl-phenoxy]acetyl]-4- piperidyl] ethyl] -1 -piperidyl] acetic acid ;

[0121] 2-[4-[[4-[[2-[3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methyl-phenoxy]acetyl]amino]-l- piperidyl] methyl] -1 -piperidyl] acetic acid ;

[0122] 2-[4-[4-[2-[3-(2,4-Dioxohexahydropyrimidin- 1 -yl)-4-methyl-phenoxy]acetyl]piperazin- 1 -yl]- 1 - piperidyl] acetic acid ;

[0123] 2-[4-[[4-[2-[3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methyl-phenoxy]acetyl]piperazin-l- yl]methyl]-l-piperidyl]acetic acid ;

[0124] 2-[4-[[ 1 -[2-[3-(2,4-Dioxohexahydropyrimidin- 1 -yl)-4-methyl-phenoxy]acetyl] -4-piperidyl]oxy] - 1 -piperidyl] acetic acid ;

[0125] 2-[4-(2,4-dioxohexahydropyrimidin-l-yl)-3-methyl-phenoxy] acetic acid ;

[0126] 2-[4-(2,4-dioxohexahydropyrimidin-l-yl)-3-methyl-phenoxy] acetic acid;

[0127] 2 2-[4-[[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl]-l- piperidyl] acetic acid ;

[0128] 1 - [2 -methoxy-5 - [4 -(4 -piperidylmethyl)piperidine - 1 -carbonyl] phenyl]hexahydropyrimidine -2,4- dione ;

[0129] N-(4-Aminobutyl)-3-(2,4-dioxohexahydropyrimidin-l-yl)-4-methoxy-benzamide ;

[0130] 1 - [2 -Methoxy-5 -(piperazine - 1 -carbonyl)phenyl] hexahydropyrimidine -2,4-dione ;

[0131] 1 -[5 -[4-(2-Aminoethyl)piperidine- 1 -carbonyl] -2-methoxy-phenyl]hexahydropyrimidine-2,4- dione ;

[0132] 1 -[5 -[4-(2-Aminoethoxy)piperidine- 1 -carbonyl] -2 -methoxy-phenyl] hexahydropyrimidine-2, 4- dione ; l-[5-(3,9-Diazaspiro[5.5]undecane-3-carbonyl)-2 -methoxy-phenyl] hexahydropyrimidine-2, 4- dione ; l-[5-(2,9-Diazaspiro[5.5]undecane-2-carbonyl)-2 -methoxy-phenyl] hexahydropyrimidine-2,4- dione ;

[0133] 1- [2 -Methoxy-5 -[4 -(4 -piperidyl) piperidine- 1 -carbonyl] phenyl] hexahydropyrimidine-2, 4-dione ;

[0134] 1 -[2 -Methoxy-5 -[4 -(4 -piperidyloxy) piperidine- 1 -carbonyl]phenyl] hexahydropyrimidine-2, 4- dione ;

[0135] 1 - [2 -Chloro-5 - [4 -(4 -piperidylmethyl) piperidine- 1 -carbonyl]phenyl] hexahydropyrimidine -2,4- dione ;

[0136] 1 - [2 -Methoxy-5 - [4 - [2 -(4-piperidyl) ethyl]piperidine - 1 -carbonyl]phenyl] hexahydropyrimidine -

[0137] 2,4-dione ;

[0138] 1 -[2-Methoxy-5-(4-piperazin- 1 -ylpiperidine- 1 -carbonyl)phenyl] hexahydropyrimidine-2, 4- dione ;

[0139] 3-(2,4-Dioxohexahydropyrimidin l yl) 4 methoxy N (4 piperidyl)benzamide ; 3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methoxy-N-(4-piperidylmethyl) benzamide ;

[0140] 3-(2,4-Dioxohexahydropyrimidin-l-yl)- y-N-[(3R)-3-piperidyl] benzamide ;

[0141] 3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methoxy-N-[(3S)-3-piperidyl] benzamide ;

[0142] 1 -[5 -[4-(4-Aminopiperidine- 1 -carbonyl)piperidine- 1 -carbonyl] -2-methoxy- phenyl]hexahydropyrimidine-2, 4-dione ;

[0143] 1 -[5 -[4-[4-(Aminomethyl)piperidine- 1 -carbonyl]piperidine- 1 -carbonyl] -2-methoxy- phenyl]hexahydropyrimidine-2, 4-dione ;

[0144] 1 -[5 -[4-[4-(2-Aminoethyl)piperidine- 1 -carbonyl]piperidine- 1 -carbonyl] -2 -methoxy - phenyl]hexahydropyrimidine-2, 4-dione ;

[0145] 1 -[5 -[4-[4-(aminomethyl)benzoyl]piperazine- 1 -carbonyl] -2-methoxy- phenyl]hexahydropyrimidine-2, 4-dione ;

[0146] 1 -[5 -[4-[[4-(aminomethyl)phenyl]methyl] -piperazine- 1 -carbonyl] -2 -methoxy - phenyl]hexahydropyrimidine-2, 4-dione ; l-[2-methoxy-5-(4-{[(lr,3r)-3-aminocyclobutyl]methyl}pipe- razine-l-carbonyl)phenyl]-l,3- diazinane-2, 4-dione ; l-[2-Methoxy-5-[4-[[l-(4-piperidylmethyl)-4-piperidyl]methyl]piperidine-l- carbonyl] phenyl] hexahydropyrimidine-2,4 -dione ;

[0147] 3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methoxy-N-[l-(4-piperidylmethyl)-4- piperidyl] benzamide ;

[0148] 3-(2,4-dioxohexahydropyrimidin-l-yl)-4-methoxy-N-[[l-(4-piperidylmethyl)-4- piperidyl]methyl]benzamide ;

[0149] 3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methoxy-N-[(3S)-l-(4-piperidyl methyl)-3- piperidyl] benzamide ;

[0150] 3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methoxy-N-[(3R)-l-(4-piperidylmethyl)-3- piperidyl] benzamide ;

[0151] 1 -[2-methoxy-4-[4-(piperidine-4-carbonyl)piperazine- 1 -carbonyl] phenyl] hexahydropyrimidine -

[0152] 2,4-dione ; l-(2-methyl-5-(2-oxo-2-(piperazin-l-yl)ethoxy)phenyl)dihydropyrimidine-2,4(lH,3H) -dione hydrochloride; l-[5-[2-[4-(2-Aminoethyl)-l-piperidyl]-2-oxo-ethoxy]-2-methyl-phenyl] hexahydropyrimidine -

[0153] 2,4-dione hydrochloride ;

[0154] 1 - [2 -Methyl-5 - [2 -oxo-2- [4 -(4-piperidylmethyl) - 1 - piperidyl] ethoxy] phenyl] hexahydropyrimidine-2,4 -dione hydrochloride ; l-[2-Methyl-5-[2-oxo-2-[4-(4-piperidyl)-l-piperidyl]ethoxy]phenyl] hexahydropyrimidine-2,4- dione ;

[0155] 1 - [2 -Methyl-5 - [2 -oxo-2- [4 -(4-piperidyloxy) - 1 -piperidyl] ethoxy] phenyl]hexahydropyrimidine -

[0156] 2,4-dione ; 1 - [2 -Methyl-5 - [2 -oxo-2- [4 - [2 - (4 -piperidyl)ethyl] - 1 -piperidyl] ethoxy] phenyl]hexahydropyrimidine-2, 4-dione ;

[0157] 2-[3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methyl-phenoxy]-N-(4-piperidyl)acetamide ;

[0158] 2-[3-(2,4-Dioxohexahydropyrimidin-l-yl)-4-methyl-phenoxy]-N-(4-piperidylmethyl)acetamide ;

[0159] 1 -[2-Methyl-5-[2-oxo-2-(4-piperazin- 1 -yl- 1 -piperidyl)ethoxy]phenyl]hexa hydropyrimidine -2,4- dione ;

[0160] 1-[5-[2-(3,9-Diazaspiro[5.5]undecan-3-yl)-2-oxo-ethoxy]-2-methyl-phenyl] hexahydropyrimidine-2, 4-dione ;

[0161] 1 -[5 -[2-[4-(4-Aminopiperidine- 1 -carbonyl)- 1 -piperidyl] -2 -oxo-ethoxy] -2 -methyl - phenyl]hexahydropyrimidine-2, 4-dione ;

[0162] 1 -[5 -[2-[4-[4-(aminomethyl)piperidine- 1 -carbonyl] -1 -piperidyl] -2 -oxo-ethoxy] -2 -methyl - phenyl]hexahydropyrimidine-2, 4-dione ;

[0163] 1 -[5 -[2-[4-[[4-(aminomethyl)phenyl]methyl]piperazin- 1 -yl] -2 -oxo-ethoxy] -2 -methyl - phenyl]hexahydropyrimidine-2, 4-dione ;

[0164] 1 -[5 -[4-[(3-aminocyclobutyl)methyl]piperazine- 1 -carbonyl] -2 -methoxy - phenyl]hexahydropyrimidine-2, 4-dione ;

[0165] 2-[3 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methyl -phenoxy] -N-[ 1 -(4-piperidylmethyl)-4- piperidyl] acetamide ;

[0166] 2 2-[3-(2,4-dioxohexahydropyrimidin-l-yl)-4-methyl-phenoxy]-N-[[l-(4-piperidyhnethyl)-4- piperidyl] methyl] acetamide ; l-[2-methyl-5-[2-oxo-2-[4-[[l-(4-piperidylmethyl)-4-piperidyl]methyl]-l- piperidyl]ethoxy]phenyl]hexahydropyrimidine-2, 4-dione ; l-[2-methyl-5-[2-oxo-2-[4-[l-(4-piperidyhnethyl)-4-piperidyl]-l- piperidyl]ethoxy]phenyl]hexahydropyrimidine-2, 4-dione ;

[0167] 1 - [2 -methyl-5 - [2 -oxo-2- [4 -(4-piperidylmethyl)piperazin- 1 - yl]ethoxy]phenyl]hexahydropyrimidine-2, 4-dione ; l-[2-Methyl-4-[2-oxo-2-[4-(4-piperidyloxy)-l-piperidyl]ethoxy]phenyl]hexahydropyrimidine- 2, 4-dione ;

[0168] 1 - [2 -Methyl-4- [2 -oxo-2- [4 -(4-piperidylmethyl) - 1 -piperidyl] ethoxy]phenyl]hexahydropyrimidine-2, 4-dione ;

[0169] 1-[2-Methyl-4-[2-oxo-2-[4-(4-piperidyl)-l-piperidyl]ethoxy]phenyl] hexahydropyrimidine-2, 4- dione ;

[0170] 2-(2,6-dioxo-3-piperidyl)-4-[4-(4-piperidylmethyl)-l-piperidyl]isoindoline-l,3-dione ; and

[0171] 3-(3-{4-[(piperidin-4-yl)methyl]piperidine-l-carbonyl}phenyl)piperidine-2, 6-dione Said intermediate may be in the form of a salt, such as a trifluoroacetate salt.

[0172] The present disclosure presents non-limiting examples of the conjugates according to the present invention. In some embodiments said conjugate is selected from the list consisting of: 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH- yl]piperazin- 1 -yl }methyl)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0173] 2'-Chloro-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{ l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro- lH-isoindol-5 -yl]piperidin-4-yl } acetamido)cyclohexyl] amino } ethyl)-5 -[(pyridin-2-yl)methoxy] - [1, l'-biphenyl]-2 -carboxamide;

[0174] 2'-Chloro-6-fluoro-5 - { [(2S)-oxolan-2-yl]methoxy } -5 '-( 1 -phenyl -2- { [( 1 r,4r)-4-(2- { [2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0175] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(4-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl }piperidin- 1 - yl)acetamido] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0176] 2'-chloro-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-

[0177] 2.3-dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l-yl]acetamido}cyclohexyl]amino}ethyl)- 5-[(pyridin-2-yl)methoxy] -[ 1 , 1' -biphenyl] -2 -carboxamide;

[0178] 2'-Chloro-6-fluoro-5-methoxy-5'-(l-phenyl-2-{[(lr,4r)-4-(8-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-4-yl]oxy}octanamido)cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2- carboxamide;

[0179] 2'-Chloro-6-fluoro-5-methoxy-5'-(l-phenyl-2-{[(lr,4r)-4-(3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4- yl] amino } ethoxy)ethoxy] ethoxy } propanamido)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ; l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]-JV-[(lr,4r)-4-[(2-{6'- carbamoyl-6-chloro-2'-fluoro-3 '-methoxy-[ 1 , 1 '-biphenyl] -3 -yl } -2- phenylethyl)amino] cyclohexyl] piperidine -4-carboxamide ;

[0180] 2'-Chloro-6-fluoro-5-methoxy-5'-(l-phenyl-2-{[(lr,4r)-4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-

[0181] 1.3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}ethoxy)propanamido]cyclohexyl]amino}ethyl)-[l,l'- biphenyl] -2-carboxamide;

[0182] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(3-{2-[2-(2-{[3-(2,4-dioxo-

[0183] 1 ,3 -diazinan- 1 -yl)-4- methoxyphenyl] formamido } ethoxy)ethoxy] ethoxy } propanamido)cyclohexyl] amino } ethyl) -[1,1'- biphenyl] -2-carboxamide;

[0184] 2'-Chloro-6-fluoro-5-(2-hydroxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{4-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methoxybenzoyl]piperazin- 1 -yl } acetamido)cyclohexyl] amino } ethyl)-[ 1 , 1 '-biphenyl] -2- carboxamide;

[0185] 2'-Chloro-5,6-difluoro-5'-[(lR)-l-phenyl-2-{[(lr,4r)-4-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]-[l,l'-biphenyl]-2- carboxamide; 2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(lR)-l-phenyl-2-{[(lr,4r)-4-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- yl]oxy}acetamido)cyclohexyl]amino}ethyl]- [1, l'-biphenyl]-2 -carboxamide;

[0186] 2',4'-dichloro-6-fluoro-5-(2-methoxyethoxy)-5'-[(lR)-l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4-yl } oxy)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl] -[1,1 '-biphenyl] -2-carboxamide ;

[0187] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-JV-methyl-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4-yl } oxy)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0188] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazin- 1 -yl }methyl)piperidine- 1 - carbonyl] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0189] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl [ piperidine- 1 - carbonyl)cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2 -carboxamide;

[0190] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({2-[2-(2-{[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4- yl] amino } ethoxy)ethoxy] ethyl } carbamoyl) cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0191] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[(2-{l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4- yl } ethyl)carbamoyl] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0192] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{l'-[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl] -[4,4'-bipiperidine] - 1 -carbonyl } cyclohexyl] amino } ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0193] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4-yl } oxy)piperidine- 1 - carbonyl] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0194] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{[l-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]oxy}piperidine- 1 -carbonyl)cyclohexyl] amino } ethyl)- [ 1,1' -biphenyl] -2-carboxamide ;

[0195] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({2-[l-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetyl)piperidin-4- yl] ethyl } carbamoyl)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0196] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazine- 1 -carbonyl}cyclohexyl]amino}ethyl)-[ 1 , 1 '- biphenyl] -2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(2,6-dioxopiperidin- 3 -yl)- 1 ,3 -dioxo-2, 3 -dihydro- lH-isoindol-4-yl]p p yl } methyl)carbamoyl] cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2 -carboxamide ;

[0197] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({l-[2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]azetidin-3-yl}carbamoyl)cyclohexyl]amino}ethyl)-[l,r- biphenyl] -2 -carboxamide;

[0198] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]azetidin-3-yl}methyl)carbamoyl]cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0199] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({[l-(2-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2, 3 -dihydro-lH-isoindol-4-yl]piperazin- 1 -yl} -2 -oxoethyl)- lH-pyrazol-4- yl]methyl } amino)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0200] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(4-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2, 3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl }piperidin- 1 -yl)-2- oxoethyl] - lH-pyrazol-4-yl}methyl)amino]cyclohexyl]amino} ethyl)-[ 1 , 1 '-biphenyl]-2 -carboxamide;

[0201] 2'-Chloro-JV-(2-{ 1 -[2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxo-2, 3 -dihydro-lH-isoindol-4- yl]piperidin-4-yl}ethyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0202] 2'-Chloro-JV-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]amino}ethoxy)ethoxy]ethyl}-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0203] 2'-Chloro-JV-({l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]azetidin-3- yl}methyl)-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-aminocyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2 -carboxamide;

[0204] 2'-Chloro-5 -(2- { [ 1 -(2- { 1 -[2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2, 3 -dihydro- lH-isoindol-5 - yl]piperidin-4-yl } acetyl)azetidin-3 -yl]oxy } ethoxy)-6-fluoro-5 '-( 1 -phenyl -2- { [( 1 r,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0205] 2'-Chloro-5-[2-( { 1 -[3 -(2-{ [2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxo-2,3 -dihydro- lH-isoindol-4- yl]amino } ethoxy )propanoyl]azetidin-3 -yl } oxy)ethoxy] -6-fluoro-5 '-( 1 -phenyl -2- { [( 1 r,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ;

[0206] 2'-Chloro-5-[2-({l-[2-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]piperazine- 1 -carbonyl } pi pcridin- 1 -yl)acetyl]azetidin-3 -yl } oxy)ethoxy] -6-fluoro-5 '-( 1 -phenyl -2- { [( lr,4r)-4-aminocyclohexyl]amino}ethyl)-[ 1 , l'-biphenyl] -2 -carboxamide;

[0207] 2'-Chloro-5-{2-[(l-{l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5- yl]piperidine-4-carbonyl}azetidin-3-yl)oxy]ethoxy}-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide ; and

[0208] 2'-Chloro-5 -(2- { [ 1 -(2- { [2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2, 3 -dihydro- lH-isoindol-5 - yl]oxy}acetyl)azetidin-3 yl]oxy}ethoxy) 6 fluoro 5' (l phenyl 2 {[(lr 4r) 4 aminocyclohcxyl |amino[cthyl)-| 1.1 '-biphenyl |-2-carboxamidc: and / or selected from the group consisting of

[0209] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{4-[4-(2,4-dioxo-l,3-diazinan-l- yl)-3-methoxybenzoyl]piperazine-l-carbonyl}piperidine-l-carbonyl)cyclohexyl]amino}ethyl)-[l,r- biphenyl] -2-carboxamide;

[0210] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[3-(2,4-dioxo-l,3-diazinan-l- yl)-4-methoxybenzoyl]piperidin-4-yl } oxy)piperidine- 1 -carbonyl] cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide;

[0211] 2'-Chloro-6-fluoro-5 -(2-methoxyethoxy)-5 '-( 1 -phenyl-2- { [( 1 r,4r)-4- [4-( { 1 - [2-(2,6-dioxopiperidin-3 -yl)-

[0212] 1.3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4-yl}oxy)piperidine-l-carbonyl] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0213] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[(2-{l-[2-(2,6-dioxopiperidin-3-yl)-

[0214] 1.3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4-yl}ethyl)carbamoyl]cyclohexyl]amino}ethyl)-[l,r- biphenyl] -2-carboxamide;

[0215] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[3-(2,4-dioxo-l,3-diazinan-l- yl)-4-methoxybenzoyl]piperidin-4-yl}methyl) piperidine- 1 -carbonyl] cyclohexyl] amino } ethyl)- [1,1'- biphenyl] -2-carboxamide;

[0216] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-(2-{l-[3-(2,4-dioxo-l,3-diazinan-

[0217] 1 -yl)-4-methoxybenzoyl]piperidin-4-yl } ethyl) piperidine- 1 -carbonyl] cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide;

[0218] 2'-Chloro-6-fhroro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[(l-{2-[3-(2,4-dioxo-l,3- diazinan-l-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidine-l-carbonyl} cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0219] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[(2-{l-[3-(2,4-dioxo-l,3-diazinan-l- yl)-4-methoxybenzoyl]piperidin-4-yl } ethyl) carbamoyl] cyclohexyl] amino [ethyl)- [ 1 , 1 '-biphenyl] -2- carboxamide;

[0220] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[(4-{[3-(2,4-dioxo-l,3-diazinan-l- yl)-4-methoxyphenyl]formamido}butyl)carbamoyl]cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2- carboxamide;

[0221] 2'-Chloro-6-fhroro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{[2-(l-{2-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methylphenoxy]acetyl[ piperidin-4-yl)ethyl] carbamoyl [cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide;

[0222] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(l'-{2-[3-(2,4-dioxo-l,3-diazinan-l- yl)-4-methylphenoxy]acetyl } - [4,4'-bipiperidine] - 1 -carbonyl)cyclohexyl] amino [ethyl)- [ 1 , 1 '-biphenyl] -2- carboxamide;

[0223] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{9-[3-(2,4-dioxo-l,3-diazinan-l-yl)- 4-methoxybenzoyl]-3,9-diazaspiro[5;5] undecane-3-carbonyl[cyclohexyl] amino}ethyl)-[l,l'-biphenyl]- 2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{r-[3-(2,4-dioxo-l,3-diazinan-l-yl)-

[0224] 4-methoxybenzoyl]-[4,4'-bipiperidine]-l-carbony } y xyl]amino}ethyl)-[l,l'-biphenyl]-2- carboxamide;

[0225] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{2-[3-(2,4-dioxo-l,3-diazinan-l- yl)-4-methylphenoxy]acetyl }piperazine- 1 -carbonyl)cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2- carboxamide;

[0226] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[4-chloro-3-(2,4-dioxo-l,3- diazinan- 1 -yl)benzoyl]piperidin-4-yl }methyl) piperidine- 1 -carbonyl] cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide;

[0227] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[3-(2,4-dioxo-l,3-diazinan-l-yl)- 4-methoxybenzoyl]piperazine- 1 -carbonyl } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0228] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{[2-({l-[3-(2,4-dioxo-l,3-diazinan-

[0229] 1 -yl)-4-methoxybenzoyl]piperidin-4-yl } oxy) ethyl] carbamoyl } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] - 2-carboxamide;

[0230] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[3-(2,4-dioxo-l,3-diazinan-l-yl)- 4-methoxybenzoyl]-2,9-diazaspiro[5;5]undecane-9-carbonyl}cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2- carboxamide;

[0231] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{l'-[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro- lH-isoindol-4-yl] - [4,4'-bipiperidine] - 1 -carbonyl } cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide;

[0232] 2'-Chloro-6-fluoro-5 -(2-methoxyethoxy)-5 '-( 1 -phenyl-2- { [( 1 r,4r)-4- [4-( { 1 - [2-(2,6-dioxopiperidin-3-yl)-

[0233] 1.3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4-yl}methyl)piperidine-l- carbonyl] cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0234] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-(2-{l-[3-(2,4-dioxo-l,3- diazinan- l-yl)-4-methoxybenzoyl]piperidin-4-yl}ethyl)piperidine-l-carbonyl]cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2-carboxamide;

[0235] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[3-(2,4-dioxo-l,3- diazinan- l-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidine-l-carbonyl] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0236] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4-(4- { [4-( { 1 -[3-(2,4-dioxo-

[0237] 1.3-diazinan-l-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl) piperidin-l-yl]methyl}piperidine-l- carbonyl)cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide;

[0238] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{[(lr,3r)-3-({4-[3-(2,4- dioxo- 1 ,3-diazinan- 1 -yl)-4-methoxybenzoyl]piperazin- 1 -yl } methyl)cyclobutyl]carbamoyl } cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0239] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({4-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methoxybenzamido]piperidin- 1 -yl }methyl)piperidine- 1 -carbonyl] cyclohexyl] amino } ethyl) [1 1 ' biphenyl] 2 carboxamide; 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{[4-({[3-(2,4-dioxo-l,3- diazinan-l-yl)-4-methoxyphenyl]formamido}m y )p p idin-l-yl]methyl}piperidine-l-carbonyl) cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0240] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{[(3S)-3-[3-(2,4-dioxo-

[0241] 1 ,3 -diazinan- 1 -yl)-4-methoxybenzamido]piperidin- 1 -yl]methyl [piperidine- 1 -carbonyl) cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0242] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(4-{[(3R)-3-[3-(2,4-dioxo-

[0243] 1 ,3 -diazinan- 1 -yl)-4-methoxybenzamido]piperidin- 1 -yl]methyl [piperidine- 1 -carbonyl) cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0244] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- { [2-( 1 - { 1- [3-(2,4-dioxo-

[0245] 1.3-diazinan-l-yl)-4-methoxybenzoyl]piperidine-4-carbonyl[piperidin-4- yl)ethyl]carbamoyl[cyclohexyl]amino[ethyl)-[l,r-biphenyl]-2-carboxamide;

[0246] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy[-5'-(l-phenyl-2-{[(lr,4r)-4-{[(l-{ l-[3-(2,4-dioxo-l,3- diazinan- l-yl)-4-methoxybenzoyl]piperidine-4-carbonyl[ piperidin-4-yl)methyl]carbamoyl[ cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0247] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy[-5'-(l-phenyl-2-{[(lr,4r)-4-[(l-{l-[3-(2,4-dioxo-l,3- diazinan- l-yl)-4-methoxybenzoyl]piperidine-4-carbonyl[piperidin-4-yl)carbamoyl] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0248] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy[-5'-(l-phenyl-2-{[(lr,4r)-4-{[(4-{4-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methoxybenzoyl]piperazine- 1 - carbonyl } phenyl)methyl] carbamoyl } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0249] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy[-5'-(l-phenyl-2-{[(lr,4r)-4-({[4-({4-[3-(2,4-dioxo-l,3- diazinan- l-yl)-4-methoxybenzoyl]piperazin-l-yl[methyl) phenyl]methyl } carbamoyl)cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide;

[0250] 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy[-5'-(l-phenyl-2-{[(lr,4r)-4-{[2-(l-{l-[3-(2,4- dioxo- 1,3-diazinan- l-yl)-4-methoxybenzoyl]piperidine-4-carbonyl[piperidin-4- yl)ethyl]carbamoyl[cyclohexyl]amino[ethyl)-[l,r-biphenyl]-2-carboxamide;

[0251] 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy[-5'-(l-phenyl-2-{[(lr,4r)-4-({[l-(l-{2-[3-(2,4- dioxo- 1,3-diazinan- l-yl)-4-methylphenoxy]acetyl[piperidine-4-carbonyl)piperidin-4- yl]methyl } carbamoyl) cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0252] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy[-5'-(l-phenyl-2-{[(lr,4r)-4-({[l-(l-{2-[3-(2,4-dioxo-

[0253] 1.3-diazinan- l-yl)-4-methylphenoxy]acetyl[piperidine-4-carbonyl)piperidin-4-yl]methyl[ carbamoyl)cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide;

[0254] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- { [ 1 -( 1 - {2- [3-(2,4-dioxo-

[0255] 1.3-diazinan-l-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)piperidin-4-yl]carbamoyl[ cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide; 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[({4-[(4-{2-[3-(2,4-dioxo-

[0256] 1.3-diazinan-l-yl)-4-methylphenoxy]acetyl}pip yl)methyl]phenyl }methyl)carbamoyl] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0257] 2',4'-Dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[({4-[(4-{2-[3-(2,4- dioxo- l,3-diazinan-l-yl)-4-methylphenoxy]acetyl}piperazin-l- yl)methyl]phenyl }methyl)carbamoyl] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0258] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- {4-[( 1 - {2- [3-(2,4-dioxo-

[0259] 1.3-diazinan-l-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidine-l-carbonyl} cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0260] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{[(lr,3r)-3-[(4-{2-[3-(2,4- dioxo- l,3-diazinan-l-yl)-4-methylphenoxy] acetyl [piperazin- l-yl)methyl] cyclobutyl] carbamoyl } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide;

[0261] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[2-(l-{2-[3-(2,4-dioxo-

[0262] 1.3-diazinan-l-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)ethyl]piperidine-l-carbonyl} cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0263] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- {4-[(4- {2- [3-(2,4-dioxo-

[0264] 1.3-diazinan-l-yl)-4-methylphenoxy]acetamido}piperidin-l-yl)methyl]piperidine-l-carbonyl} cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0265] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4-(4- { [4-({2-[3-(2,4-dioxo-

[0266] 1.3-diazinan-l-yl)-4-methylphenoxy]acetamido}methyl)piperidin-l-yl]methyl}piperidine-l- carbonyl)cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0267] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({4-[(l-{2-[3-(2,4- dioxo- l,3-diazinan-l-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin-l-yl}methyl) piperidine- 1 -carbonyl] cyclohexyl] amino} ethyl)-[l,l'-biphenyl]-2-carboxamide;

[0268] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[(l'-{2-[3-(2,4-dioxo-

[0269] 1 ,3 -diazinan- 1 -yl)-4-methylphenoxy]acetyl } - [4,4'-bipiperidin] - 1 -yl)methyl]piperidine- 1 -carbonyl } cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0270] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- {4-[(4- {2- [3-(2,4-dioxo-

[0271] 1.3 -diazinan- 1 -yl)-4-methylphenoxy]acetyl [piperazin- 1 -yl)methyl]piperidine- 1 -carbonyl } cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0272] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- {4-[( 1 - {2- [3-(2,4-dioxo-

[0273] 1.3-diazinan-l-yl)-4-methylphenoxy]acetyl[piperidin-4-yl)oxy]piperidine-l-carbonyl[ cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0274] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(l'-{2-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methylphenoxy]acetyl[ - [4,4'-bipiperidine] - 1 -carbonyl)cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide; 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- {4-[( 1 - {2- [4-(2,4-dioxo-

[0275] 1.3-diazinan-l-yl)-3-methylphenoxy]acetyl}pip y )methyl]piperidine-l-carbonyl} cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0276] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[(l-{2-[4-(2,4-dioxo-

[0277] 1.3-diazinan-l-yl)-3-methylphenoxy]acetyl}piperidin-4-yl)oxy]piperidine-l-carbonyl} cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0278] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(l'-{2-[4-(2,4-dioxo-l,3- diazinan-l-yl)-3-methylphenoxy]acetyl}-[4,4'-bipiperidine]-l-carbonyl)cyclohexyl] amino}ethyl)-[l,l'- biphenyl] -2-carboxamide;

[0279] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4-yl}oxy)piperidine-l- carbonyl] cyclohexyl] amino}ethyl)-[l, l'-biphenyl]-2-carboxamide;

[0280] 2',4'-dichloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4-yl}oxy)piperidine-l-carbonyl] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0281] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[3-(2,4-dioxo-

[0282] 1 ,3 -diazinan- 1 -yl)-4-methoxybenzoyl]piperidin-4-yl } oxy)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0283] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[3-(2,4-dioxo-

[0284] 1.3-diazinan-l-yl)-4-methoxybenzoyl]piperidin-4-yl}methyl)piperidin-l- yl] acetamido } cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0285] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[4-chloro-3- (2,4-dioxo- 1 ,3-diazinan- 1 -yl)benzoyl]piperidin-4-yl}methyl)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0286] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{l'-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methoxybenzoyl] - [4,4'-bipiperidin] - 1 -yl } acetamido)cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide;

[0287] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{9-[3-(2,4-dioxo-l,3- diazinan- 1 -yl)-4-methoxybenzoyl] -3 ,9-diazaspiro [5 ;5]undecan-3 - yl } acetamido)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0288] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-(2-{l-[3-(2,4-dioxo-

[0289] 1.3-diazinan- 1 -yl)-4-methoxybenzoyl]piperidin-4-yl } ethyl)piperidin- 1 -yl] acetamido } cyclo hexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0290] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(4-{l-[3-(2,4-dioxo-

[0291] 1 ,3-diazinan- 1 -yl)-4-methoxybenzoyl]piperidin-4-yl [piperazin- 1 -yl)acetamido] cyclohexyl] amino } ethyl)- [1, l'-biphenyl]-2-carboxamide;

[0292] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-({l-[3-(2,4- dioxo- l,3-diazinan-l-yl) 4 methoxybenzoyl]piperidin 4 yl } oxy)cyclohexaneamido] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide ;

[0293] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy} ( phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-({ l-[4-chloro-3-

[0294] (2,4-dioxo-l,3-diazinan-l-yl)benzoyl]piperidin-4-yl}oxy)cyclohexaneamido]cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2-carboxamide;

[0295] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-{4-[4-chloro-3-

[0296] (2,4-dioxo- 1 ,3-diazinan- 1 -yl)benzoyl]piperidin- 1 -yl } cyclohexaneamido] cyclohexyl] amino } ethyl)- [1,1'- biphenyl] -2-carboxamide; l-{ l-[3-(2,4-Dioxo-l,3-diazinan-l-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}-N-[(lr,4r)-4-{[2-(6'- carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxolan-2-yl]methoxy}-[l,l'-biphenyl]-3-yl)-2- phenylethyl] amino} cyclohexyl]piperidine-4-carboxamide;

[0297] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(l-{ l-[3-(2,4-dioxo-

[0298] 1.3-diazinan-l-yl)-4-methoxybenzoyl]piperidine-4-carbonyl}piperidin-4-yl)acetamido]cyclo hexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0299] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[3-(2,4-dioxo-l,3- diazinan-l-yl)-4-methylphenoxy]acetamido}cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2-carboxamide;

[0300] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(l'-{2-[3-(2,4-dioxo-

[0301] 1.3-diazinan- 1 -yl)-4-methylphenoxy]acetyl } - [4,4'-bipiperidin] - 1 -yl)acetamido] cyclohexyl] amino } ethyl)- [1, l'-biphenyl]-2-carboxamide;

[0302] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(9-{2-[3-(2,4-dioxo-

[0303] 1.3-diazinan- l-yl)-4-methylphenoxy]acetyl}-3,9-diazaspiro[5;5]undecan-3- yl)acetamido] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0304] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{4-[(l-{2-[3-(2,4- dioxo- 1,3-diazinan- l-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)methyl]piperidin- 1- yl } acetamido)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0305] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{4-[2-(l-{2-[3-(2,4- dioxo- 1,3-diazinan- l-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)ethyl]piperidin-l-yl}acetamido) cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0306] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4-(2- {4- [(4- { 2- [3 - (2,4- dioxo- 1 ,3-diazinan- 1 -yl)-4-methylphenoxy] acetamido [piperidin- 1 -yl)methyl]piperidin- 1 -yl } acetamido) cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide;

[0307] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-(l-{2-[3-(2,4-dioxo-

[0308] 1.3-diazinan- 1 -yl)-4-methylphenoxy]acetyl }piperidin-4-yl)piperazin- 1 -yl] acetamido } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0309] 2'-chloro-6-fluoro-5 - { [(2S)-oxolan-2-yl]methoxy } -5 '-( 1 -phenyl-2- { [( 1 r,4r)-4-(2- {4- [(4- {2- [3 -(2,4-dioxo-

[0310] 1 ,3-diazinan- 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)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-(2-{4-[(l-{2-[3-(2,4- dioxo-l,3-diazinan-l-yl)-4-methylphenoxy]acety }p p n-4-yl)oxy]piperidin-l- yl } acetamido)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0311] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-(4-{2-[3-(2,4-dioxo- l,3-diazinan-l-yl)-4-methylphenoxy]acetyl}piperazin-l-yl) cyclohexaneamido]cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2-carboxamide; l-(l-{2-[3-(2,4-dioxo-l,3-diazinan-l-yl)-4-methylphenoxy]acetyl}piperidine-4-carbonyl)-N-[(lr,4r)-4-

[0312] {[2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-{[(2S)-oxolan-2-yl]methoxy}-[l,r-biphenyl]-3-yl)-2- phenylethyl]amino}cyclohexyl]piperidine-4-carboxamide;

[0313] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-[(l-{2-[3-(2,4- dioxo- l,3-diazinan-l-yl)-4-methylphenoxy] acetyl}piperidin-4-yl)oxy]cyclohexane amido]cyclohexyl]amino}ethyl)-[l,r-biphenyl]-2-carboxamide;

[0314] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4-[2-( 1 '- {2-[4-(2,4-dioxo-

[0315] 1 ,3 -diazinan- 1 -y 1) - 3 -methylphenoxy] acetyl } - [4,4'-bipiperidin] - 1 -yl)acetamido] cyclohexyl] amino } ethyl)- [1, l'-biphenyl]-2-carboxamide;

[0316] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4-(2- { [2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2-carboxamide;

[0317] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- { 2- [4-( { 1 - [2-(2, 6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4-yl}oxy)piperidin-l- yl] acetamido } cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0318] 2'-Chloro-6-fluoro-5- { [(2S)-oxolan-2-yl]methoxy } -5'-( 1 -phenyl-2- { [( lr,4r)-4- { 2- [4-( { 1- [2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]piperidin-4-yl}methyl)piperidin-l- yl] acetamido } cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0319] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(4-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2,3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl [pipcridin- 1 - yl)acetamido] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ;

[0320] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-[(l-{2-[3-(2,4- dioxo- 1,3-diazinan- l-yl)-4-methylphenoxy]acetyl}piperidin-4- yl)oxy]cyclohexaneamido]cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2-carboxamide;

[0321] 2'-Chloro-6-fluoro-5-methoxy-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-[(l-{2-[3-(2,4-dioxo-l,3-diazinan-l- yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamido]cyclohexyl]amino}ethyl)-[l,l'- biphenyl] -2-carboxamide;

[0322] 2'-Chloro-5-(dimethylcarbamoyl)methoxy]-3',6-difluoro-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-[(l-{2-[3- (2,4-dioxo-l,3-diazinan-l-yl)-4-methylphenoxy]acetyl} piperidin-4-yl)oxy]cyclohexaneamido] cyclohexyl] amino } ethyl)- [1,1 '-biphenyl] -2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-N-methyl-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-[(l-{2-[3-(2,4- dioxo- 1,3-diazinan- l-yl)-4-methylphenoxy]acety }p p n-4- yl)oxy]cyclohexaneamido]cyclohexyl]amino}ethyl)-[l,l'-biphenyl]-2-carboxamide;

[0323] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-[(l-{2-[3-(2,4-dioxo-l,3- diazinan-l-yl)-4-methylphenoxy]acetyl}piperidin-4-yl)oxy]cyclohexaneamido]cyclohexyl]amino}ethyl)- [1, l'-biphenyl]-2-carboxamide;

[0324] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({l-[3-(2,6- dioxopiperidin-3-yl)benzoyl]piperidin-4-yl}methyl)piperidine-l-carbonyl]cyclohexyl]amino}ethyl)- [1, l'-biphenyl] -2-carboxamide: and

[0325] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[4-({4-[3-(2,6- dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl]piperidin-l-yl}methyl)piperidine-l- carbonyl] cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide .

[0326] In one embodiment, said conjugate is selected from the list consisting of:

[0327] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(2,6-dioxopiperidin- 3 -y 1) - 1 ,3 -dioxo-2, 3 -dihydro- lH-isoindol-4-yl]piperidin-4- yl } me thy I jcarbam oy 11 cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide

[0328] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({[l-(2-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2, 3 -dihydro-lH-isoindol-4-yl]piperazin- 1 -yl} -2 -oxoethyl)- lH-pyrazol-4- yl]methyl } amino)cyclohexyl] amino } ethyl) - [ 1 , 1 '-biphenyl] -2-carboxamide 2'-chloro-6-fluoro-5 - { [(2S)- oxolan-2-yl]methoxy}-5'-(l -phenyl -2-{[(lr,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2, 3- dihydro- lH-isoindol-4-yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl] acetamido } cyclohexyl] amino } ethyl) - [1,1 '-biphenyl] -2-carboxamide

[0329] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(4-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2, 3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl } pipcridin- 1 - yl)acetamido] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide

[0330] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-[({l-[2-(4-{4-[2-(2,6- dioxopiperidin-3-yl)- 1 ,3 -dioxo-2, 3 -dihydro-lH-isoindol-4-yl]piperazine- 1 -carbonyl [pipcridin- 1 -yl) -2- oxoethyl] - lH-pyrazol-4-yl}methyl)amino]cyclohexyl]amino} ethyl)-[ 1 , 1 '-biphenyl] -2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({2-[l-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetyl)piperidin-4- yl] ethyl } carbamoyl)cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide

[0331] 2'-Chloro-6-fluoro-5 - { [(2S)-oxolan-2-yl]methoxy } -5 '-( 1 -phenyl -2- { [( 1 r,4r)-4-(2- { [2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl)- [1,1 '-biphenyl] -2-carboxamide

[0332] 2',4'-dichloro-6-fhioro-5-(2-methoxyethoxy)-5'-[(lR)-l-phenyl-2-{[(lr,4r)-4-(2-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]oxy}acetamido)cyclohexyl]amino}ethyl]- [1,1 '-biphenyl] -2-carboxamide 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({l-[2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]az y }carbamoyl)cyclohexyl]amino}ethyl)-[l,r- biphenyl] -2 -carboxamide

[0333] 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-{4-[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazine- 1 -carbonyl}cyclohexyl]amino}ethyl)-[ 1 , 1'- biphenyl] -2 -carboxamide

[0334] 2'-Chloro-5 -(2- { [ 1 -(2- { 1 -[2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-5 - yl]piperidin-4-yl } acetyl)azetidin-3 -yl]oxy } ethoxy)-6-fluoro-5 '-( 1 -phenyl -2- { [( 1 r,4r)-4- aminocyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2 -carboxamide and

[0335] 2'-chloro-6-fluoro-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- 2,3-dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l-yl]acetamido}cyclohexyl]amino}ethyl)- 5 - [(pyridin-2-yl)methoxy] -[1,1' -biphenyl] -2 -carboxamide .

[0336] In a specifically preferred embodiment, the conjugate is selected from the group consisting of

[0337] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(4-{4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazine- 1 -carbonyl} piperidin;

[0338] 2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({4-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperazin- 1 -yl }methyl)piperidin- 1 - yl] acetamido } cyclohexyl] amino } ethyl)- [ 1 , 1 '-biphenyl] -2-carboxamide ;

[0339] 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(l-phenyl-2-{[(lr,4r)-4-({2-[2-(2-{[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-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'-(l-phenyl-2-{[(lr,4r)-4-[(2-{l-[2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl]piperidin-4- yl } ethyl)carbamoyl] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide .

[0340] In one embodiment, said conjugate is selected from the group consisting of:

[0341] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[4- chloro-3 -(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)benzoyl]piperidin-4-yl }methyl)piperidin- 1 - yl]acetamido}cyclohexyl]amino}ethyl)-[l,r-biphenyl]-2-carboxamide;2'-Chloro-6-fluoro-5-{[(2S)- oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-{2-[4-({l-[3-(2,4-dioxo-I,3-diazinan-l-yl)-4- methoxybenzoyl]piperidin-4-yl }methyl)piperidin- 1 -yl] acetamido } cyclohexyl] amino } ethyl)- [ 1,1'- biphenyl] -2-carboxamide;

[0342] 2'-Chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[2-(l'-{2-[3-(2,4- dioxo- 1 ,3-diazinan- 1 -yl)-4-methylphenoxy] acetyl } - [4,4'-bipiperidin] - 1 - yl)acetamido] cyclohexyl] amino } ethyl) -[1,1 '-biphenyl] -2-carboxamide ; and

[0343] 2'-Chloro-6-fhioro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(l-phenyl-2-{[(lr,4r)-4-[(lr,4r)-4-[(l-{2- [3-(2,4-dioxo-I,3-diazinan-l-yl)-4-methylphenoxy] acetyl}piperidin-4-yl)oxy]cyclohexane amido] cyclohexyl] amino } ethyl) - [ 1 , 1 '-biphenyl] -2-carboxamide A conjugate obtainable by reacting said intermediate B-C with a compounds of formula I is within the scope of the present disclosure.

[0344] In a third aspect, there is provided a pharmaceutical composition 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 composition or conjugate of the invention or a pharmaceutically acceptable salt thereof, form the pharmaceutical composition together with at least one pharmaceutically acceptable diluent, carrier and / or excipient, in a form that is suitable for oral or parenteral administration. Suitable pharmaceutically acceptable diluent, carrier and / or excipients are apparent to a person of skill in the art.

[0345] In a fourth aspect, there is provided a pharmaceutical composition 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 the third aspect; for use as a medicament.

[0346] There is also provided a pharmaceutical composition 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 the third aspect; for use in binding to TEAD. TEAD may be any or all of TEAD 1, 2, 3, and / or 4. The compounds and / or conjugates may bind TEAD1, TEAD2, TEAD3 and / or TEAD4 (TEADx) with high affinity, as discussed above. High affinity according to the present disclosure may include affinities of a KD value below 500 μM, such as below 400 μM , such as below 300 μM , such as below 200 μM , such as below 100 μM , such as below 50 μM, such as below 40 μM, such as below 30 μM, such as below 20 μM, such as below 15 μM, such as below 10 μM, such as below 7.5 μM, or preferably below 5 μM, such as below 4 μM, such as below 3 μM.

[0347] There is also provided a pharmaceutical composition 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 the third aspect; for use in suppression or deactivation of the Hippo pathway and / or for use in suppression or blocking of TEAD-mediated gene transcription.

[0348] In a fifth aspect, there is provided a pharmaceutical composition 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 the third aspect; for use in the treatment of a disease or a disorder wherein the Hippo pathway is hyperactivated. According to this aspect, the Hippo pathway may be hyper-activated for example due to overexpression of YAP, or due to mutations or deletion of LATS2, or due to neurofibromatosis type 2 (NF2), or due to hypermethylation of the LATS2 promoter. The skilled person is aware of that NF2 deficient tumors includes schwannoma and meningioma In a sixth aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any embodiments of the first aspect, or a conjugate according to any one of the embodiments of the second aspect, or a pharmaceutical composition according the third aspect; for use in the treatment of cancer by administration of said compound, conjugate or composition; to a patient in need thereof. In some embodiments of the sixth aspect, said 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.

[0349] In some embodiments of the sixth aspect, the administration is in combination 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-alpha inhibitors; ABL1 inhibitors; and XP01 inhibitors. In some embodiments, the administration is in combination 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.

[0350] As mentioned in the background of the invention, the Hippo signalling 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 that are regulated by TEAD

[0012] , Therefore, blocking TEAD-mediated gene transcription has potential applications in the treatment and prevention of fibrotic diseases

[0013] , Thus, in a seventh aspect, there is provided a pharmaceutical composition 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 the third aspect; for use in the treatment of fibrosis by administration of said compound, conjugate or composition; to a patient in need thereof.

[0351] In some embodiments of the seventh aspect, said fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis; scleroderma; or fibrosis associated with chronic diseases in major organs such as the liver (cirrhosis), heart, lungs, and / or the kidneys. In some embodiments, said fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

[0352] In an eight aspect, there is provided a method of treating cancer, comprising administering 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 the third aspect, to a patient in need thereof. In some embodiments of the eight aspect, said cancer is selected from the group consisting of bone cancer, breast cancer, colorectal cancer, esoph g cer, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and malignant pleural mesothelioma.

[0353] As apparent to a person of skill in the art, treatment of cancer may be beneficial when the treatment is in combination with a targeted cancer therapy. For example, a combination treatment according to the present disclosure may be relevant when one wants to overcome drug resistance caused by TEAD overactivation. As such, in some embodiments, the administration is in combination 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-alpha inhibitors; ABL1 inhibitors; and XP01 inhibitors. In some embodiments, the administration is in combination 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.

[0354] In a ninth aspect, there is provided a method of treating fibrosis, comprising administering 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 the third aspect, to a patient in need thereof.

[0355] In some embodiments, said fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis; scleroderma; or fibrosis associated with chronic diseases in major organs. Major organs may be the liver (cirrhosis), heart, lungs, and / or the kidneys.

[0356] In some embodiments, said fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

[0357] In a tenth aspect, there is provided a pharmaceutical composition 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 the third aspect for use in the manufacture of a medicament for use in the treatment of cancer. In some embodiments, said 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.

[0358] In an eleventh aspect, there is provided a pharmaceutical composition 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 the third aspect for use in the manufacture of a medicament for use in the treatment of fibrosis. In some embodiments, said fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis; scleroderma; or fibrosis associated with chronic diseases in major organs. Major organs may be the liver (cirrhosis), heart, lungs, and / or the kidneys. In p embodiment, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

[0359] The conjugates according to the second aspect of the present invention may be prepared in accordance with the examples presented below. Thus, in a twelth aspect, there is provided a method for preparing of a conjugate according to formula II. The method comprises:

[0360] Reacting a ligase binder C with a linker B, the ligase binder and the linker being as laid out in the second aspect of the present disclosure. By such reaction, an intermediate B-C is formed. In addition, the method further comprises:

[0361] Reacting said intermediate with a compound of formula I according to the first aspect, thereby forming a conjugate of formula II according to the second aspect. As apparent to a person of skill in the art, the method is performed under conditions that allows for formation of the intermediate and the conjugate, of which conditions the skilled person is aware.

[0362] Racemic and diastereomeric mixtures as well as single stereoisomers of the disclosed and claimed compounds are within the scope of the present invention. Depending on the choice of the starting materials and procedures, the conjugates can be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as stereoisomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms. Optically active (R)- and (.S')- stereoisomers may 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, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0363] The compounds of the present invention may form salts, which are within the scope of the present invention. Salts of compounds of formula (I) suitable for use in medicine are for example those wherein a counter ion is pharmaceutically acceptable.

[0364] Suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable acid addition salts according to the present invention include those formed with mineral acids, strong organic carboxylic acids, or with organic alkyl or aryl sulfonic acids, optionally substituted with halogen.

[0365] Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, salicylic, oxaloacetic, methanesulfonic, ethane-sulfonic, p- toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic or glutamic acids, as well as from lysine or arginine.

[0366] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases for example dicyclohexylamine N methyl D glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or tri lower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dime y p py amine, or a mono- ,di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine.

[0367] Corresponding internal salts of the compounds of the present invention may furthermore be formed.

[0368] The compounds of the present invention may also be isotopically labelled. As such, compounds which are structurally identical to those disclosed above but with one or more atoms replaced by an atom having an atomic mass or mass number which is different than that usually found in nature are within the scope of the present invention. Example of isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,nC,13C,14C,13N,15N,150,17O,180,31P,32P,35S,18F and36C1, respectively.

[0369] Compounds of the present invention, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, which contain any of the above mentioned isotopes and / or other isotopes are within the scope of the present invention.

[0370] Isotopically labelled compounds of the present invention may be useful in the field of drug discovery and development, for example in drug and / or substrate tissue distribution and target occupancy assays. Further, compounds that are isotopically labelled with heavier isotopes, such as2H, in certain positions of the molecule in question may afford certain therapeutic advantages due to a decrease in the rate of metabolism which may result in an increased in vivo half-life or lowered dosage requirements.

[0371] Isotopically labelled compounds of the present invention may be prepared by methods known in the field of organic chemistry, for example by carrying out known synthetic procedures and by substituting an available isotopically labelled reagent for a corresponding non-isotopically labelled reagent.

[0372] As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. As used herein, the term "halo" means fluoro, chloro, bromo or iodo.

[0373] As used herein, the term ”Ci-C2alkyl” means saturated hydrocarbon groups with 1 or 2 carbon atoms. Examples of ”Ci-C2alkyl” groups are methyl and ethyl.

[0374] As used herein, the term ’’C1-C3 alkyl” means both linear and branched chain saturated hydrocarbon groups with from 1 to 3 carbon atoms. Non-limiting examples of C1-C3 alkyl groups include methyl, ethyl, n-propyl and isopropyl groups.

[0375] As used herein, the term ’’C2-C3 alkyl” means both linear and branched chain saturated hydrocarbon groups with from 2 to 3 carbon atoms. Non-limiting examples of C2-C3 alkyl groups include ethyl, n-propyl and isopropyl groups.

[0376] As used herein, the term ’’C2-C6 alkyl” means both linear and branched chain saturated hydrocarbon groups with from 2 to 6 carbon atoms. Non-limiting examples of C2-C6 alkyl groups include ethyl, n-propyl, isopropyl groups, n-butane, s-butane, t-butane, n-pentane, isopentane and hexane.

[0377] As used herein, the term "Ci-C2haloalkyl" means saturated hydrocarbon groups, with 1 or 2 carbon atoms and with 1 to all hydrogens substituted by a halogen of different or same type. Examples of Ci- C2haloalkyl groups include methyl substituted with 1 to 3 halogen atoms and ethyl substituted with 1 to 5 halogen atoms. As used herein, the term "C2-C3haloalkyl" means both linear and branched chain saturated hydrocarbon groups, with 2 or 3 carbon atoms and with 1 to all hydrogens substituted by a halogen of different or same type. Examples of C2-C3haloalkyl groups include ethyl substituted with 1 to 5 halogen atoms, and n-propyl or iso-propyl substituted with 1 to 7 halogen atoms. substituted with 1 to 3 halogen atoms. Examples of halomethyl groups include, but are not limited to, difluoromethyl, trifluoromethyl, dichloromethyl and trichloromethyl. As used herein, the term CHO means aldehyde. As used herein, the term =O means double bonded oxygen. 1-C3 -C1-C3 1-C3 used as described above. Examples of C1-C3alkoxy groups include methoxy, ethoxy, isopropoxy and n- propoxy. As used herein, the term "C1-C3haloalkoxy" means both linear and branched chain saturated alkoxy groups, with 1 to 3 carbon atoms and with 1 to all hydrogen atoms substituted by a halogen atom of different or same type. Examples of C1-C3haloalkoxy groups include methoxy substituted with 1 to 3 halogen atoms, ethoxy substituted with 1 to 5 halogen atoms, and n-propoxy or iso-propoxy substituted with 1 to 7 halogen atoms. atoms wherein from one to three of the carbon atoms is / are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. Examples of monocyclic heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl. As used herein, the terms heteroaliphatic ring and heterocyclic ring are used interchangeably and means a non-aromatic ring with at least one heteroatom selected from N, O, S. As used herein, the term "C3-C6cycloalkyl" means a cyclic saturated hydrocarbon group, with 3 to 6 carbon atoms. Examples of C3-C6cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. group of carbon atoms wherein from one to three of the carbon atoms is / are replaced by one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups and heterocyclic rings include oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetedinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxanyl. As used herein, the term TEAD means TEA domain transcription factor and includes all four TEAD orthologs designated TEAD1, TEAD2, TEAD3, and TEAD4. As used herein, the term “excipient” encompasses adjuvants and diluents. The skilled person appreciates that any adjuvants and diluents a d herein are suitable in said pharmaceutical composition and it is withing the knowledge of the skilled person to make the appropriate choice thereof. The skilled person appreciates that the pharmaceutical composition may be adapted to be suitable for the desired administered dose.

[0378] It is noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” also include plural referents unless the context clearly dictates otherwise.

[0379] The term "a therapeutically effective amount" of a conjugate of the present disclosure refers to an amount of the conjugate of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction, inhibition or degradation of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.

[0380] As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0381] The skilled person knows that numerical values relating to measurements are subject to measurement errors which place limits on their accuracy. For this reason, the general convention in the scientific and technical literature is applied: the last decimal place of a numerical value indicates its degree of accuracy. Where no other error margins are given, the maximum margin is ascertained by applying the rounding -off convention to the last decimal place e.g. for a measurement of 3.5 cm, the error margin is 3.45-3.54. When interpreting ranges of values in patent specifications, the skilled person proceeds on the same basis.

[0382] References

[0383] 1. Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med. 2015;5(4).

[0384] 2. Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T, et al. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther. 2021;6(l):201.

[0385] 3. Chimomas D, Hornberger KR, Crews CM. Protein degraders enter the clinic - a new approach to cancer therapy. Nat Rev Clin Oncol. 2023;20(4):265-78.

[0386] 4. Martin-Acosta P, Xiao X. PROTACs to address the challenges facing small molecule inhibitors. Eur J Med Chem. 2021;210: 112993.

[0387] 5. Swinney DC. Biochemical mechanisms of drug action: what does it take for success? Nat Rev Drug Discov. 2004;3(9):801-8.

[0388] 6. Ambrosini M, Fuca G, Duca M, Damian S, De Santis F, Corti F, et al. Targeted protein degraders from an oncologist point of view: The Holy Grail of cancer therapy? Crit Rev Oncol Hematol. 2022;169: 103532. 7. Wu Z, Guan KL. Hippo Signaling in Embryogenesis and Development. Trends Biochem

[0389] Sei. 2021;46(l):51-63.

[0390] 8. Cao X, Wang C, Liu J, Zhao B . Regulation and functions of the Hippo pathway in sternness and differentiation. Acta Biochim Biophys Sin (Shanghai). 2020;52(7):736-48.

[0391] 9. Matthaios D, Tolia M, Mauri D, Kamposioras K, Karamouzis M. YAP / Hippo Pathway and Cancer Immunity: It Takes Two to Tango. Biomedicines. 2021;9(12).

[0392] 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.

[0393] 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.

[0394] 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.

[0395] 13. Kim CL, Choi SH, Mo JS. Role of the Hippo Pathway in Fibrosis and Cancer. Cells. 20I9;8(5).

[0396] 14. Piccolo S, Dupont S, Cordenonsi M. The biology of YAP / TAZ: hippo signaling and beyond. Physiol Rev. 2014;94(4): 1287-312.

[0397] 15. Yamaguchi N. Multiple Roles of Vestigial -Like Family Members in Tumor Development. Front Oncol. 2020; 10: 1266.

[0398] 16. Pobbati AV, Kumar R, Rubin BP, Hong W. Therapeutic targeting of TEAD transcription factors in cancer. Trends Biochem Sci. 2023;48(5):450-62.

[0399] Brief description of the figures

[0400] Figure 1 shows a western blot probed for panTEAD for representative examples after 4 h incubation with example compound.

[0401] Figure 2 shows a bar graphs highlighting the relative expression of panTEAD normalised to HSP90 levels and DMSO after 4 h incubation with example compound.

[0402] Figure 3 shows inhibition of cell proliferation by example conjugate compounds 165, 166, 167, 178, and 188 in the cell lines NCI-H226, NCI-H2052, NCI-H2452, and NCI-H28.

[0403] Figure 4 shows inhibition of cell proliferation by reference TEAD palmitoylation inhibitors IK- 930, VT-103, and GNE-7883 in the cell lines NCI-H226, NCI-H2052, NCI-H2452, and NCI-H28.

[0404] Examples

[0405] Below follows a number of non-limiting Examples of the invention.

[0406] Preparation of compounds

[0407] The compounds in the present invention can be prepared as a free base or a pharmaceutically acceptable salt thereof by the methods described below Throughout the following description of such methods, it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Protective Groups in Organic Synthesis by T.W. Greene, P.G.M Wutz, 4th Edition, Wiley-Interscience, New York, 2006. It is understood that microwaves can alternatively be used for the heating of reaction mixtures. General Methods All the reactions were performed in oven-dried glassware. Unless otherwise stated, all the reagents were used as received at the highest commercial quality and without further purification. Progress of the reaction was monitored by thin layer chromatography (Merck Silica gel 60 F-254, pre-coated plates on alumina) with UV light (254 nm) as the visualization agent. For heating the reaction, an oil bath or heating block was used as heat source. Yields refer to isolated and homogenous material, unless otherwise stated. LC-MS data collected on Shimadzu LC-MS-2020 or Agilent 1260 Infinity lab LC / MSD by using the column Kinetex C18 (4.6 x 30 mm), 2.6 µm, 100 A; mobile phase: A: 0.1% HCO2H or 0.1% TFA in H2O; mobile phase B: MeCN (100%). HPLC collected by using UHPLC (or) HPLC Arc system by using column Kinetex EVO C18, 4.6x150mm, 5 um (or) YMC Triart ExRS C184.6 x 150 mm, 5 µm; mobile phase: A:0.1% HCO2H in H2O / 0.01 M NH4OAc in H2O / 0.1% TFA H2O; mobile phase B: MeCN (100%). The crude reaction mixtures were purified by silica gel column chromatography (E. Merck silica gel, 100-200 mesh) or / and preparative reversed phase HPLC performed using the mobile phase A :0.1% HCO2H in H2O / 0.01 M NH4OAc in H2O / 0.1% TFA in H2O; mobile phase B: MeCN (100%) with the column Kinetex EVO C18 (20* 21.2 mm), 5 µm.1H NMR spectra were recorded on JEOL NMR or Varian spectrometer at 400 M Hz. The chemical shifts for1H NMR were referenced to tetramethylsilane (= 0) via residual solvent signals (1H, CDCl3at 7.26 ppm;1H, DMSO-d6at 2.45 ppm;1H, methanol-d4at 3.31 ppm) and abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Abbreviations: The following abbreviation have been used in the examples Example 1.

[0408] Synthesis of 5'-(2-amino-l-phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0409] Step 1: (3-Bromo-4-chlorophenyl)(phenyl)methanone (2)

[0410] To a stirred solution of the 3-bromo-4-chlorobenzoic acid (1) (5.0 g, 21.37 mmol) in a 50 mL round-bottom flask was added SOCI2 (8.0 mL) at RT and stirred at 80 °C for 4 h. After reaction completion (monitored by TLC), the excess of SOCI2 was removed under vacuum. The obtained crude was dissolved in 60 mL benzene, AICI3 (7.3 g, 64.11 mmol) was added portion wise, and the reaction mixture was heated at 90°C for 6 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum and diluted with ice cold H2O. The obtained solid was filtered and washed with aq. sat. NaHCCL solution to afford the title compound (2) (4 g, 63%) as an off-white solid. LC-MS: No ionization, tR = 3.01. LC-MS purity: 98.31%. >H NMR (400 MHz, DMSO-de) = 5 ppm 8.04 (s, 1H), 7.84-7.70 (m, 5H), 7.60- 7.57 (m, 2H).

[0411] Step 2: 2-(3-Bromo-4-chlorophenyl)-2-phenyloxirane (4)

[0412] To a stirred solution of MesSI (3) (1.37 g, 6.75 mmol) in DMSO / THF (1: 1, 12 mL) was added NaH (270 mg, 6.75 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. Then (3-bromo-4- chlorophenyl)(phenyl)methanone (2) (1.0 g, 3.37 mmol) was added at 0 °C and stirred at the same temperature for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc. The combined organic layers were dried overNa2SC>4 and concentrated under vacuum to afford the title compound (4) (850 mg, crude, 81%) as a yellow liquid. LC-MS: m / z 308.9 [M-H]+; tR= 1 .95 min LC-MS purity: 70%.1H NMR (400 MHz, DMSO-de) = 5 ppm 7.61 (s, 1H), 7.35 (s, 6H), 7.26-7.22 (m, 1H), 3.32 (s, 1H), 3.20 (s, 1H).

[0413] Step 3: 2-(3-Bromo-4-chlorophenyl)-2-phenylacetaldehyde (5)

[0414] To a stirred solution of 2-(3-bromo-4-chlorophenyl)-2 -phenyloxirane (4) (850 mg, 2.74 mmol) in Et2O (6 mL) was added BF3 Et2O (779 mg, 5.49 mmol) at 0 °C, then the reaction mixture was stirred at the same temperature for 10 min. After reaction completion (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 afford the title compound (5) as a yellow liquid (600 mg, crude, 100%). The crude compound was used in the next step without further purification. Step 4: 2-(3-Bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-2-phenylethan-1-amine (7) To a stirred solution of 2-(3-bromo-4-chlorophenyl)-2-phenylacetaldehyde (5) (1.0 g, 3.23 mmol) in MeOH / DCM (1:1, 8 mL) were added (4-methoxyphenyl)methanamine (6) (1.3 g, 9.69 mmol) followed by AcOH (0.01 mL) at RT 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 reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (2 x150 mL). The combined organic layers were dried over Na2SO4 filtered and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 35% EtOAc in hexane to afford the title compound (7) (0.82 g, 58%) as a brown gummy liquid. LC- MS: m / z 430.1 and 432.2 [M+H and M+3H]+; tR= 2.19. LC-MS purity: 74.82%.1H NMR (400 MHz, DMSO-d6 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). Step 5: 2-(4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-methoxybenzyl)-2- phenylethan-1-amine (9) To a stirred solution of 2-(3-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-2-phenylethan-1-amine (7) (800 mg, 1.85 mmol) in 1,4-dioxane (8 mL) was added KOAc (546 mg, 5.57 mmol), bis(pinacolato)diboron (8) (613 mg, 2.41 mmol) 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 reaction mixture was again degassed with argon for 5 min. Then the reaction mixture was heated at 100°C for 16 h. After reaction completion (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 brine solution (50 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (9) as a brown liquid (1.0 g, crude, 110%). LC-MS: m / z 478.0 [M +H]+; tR= 1.52 min. LC-MS purity: 35.62%.1H NMR (400 MHz, DMSO- d6-7.15 (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). Step 6: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2- carbonitrile (11) To stirred cooled solution of 2-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4- methoxybenzyl)-2-phenylethan-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) were added K3PO4(799 mg, 3.76 mmol), N-XantPhos (69 mg, 0.12 mmol) and Pd2(dba)3(57 mg, 0.06mmol) at RT and the reaction mixture was degassed with argon for 5 min. Then the reaction mixture was heated at 100°C for 16 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 x 150 mL). The organic layers were washed with brine (200 mL), and dried over Na2SO4, filtered, and concentrated under vacuum The crude was purified by combiflash chromatography (2 x 4 g silica gel column) using 50% of EtOAc in hexane to afford the title compound (11) as a brown liquid (250 mg, 41%). LC-MS: m / z 471.1 [M +H]+; tR = 2.24 min. LC MS purity: 69.7%.1H NMR (400 MHz, DMSO-d6 ppm 7.85-7.72 (m, 2H), 7.53-7.11(m, 7H), 6.76 (bs, 1H), 4.22 (bs, 1H), 4.01-3.90(m, 2H), 3.67(s, 3H), 3.06 (bs, 1H), 2.75 (bs, 3H), 1.97(s, 1H), 1.22-1.05(m, 3H). Step 7: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2- carboxamide (13) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'- biphenyl]-2-carbonitrile (11) (250 mg, 0.53 mmol) in EtOH / H2O (5:1, 8 mL) was added Parkins catalyst (12) (68 mg, 0.15 mmol) at RT, then the reaction mixture was heated at 80 °C for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organics layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (4 g silica gel column) using 7% MeOH in DCM to afford title compound (13) as a brown solid (160 mg, 60%). LC- MS: m / z 489.2 [M +H]+; tR = 2.14 min. LC-MS purity: 68.4%. Step 8: 5'-(2-Amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 1) To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'- biphenyl]-2-carboxamide (13) (50 mg, 0.08 mmol) in MeCN / H2O (1 mL) was added ceric ammonium nitrate (179 mg, 0.32 mmol) at 0 °C, then the reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with aq. sat. NaHCO3(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 afford the crude compound which was purified by prep-HPLC [column: ZORBAX BONUS-RP (150 x 4.6 mm; 5 ); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow: 1.0 ml / min; gradient time(min) / %B: 0 / 5, 2 / 5, 6 / 60, 9 / 100, 13 / 100, 14 / 5, 15 / 5]. The pure prep. fractions were lyophilized to afford the trifluoroacetate salt of the title compound (Example 1) (5 mg, 4.7%) as an off-white solid. LC-MS: m / z 369.1 [M+H]+; tR= 1.92 min. LC-MS purity: 98.52%, tR= 5.50 min. HPLC purity: 96.35%.1H NMR (400 MHz, DMSO-d6and D2O) = -7.28 (m, 12H), 4.31-4.27 (m, 1H), 3.56-3.51(m, 2H). Example 2. Synthesis of 5'-(2-(((R)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2- carboxamide trifluoroacetate

[0415] Step 1: (4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (3) To a stirred solution of (3-bromo-4-chlorophenyl)(phenyl)methanone (1) (1.0 g, 3.38 mmol) in 1,4-dioxane (20.0 mL) was added bis(pinacolato)diboron (2) (1.288 g, 5.07 mmol) and KOAc (0.995 g, 10.1 mmol) and the reaction mixture was degassed with nitrogen for 10 min. To this solution, PdCl2(dppf)·DCM complex (0.276 g, 0.338 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, precipitated solid was filtered through a Büchner funnel with celite 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 was purified by combiflash chromatography (40 g silica gel column) using 8% EtOAc in hexane to afford the title compound (3) as an off-white solid (700 mg, 60.86%). LC-MS: m / z 343.1 [M+H]+; tR= 3.20 min. LC-MS purity: 44.93%. Step 2: 5'-Benzoyl-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carbonitrile (5) 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-dioxaborolan-2-yl)phenyl)(phenyl)methanone (3) (0.685 g, 1.999 mmol) in DME / H2O (4:1, 15 mL), K2CO3 (0.829 g, 5.999 mmol) was added. 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 reaction completion (monitored by TLC), the reaction mixture was cooled to room temperature, precipitated solid was filtered through Celite, and 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 was purified by combiflash chromatography (24 g silica gel column) using 10% EtOAc in hexane to afford the title compound (5) as a white solid (250 mg, 37.09%). LC-MS: m / z 336.25 [M + H]+; tR = 1.81 min. LC-MS purity: 89.52%.1H NMR (400 MHz, DMSO-d6 -7.91 (m, 4H), 7.82-7.69 (m, 5H), 7.60-7.56 (m, 2H). Step 3: 2'-Chloro-6-fluoro-5'-(2-phenyloxiran-2-yl)-[1,1'-biphenyl]-2-carbonitrile (7) To a stirred solution of Me3SI (6) (0.790 g, 3.871 mmol), in DMSO (10.0 mL), was added NaH (0.15g, 3.871 mmol, 60% dispersion in mineral oil) at RT and the reaction mixture was stirred at RT for 2 h, then 5'-benzoyl-2'-chloro-6-fluoro-[11'-biphenyl]-2-carbonitrile (5) (0650 g 1935 mmol dissolved in 5.00 mL of THF) was added and the reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC), the reaction mixture was RT and added H2O (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were washed brine (50 mL), dried over Na2SC>4, and concentrated under vacuum. The crude was purified by combiflash chromatography (4 g silica gel column) using 8% EtOAc in hexane to afford the title compound (7) as an off-white solid (550 mg, 81.24%). LC-MS: m / z 350.10 [M + H]+; tR= 1.86 min. LC-MS purity: 93.03%.1H NMR (400 MHz, DMSO-de) = 5 ppm 7.90- 7.33 (m, 11H), 3.39-3.35 (m, 1H), 3.29-3.25 (m, 1H).

[0416] Step 4: 2'-Chloro-6-fluoro-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2-carbonitrile (8)

[0417] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-phenyloxiran-2-yl)-[l,l'-biphenyl]-2 -carbonitrile (7) (100 mg, 0.28 mmol) in THF (2 mL) was added BF3 Et2O (81 mg, 0.57 mmol) at 0 °C, then the reaction mixture was stirred at the same temperature for 10 min. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with Et2O (2 x 30 mL). The organic layers were washed with brine (50 mL), dried over Na2SC>4, and concentrated under vacuum to afford 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 [M-H]+; tR= 2.71 min. LC-MS purity: 69.39%.

[0418] Step 5: tert- Butyl (47?)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[l,l'-biphenyl]-3-yl)-2- phenylethyl)amino)azepane-l-carboxylate (10)

[0419] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2-carbonitrile (8) (100 mg, 0.28 mmol) in MeOH / DCM (2 mL) were added tert-butyl (4 / ?)-4-aminoazcpanc- 1 -carboxylate (9) (61 mg, 0.28 mmol) followed by AcOH (2 drops) at RT. The reaction mixture was stirred at the RT for 4 h, then added NaCNEftL (35 mg, 0.28 mmol) and the reaction mixture was stirred at the RT for 20 h. After reaction 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 brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (4 g silica gel column) using 2% MeOH in DCM to afford the title compound (10) as a yellow liquid (55 mg, 35%). LC-MS: m / z 548.3 [M + H]+; tR= 2.29 min. LC-MS purity: 98.10%. 'H NMR (400 MHz, DMSO-de) = 5 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).

[0420] Step 6: tert-butyl (47?)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[l,l'-biphenyl]-3-yl)-2- phenylethyl)amino)azepane-l-carboxylate (11)

[0421] To a stirred solution of tert-butyl (4 / ?)-4-((2-(6-chloro-2'-cyano-6'-fluoro-| 1. 1 '-biphenyl |-3-yl)-2- phenylethyl)amino)azepane-l -carboxylate (10) (53 mg, 0.096 mmol) in EtOH / lLO (2.4 mL, 1: 1) was added Parkins catalyst (12 mg, 0.029 mmol ) at RT, then the reaction mixture heated to 80 °C for 6 h. After reaction completion (monitored by TLC), the reaction mixture was cooled to RT and 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 afford the title compound (11) (50 mg 91%) as an off white solid LC MS: m / z 566.3 [M + H]+; tR= 2.19 min. LC-MS purity: 91.37%. HPLC purity: 93.55%, tR= 7.30 min. ’H NMR (400 MHz, DMSO-de) = 5 ppm 8.10 (bs, 1H), 7.90 (s, 1H), 7 (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).

[0422] Step 7: 5'-(2-(((7?)-Azepan-4-yl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl]-2- carboxamide trifluoroacetate (Example 2)

[0423] To a stirred solution of tert-butyl (4 / ?)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-| 1. 1 '-biphenyl |-3-yl)-2- phenylethyl)amino)azepane-l -carboxylate (11) (50 mg, 0.088 mmol) in DCM (1 mL) was added TFA (30 mg, 0.264 mmol) at 0 °C, then the reaction mixture was allowed to warm to RT and stirred for 2 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was purified by prep-HPLC [column: X-Select CSH C18 (250 mm x 19 mm; 5.0 pm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow: 12 mL / min; gradient time (min) / %B: 0 / 25, 2 / 25, 10 / 55] to afford the trifluoroacetate salt of the title compound (Example 2) (23 mg, 46%) as a white solid. LC-MS: m / z 466.2 [M+H]+; tR= 1.77 min. LC-MS purity: 99.95%, HPLC purity: 97.01% , tR= 6.66 min, ’H NMR (400 MHz, DMSO-de) = 5 ppm 8.770 - 8.570 (m, 4H), 7.811 - 7.796 (m, 1H), 7.557 - 7.467 (m, 2H), 7.447 - 7.350 (m, 7H), 7.295 - 7.278 (m, 2H), 4.411 - 4.380 (m, 1H), 3.345 - 3.272 (m, 2H), 3.128 (m, 1H), 3.002 (m, 2H), 2.203 - 2.145 (m, 2H), 1.916 - 1.884 (m, 2H), 1.695 - 1.583 (m, 2H).

[0424] Example 3.

[0425] Synthesis of 5'-(2-(((5)-azepan-4-yl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl]-2- carboxamide trifluoroacetate

[0426] Step 1: tert- Butyl (4X)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[l,l'-biphenyl]-3-yl)-2-phenylethyl)amino) azepane-l-carboxylate (3)

[0427] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-oxo-l-phenylethyl)-[l,r-biphenyl]-2-carbonitrile (1) (100 mg, 0.28 mmol) in MeOH / DCM (2 mL) were added tert-butyl (.S)-4-aminoazcpanc- l -carboxylate (2) (61 mg, 0.28 mmol) followed by AcOH (2 drops) at RT, and the reaction mixture was stirred at the same temperature for 4 h. Then NaCN(BHs) (35 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT for 20 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 60 mL). The organic layers were washed with H2O (200 mL), brine (200 mL), dried over Na2SC>4, and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 2% MeOH in DCM to afford the title compound (3) as an off-white solid (75 mg, 48%). LC-MS: m / z 548.3 [M+H]+; tR= 2.31 min. LC-MS purity: 98.45%. Step 2: tert- Butyl (45)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-[l,l'-biphenyl]-3-yl)-2- phenylethyl)amino) azepane-l-carboxylate (5)

[0428] To a stirred solution of tert-butyl (4S)-4-((2-(6-chloro-2'-cyano-6'-fluoro-[ l,l'-biphenyl]-3-yl)-2- phenylethyl)amino)azepane-l -carboxylate (3) (73 mg, 0.133 mmol) in EtOH / lLO (2.4 mL) was added Parkins catalyst (17 mg, 0.039 mmol ) at RT, the reaction mixture was heated to 80 °C, and stirred for 18 h. TLC shows 20% of the starting material, again Parkins catalyst (17 mg, 0.039 mmol ) was added at RT, then the reaction mixture was stirred at 80 °C for 6 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 40 mL). The organic layers were washed with H2O (200 mL), brine (200 mL) dried over Na2SC>4, and concentrated under vacuum to afford the crude title compound (4) (70 mg, crude, 101%) as an off-white solid. LC-MS: m / z 566.3 [M+H]+; tR = 2.20 min. LC-MS purity: 79.92%.

[0429] Step 3: 5'-(2-(((5)-Azepan-4-yl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl] -2- carboxamide

[0430] To a stirred solution of tert-butyl (4.S)-4-((2-(2'-carbamoyl-6-chloro-6'-fluoro-| 1. 1 '-biphenyl |-3-yl)-2- phenyl ethyl)amino) azepane-l-carboxylate (5) (70 mg, 0.123 mmol) in DCM (1 mL) was added TFA (42 mg, 0.370 mmol) at 0 °C, then reaction mixture allowed to RT and stirred at the same temperature for 2 h. After reaction completion (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 pm); mobile phase: 0.1% TFA in H2O (A) / MeCN (B); flow: 15 ml / min; gradient, time (min) / %B: 0 / 25, 3 / 25, 10 / 50], The pure prep, fractions were lyophilized to afford the trifluoroacetate salt of the title compound (Example 3) (28 mg, 40%) as an off-white solid. LC-MS: m / z 466.2 [M+H]+; tR = 1.73 min. LC-MS purity: 99.48%. HPLC purity: 98.54%,’H NMR (400 MHz, DMSO-de) = 5 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).

[0431] Example 4.

[0432] Synthesis of 5'-(2-amino-l-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2- carboxamide trifluoroacetate Step 1: 5'-Benzoyl-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carbonitrile (3)

[0433] To a stirred solution of 2-bromo-3-fluoro-4-(2 y thoxy)benzonitrile (2) (2.2 g, 8.05 mmol) in toluene / BTO (9: 1, 50 mb) were added (4-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)(phenyl)methanone (1, prepared according to the similar reaction procedure for Int.3, Example 2) (4.2 g, 12.08 mmol), K3PO4 (5.1 g, 24.015 mmol) and XantPhos (466 mg, 0.80 mmol) at RT. The resulting reaction mixture was degassed with N2 for 10 min and then Pd2(dba)s (368 mg, 0.405 mmol) was added to the reaction mixture at RT, again degassed with N2 for 5 min, then the reaction mixture was stirred at 100 °C for 16 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (100 mb) and extracted with EtOAc (2 x 100 mb). The combined organic layers were dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 15% EtOAc in hexane to afford the title compound (3) as a colorless liquid (3.20 g, 97%). ’H NMR (400 MHz, DMS0-<4) = 5 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).

[0434] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,l'-biphenyl]-2- carbonitrile (5):

[0435] To a stirred solution of MesSI (4) (3.4 g, 17.0 mmol) in THF (18 mL) and DMSO (18 mL) was added NaH (683 mg, 60% in mineral oil, 17.0 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. 2'- Chloro-6-fluoro-5-(2- methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,T-biphenyl]-2-carbonitrile (3) (3.5 g, 8.53 mmol) was added to the reaction mixture at 0 °C, then the reaction mixture was stirred at RT for 18 h. After reaction completion (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, fdtered and concentrated under reduced pressure to afford the title compound (5) as a yellow liquid (3.0 g, crude, 82%). ' H NMR (400 MHz, DMSO-J6) = 5 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).

[0436] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2- carbonitrile (6)

[0437] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,l'-biphenyl]- 2-carbonitrile (5) (200 mg, 0.471 mmol) in Et2O (2 ml) was added BF3 OEt2 (133 mg, 0.943 mmol) at 0 °C, then the reaction mixture was stirred at the same temperature for 10 min. After reaction completion (monitored by TLC), reaction mixture was diluted with H2O (30 mL) and extracted with Et2O (2 x 50 mL), organic layers were dried over Na2SC>4 filtered and concentrated under vacuum to afford the title compound title compound (6) as a yellow liquid (200 mg, crude, 100%). LC-MS: m / z 422.0 [M-H]+; tR = 2.68, LC- MS purity: 57.9%.

[0438] Step 4: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-l-phenylethyl)-5-(2-methoxyethoxy)- [1 ,1 '-biphenyl] -2-carbonitrile (8)

[0439] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,T-biphenyl]- 2-carbonitrile (6) (200 mg 0 47 mmol) in MeOH / DCM (3 mb) were added (4- methoxyphenyl)methanamine (7) (194 mg, 1.41 mmol) followed by AcOH (3 drops) at RT, and the reaction mixture was stirred at RT for 3 h. Then N (88 mg, 1.41 mmol) was added, then the reaction mixture was stirred at RT for 21 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (4 g silica gel column) using 2% MeOH in DCM to afford the title compound (8) as an off-white solid (70 mg, 25%). LC-MS: m / z 545.2 [M +H]+; tR= 2.21 min. LC-MS purity: 90.85%.

[0440] Step 5: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-l-phenylethyl)-5-(2-methoxyethoxy)- [1,1 '-biphenyl] -2-carboxamide (10)

[0441] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-l-phenylethyl)-5-(2- methoxyethoxy)-[l,l'-biphenyl] -2 -carbonitrile (8) (50 mg, 0.09 mmol) in EtOH / lLO (5: 1, 1 mL) was added Parkins catalyst (9) (15 mg, 0.03 mmol) at RT, then the reaction mixture was heated at 80 °C for 6 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (10) as yellow liquid (50 mg, crude). LC-MS: m / z 563.2 [M+H]+; tR= 2.12 min. LC-MS purity: 74.31%.

[0442] Step 6: 5'-(2-Amino-l-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2- carboxamide trifluoroacetate (Example 4)

[0443] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-l-phenylethyl)-5-(2- methoxyethoxy)-[l,l'-biphenyl] -2 -carboxamide (10) (50 mg, 0.08 mmol) in McCN / lLO (2 mL) was added ceric ammonium nitrate (292 mg, 0.53 mmol) at 0 °C, then the reaction mixture was stirred at RT for 24 h. After reaction completion (monitored by TLC), reaction mixture was quenched with aq. sat NaHCOs solution (15 mL) and with EtOAc (2 x 50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by prep-HPLC [column: X-SELECT CSH; mobile phase A: 0.1% TLA in H2O, mobile phase B: MeCN; flow: 15 ml / min, gradient, time (min) / %B: 0 / 30, 10 / 50], The pure prep, fractions were lyophilized to afford the trifluoroacetate salt of the title compound (Example 4) as an off-white solid (5 mg, 8%). LC-MS: m / z 443.1 [M+H]+; tR= 1.93 min. LC-MS purity: 99.88%, tR= 8.09 min, HPLC purity: 99.78%. ’H NMR (400 MHz, DMSO-de and D2O) = 5 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).

[0444] Example 5.

[0445] Synthesis of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-l-phenylethyl)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate Step 1: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl) (methyl)amino)-l-phenylethyl)-5-(2- meth oxyethoxy)- [1 ,1 '-biphenyl] -2-carbonitril ( )

[0446] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,T-biphenyl]- 2-carbonitrile (1, prepared according to the similar reaction procedure for Example 4, Int.6) (100 mg, 0.23 mmol) in MeOH / DCM (2 ml) were added [(4-methoxyphenyl)methyl](methyl)amine (2) (53 mg, 0.35 mmol) followed by AcOH (2 drop) at RT and the reaction mixture was stirred at the same temperature for

[0447] 4 h. Then NaCNBHs (43 mg, 0.69 mmol) was added and the reaction mixture was stirred at the same temperature for 20 h. After reaction 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 dried over Na2SC>4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 40% EtOAc in hexane to afford the title compound (3) as a yellow liquid (30 mg, 38%). LC-MS: m / z 559.2 [M+H]+; (tR= 2.21 min). LC-MS purity: 84.99%.

[0448] Step 2: 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-l-phenylethyl)-5-(2- methoxyethoxy)- [1 ,1 '-biphenyl] -2-carboxamide (5)

[0449] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl) (methyl)amino)-l-phenylethyl)-5-(2- methoxyethoxy)-[l,l'-biphenyl] -2 -carbonitrile (3) (50 mg, 0.089 mmol) in EtOH / lLO (2.4 mL) was added Parkins catalyst (4) (11 mg, 0.026 mmol) at RT, then the reaction mixture was heated to 80 °C and stirred for 4 h. After reaction 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 dried over Na2SO4 and concentrated under vacuum to afford the title compound (5) as a yellow liquid (30 mg, crude, 58%). LC- MS: m / z 577.3 [M+H]+; (tR= 2.159 min). LC-MS purity: 85.702%. The crude was used in the next step without further purification.

[0450] Step 3: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-l-phenylethyl)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 5)

[0451] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl) (methyl)amino)-l-phenylethyl)-5-(2- methoxyethoxy)-[l,l'-biphenyl] -2 -carboxamide (5, crude) (30 mg, 0.05 mmol) in DCM (2 ml) was added DDQ (35 mg, 0.15 mmol) at 0 °C, then the reaction mixture was stirred at RT for 5 h. After reaction completion (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 overNa2SO4 and concentrated under vacuum. The crude compound was purified by prep-HPLC [column: Kinetex C18 (250 mm x 21.2 mm, 5.0 pm); mobile phase A: 0.1% TLA in H2O, mobile phase B: MeCN; flow: 15 mL / min; gradient time (min) / %B: 0 / 5, 2 / 5, 10 / 50], The pure fractions were lyophilized to afford trifluoroacetate salt of the title compound (Example 5) (3 mg, 10%) as a white solid. LC-MS: m / z 457.2 [M+H]+; (tR= 1.988 min). LC-MS purity: 98.502%. HPLC purity: 98.89%, (tR= 6.949 min at 210 nm).1H NMR (400 MHz, DMSO-de and D2O) =

[0452] 5 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).

[0453] Example 6. Synthesis of 5 -(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2 -chloro-6-fluoro-5-(2-methoxyethoxy)- [1,1 -biphenyl]-2-carboxamide trifluoroacetate Step 1: tert-Butyl (4S)-4-((2-(6-chloro-6 -cyano-2 -fluoro-3 -(2-methoxyethoxy)-[1,1 -biphenyl]-3- yl)-2-phenylethyl)amino)azepane-1-carboxylate (3) To a stirred solution of 2 -chloro-6-fluoro-5-(2-methoxyethoxy)-5 -(2-oxo-1-phenylethyl)-[1,1 - biphenyl]-2-carbonitrile (1, prepared according to Example 4, Int. 6) (150 mg, 0.35 mmol) in MeOH / DCM (3 ml) were added tert-butyl (S)-4-aminoazepane-1-carboxylate (2) (83 mg, 0.38 mmol) followed by AcOH (2 drops) at RT. After stirring the reaction mixture at RT for 4 h, NaCNBH3(44 mg, 0.71 mmol) was added, and the reaction mixture was stirred at RT for 20 h. After reaction completion (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 using (4 g silica gel column) using 40%-80% EtOAc in hexane to afford the title compound (3) (56 mg, 25%) as off-white solid. LC-MS: m / z 622.4 [M + H]+; tR = 2.21 min. LC- MS purity: 90.32%. Step 2: tert-Butyl (4S)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]- 3-yl)-2-phenylethyl)amino)azepane-1-carboxylate (5) To a stirred solution of tert-butyl (4S)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'- biphenyl]-3-yl)-2-phenylethyl)amino)azepane-1-carboxylate (3) (55 mg, 0.088 mmol) in EtOH / H2O (2.4 ml) was added Parkins catalyst (4) (11 mg, 0.026 mmol) at RT, then the reaction mixture was heated to 80 °C and stirred for 6 h. After reaction completion (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 afford the title compound (5) (50 mg, 88%) as yellow liquid. LC-MS: m / z 640.4 [M-H]+; tR = 2.2 min. LC-MS purity: 76%. Step 3: 5'-(2-(((S)-Azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide trifluoroacetate (Example 6) To a stirred solution of tert-butyl (4S)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[1,1'- biphenyl]-3-yl)-2-phenylethyl)amino)azepane-1-carboxylate (50 mg, 0.078 mmol) in DCM (1 ml) was added TFA (26 mg, 0.23 mmol) at 0 °C, then the reaction mixture was stirred at RT for 2 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC [column: Kinetex C18 (250 mm x 21.2 mm, 5.0 µm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow: 15 ml / min; gradient, time (min) / %B: 0 / 20, 2 / 20, 10 / 40]. The 76 pure fractions were lyophilized to afford the trifluoroacetate salt of the title compound (Example 6) as a white solid (11 mg, 22%). LC-MS: m / z 540.3 [ ] ; (R= 1.34 min). LC-MS purity: 99.70%. HPLC purity: 96.76% (tR= 6.43 min, 31.56% and tR= 6.51 min, 68.32% at 210 nm). ’HNMR (400 MHz, DMSO- d6and D2O) = 5 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).

[0454] Example 7.

[0455] Synthesis of 2'-chloro-5'-(2-(cyclobutylamino)-l-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate

[0456] Step 1: 2'-Chloro-5'-(2-(cyclobutylamino)-l-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carbonitrile (3)

[0457] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]- 2-carbonitrile (1, prepared according to to the similar reaction procedure for Example 4, Int.6) (150 mg, 0.35 mmol) in MeOH / DCM (3 ml) were added cyclobutylamine (50 mg, 0.70 mmol) followed by AcOH (2 drops) at RT. After stirring the reaction mixture at the same temperature for 4 h, NaCNBHs (44 mg, 0.71 mmol) was added, and the reaction mixture was stirred at the same temperature for 20 h. After reaction completion (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 overNa2SC>4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 4% MeOH in DCM to afford the title compound (3) (52 mg) as an off-white solid. LC-MS (ESI): m / z 479.2 [M+H]+; tR= 2.158 min; LC-MS purity: 54.85%.

[0458] Step 2: 2'-Chloro-5'-(2-(cyclobutylamino)-l-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 7)

[0459] To a stirred solution of 2'-chloro-5'-(2-(cyclobutylamino)-l-phenylethyl)-6-fluoro-5-(2 -methoxyethoxy)- [1,1 '-biphenyl]- 2-carbonitrile (3) (52 mg, 0.108 mmol) in EtOH / H2O (2.4 ml) was added Parkins catalyst (4) (13 mg, 0.032 mmol) at RT, then heated the reaction mixture to 80 °C and stirred for 6 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was purified by prep-HPLC [column: Kinetex Cl 8 (250 mm x 21.2 mm, 5.0 pm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow: 15 ml / min; gradient, time (min) / %B: 0 / 20, 2 / 20, 10 / 50] to afford the trifluoroacetate salt of the title compound (Example 7) as a white solid (8 mg, 13%). LC-MS: m / z 497.2 [M+H]+; (tR= 2.058 min). LC-MS purity: 99.77%. HPLC purity: 95.66% (tR= 7.2 min, at 210 nm).1H NMR (400 MHz, DMSO-de and D2O) = 5 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).

[0460] Example 8.

[0461] Synthesis of 2'-chloro-6-fluoro-5'-(2-(((lr,4r)-4-hydroxy-4-methylcyclohexyl)amino)-l-phenylethyl)- 5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0462] Step 1 : 2'-Chloro-6-fluoro-5'-(2-(((lr,4r)-4-hydroxy-4-methylcyclohexyl)amino)-l-phenylethyl) -5- (2-meth oxyethoxy)- [1,1 ' -biphenyl] -2-carbonitrile (3)

[0463] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,T-biphenyl]- 2-carbonitrile (1, prepared according to the similar reaction procedure for Example 4, Int.6) (140 mg, 0.33 mmol) in MeOH / DCM (3 ml) were added (lr,4r)-4-amino-l-methylcyclohexan-l-ol (85 mg, 0.66 mmol) followed by AcOH (2 drops) at rt. After stirring the reaction mixture for 4 h, then NaCNBHs (41 mg, 0.66 mmol) was added, then the reaction mixture was stirred at the same temperature for 20 h. After reaction completion (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 overNa2SC>4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 2% MeOH in DCM to afford the title compound (3) as an off-white solid (50 mg, 28%). LC-MS (ESI): m / z 537.2 [M- Boc+H]+; tR= 2. 122 min; LC-MS purity: 78.56%.

[0464] Step 2: 2'-Chloro-6-fluoro-5'-(2-(((lr,4r)-4-hydroxy-4-methylcyclohexyl)amino)-l-phenylethyl)-5- (2-methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 8)

[0465] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-(((lr,4r)-4-hydroxy-4-methylcyclohexyl)amino)-l- phenylethyl)-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2 -carbonitrile (3) (50 mg, 0.09 mmol) in EtOH / fLO (2.4 ml) was added Parkins catalyst (4) (11 mg, 0.02 mmol) at RT, then the reaction mixture was heated to 80 °C and stirred for 6 h. After reaction completion (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 prep-HPLC [column: Kinetex C18 (250 mm x 21.2 mm, 5.0 pm); mobile phase A: 0.1% TLA in H2O, mobile phase B: MeCN; flow: 15 ml / min; gradient, time (min) / %B: 0 / 25, 2 / 25,10 / 50) to afford the trifluoroacetate salt of the title compound (Example 8) as a white solid (50 mg, 28%). LC-MS: m / z 555.20 [M+H]+; (tR = 1.995 min). LC-MS purity: 99.48%. HPLC purity: 95.73% (tR= 6.183 min, at 210 nm). 'H NMR (400 MHz, DMSO- d6and D2O) = 5 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

[0466] - 1.583 (m, 2H), 1.434 1 342 (m 4H) 1 115 (s 3H) Example 9.

[0467] Synthesis of 2'-chloro-6-fluoro-5'-(2-(isopr py o)-l-phenylethyl)-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate

[0468] Step 1: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2- carbonitrile

[0469] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,T-biphenyl]- 2-carbonitrile (1, prepared according to similar procedure for Example 4, Int.5) (150 mg, 0.353 mmol) in Et2O (2 mL) was added BF3 Et2O (100 mg, 0.707 mmol) at 0 °C, then the reaction mixture was stirred at the same temperature for 10 min. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with Et2O (2 x 30 mL). The organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SC>4, and concentrated under vacuum to afford the title compound (2) as a crude (150 mg, crude, 100%). The crude material was used in the next step without further purification.

[0470] Step 2: 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-l-phenylethyl)-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carbonitrile (3)

[0471] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,T-biphenyl]- 2-carbonitrile (crude, 2) (150 mg, 0.35 mmol) in MeOH / DCM (3 mL) were added isopropylamine (62 mg, 1.06 mmol) followed by AcOH (2 drops) at RT, and the reaction mixture was stirred for 4 h. Then NaCNBHs (44 mg, 0.70 mmol) was added, and the reaction mixture was stirred at RT for 20 h. After reaction 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 brine (20 mL), dried over Na2SC>4, and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 2% MeOH in DCM to afford title compound (3) as an off- white solid (52 mg, 31%). LC-MS: m / z 467.2 [M + H]+; tR= 2.09 min. LC-MS purity: 95.76%.1H NMR (400 MHz, DMSO-de) = 5 ppm 7.84-7.82 (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).

[0472] Step 3: 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-l-phenylethyl)-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 9)

[0473] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-l-phenylethyl)-5-(2 -methoxyethoxy)- [1, 1'-biphenyl] -2 -carbonitrile (3) (50 mg, 0.107 mmol) in EtOH / fLO (2.4 mL) was added Parkins catalyst (4) (13.5 mg, 0.032 mmol ) at RT, then the reaction mixture was heated to 80 °C for 18 h. TLC shows 20% of the starting material, again Parkins catalyst (13.5 mg, 0.032 mmol) was added at RT, and the reaction mixture was stirred at 80 °C for 6 h After reaction completion (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 solution (10 mL), dried ov 4 and concentrated under vacuum. The crude compound was purified by preparative HPLC [column: X-Select CSH (250 mm x 21.2 mm; 5.0 pm), mobile phase: 0.1% TLA in H2O (A) / MeCN (B); gradient, time (min) / %B: 0 / 55, 10 / 85; flow rate: 15 mL / min] to afford trifluoroacetate salt of the title compound (Example 9) as an off- white solid (25 mg, 40%). LC-MS: m / z 485.2 [M+H]+, tR= 1.99 min, LC-MS purity: 99.17%, HPLC purity: 99.45%,’H NMR (400 MHz, DMSO-de) = 5 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).

[0474] Example 10.

[0475] Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)- [1,1 '-biphenyl] -2-carboxamide trifluoroacetate

[0476] Step 1: tert- Butyl ((lr,4r)-4-((2-(3-bromo-4-chlorophenyl)-2-phenylethyl)amino)cyclo hexyl)carbamate (3)

[0477] To a stirred solution of the 2-(3-bromo-4-chlorophenyl)-2 -phenylacetaldehyde (1, prepared according to Int. 5, Example 1) (600 mg, 1.96 mmol) in methanol / DCM (1: 1, 6 mL) were added tert-butyl ((lr,4r)-4- aminocyclohexyl)carbamate (2) (631 mg, 2.94 mmol) followed by AcOH (3 drops) at RT. After stirring the reaction mixture for 4 h, NaCNBHs (369 mg, 5.88 mmol) was added, and the reaction mixture was overnight. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SC>4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 40%-80% EtOAc in hexane to afford the title compound (3) as an off-white solid (400 mg, 40%). LC-MS: m / z 507.2 [M + H]+; tR= 2.21 min. LC-MS purity: 86.87%.

[0478] Step 2: Zert- Butyl (2-(3-bromo-4-chlorophenyl)-2-phenylethyl)((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)carbamate (4) To a stirred solution of tert-butyl ((lr,4r)-4-((2-(3-bromo-4-chlorophenyl)-2- phenylethyl)amino)cyclohexyl)carbamate (3) (4 g, 8 mmol) in THF / H2O (3: 1, 8 mb) were added NaHCOs (132 mg, 1.56 mmol) followed by di-tert-butyl dicarbonate (257 mg, 1.18 mmol) at 0 °C, then the reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SC>4and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 30% EtOAc in hexane to afford the title compound (4) (300 mg, 62%) as an off-white solid. LC-MS showed two peaks with the desired mass. LC-MS: m / z 495.20 [M-2tBu+H]+; tR= 2.20 min. LC-MS purity: 46.32% and LC-MS: m / z 495.00 [M-2tBu +H]+; tR = 2.23 min. LC-MS Purity 52.41%.

[0479] Step 3: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-phenylethyl)carbamate (6)

[0480] To a stirred solution of tert-butyl (2-(3-bromo-4-chlorophenyl)-2-phenylethyl)((lr,4r)-4- ((tertbutoxycarbonyl)amino)cyclohexyl)carbamate (4) (250 mg, 0.41 mmol) in 1,4-dioxane (5 mL) was added KOAc (121 mg, 1.23 mmol) and bis(pinacolato)diborane (5) (135 mg, 0.53 mmol), and the reaction mixture was degassed with argon for 5 min. Then Pd(dppf)C12-DCM (33 mg, 0.041 mmol) was added and the reaction mixture was again degassed with argon for 5 min. Then the reaction mixture was stirred in a sealed tube at 100°C for 16 h. After reaction completion (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 afford the title compound (6) as brown liquid (220 mg, crude, 81%). LC- MS: m / z 555.3 [M-Boc+H]+; tR= 3.58 min. LC-MS Purity = 49.83%.

[0481] Step 4: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro- 3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (8)

[0482] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-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 tolucnc / tLO (10: 1, 4.4 mL) were added K3PO4 (222 mg, 1.005 mmol), N-XantPhos (18.5 mg, 0.033 mmol) and Pd2(dba)s (15.3 mg, 0.016 mmol) at RT and the reaction mixture was degassed with argon for 5 min. Then the reaction mixture was stirred at 100 °C for 16 h. After reaction completion (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 60% EtOAc in hexane to afford the title compound (8) as an off-white solid (180 mg, 74%). LC-MS: m / z 566.15 [M-Boc-tBu +H]+; tR= 2.04 min. LC-MS purity = 98.33%, HPLC purity: 99.35% tR= 8.118 min, 'H NMR (400 MHz, DMSO-de) = 5 ppm 7.84-7.80 (m, 1H), 7.59-7.19 (m, 8H), 6.67-6.62 (m, 1H), 4.37-4.30 (s, 2H), 3.73-3.69 (q, J= 7.2 Hz, 3H), 3.32-3.31 (d, J = 3.6 Hz, 3H),3.05 (b s, 1H), 1.71-1.33 (m, 18H), 1.03 (m, 7H).

[0483] Step 5: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino) cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'- fluoro-3'-(2-methoxyethoxy) [l l' biphenyl] 3 yl) 2 phenylethyl)carbamate (10) To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,T-biph y ] y )-2-phenylethyl)carbamate (8) (180 mg, 0.249 mmol) in EtOH / EEO (5: 1, 12 mb) was added Parkins catalyst (9) (32 mg, 0.074 mmol) at RT, then the reaction mixture was heated to 80 °C and stirred for 16 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (20 mb) and extracted with EtOAc (2 x 80 mb). The combined organic layers were dried over Na2SC>4 and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 4% MeOH in DCM to afford the title compound (10) as an off-white solid (140 mg, 76%). LC-MS (ESI): m / z 640.40 [M-Boc+H]+, tR= 1.85 min. LC-MS purity: 95.77%; HPLC purity: 97.97% [tR= 10.47 min (22.64%) and 10.50 min (75.33%). 'H NMR (400 MHz, DMSO-de) = 5 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 (b s, 1H), 1.68-1.62 (bs, 3H), 1.33 (m, 22H). Step 6: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 10)

[0484] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)carbamate (10) (140 mg, 0.189 mmol) in DCM (2 mL) was added TFA (107 mg, 0.945 mmol) at 0 °C, then the reaction mixture was stirred at RT for 4 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was triturated with pentane to afford the crude compound (130 mg) which was purified by prep-HPLC [column: Luna Omega C18 (250 mm x 21.2 mm, 5.0 pm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow: 15 ml / min, gradient time (min) / %B: 0 / 25, 3 / 25 10 / 60] to afford trifluoroacetate salt of the title compound (Example 10) as a white solid (83 mg, 63%). LC-MS: m / z 541.40 [M+H]+; (tR= 1.34 min). LC-MS purity: 98.69%. HPLC purity: 99.88% (tR= 6.43 min 31.56% and tR= 6.51 min 68.32% at 210 nm).1H NMR (400 MHz, DMSO-de) = 5 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).

[0485] The chiral separation of Example 10 was performed by using chiral HPLC (see Example 11 and Example 12).

[0486] Example 11 and Example 12.

[0487] Stereoisomers of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 11 and Example 12)

[0488] By means of chiral HPLC, Example 10 was separated to afford two pairs of stereoisomers, Example 11 and Example 12. Column: Chiral Pak IC (250 x 4.6 mm; 5 pm); mobile phase A: 0.1% DEA in hexane, mobile phase B: EtOH; Method: isocratic elusion A:B 60:40; Flow rate: 1.0 mL / min; Column temp: 25°C; Diluent: IPA / DCM (90: 10). Example 11 (tR= 16.80 min) and Example 12 (tR= 19.06 min). The relative / absolute stereochemistry of Example 11 and 12 has not been determined.

[0489] Example 13. Synthesis of 5'-(2-(((lr,4r)-4-acetamidocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- meth oxyethoxy)- [1 ,1 '-biphenyl] -2-carboxami

[0490] Step 1: tert- Butyl ((lr,4r)-4-acetamidocyclohexyl)carbamate (3)

[0491] To a stirred solution of tert-butyl ((lr,4r)-4-aminocyclohexyl)carbamate (1) (400 mg, 1.86 mmol) in DCM (5 mL) was added EtsN (944 mg, 9.33 mmol) and acetyl chloride (2) (439 mg, 5.59 mmol) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After completion (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 brine solution and dried over Na2SC>4, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (4 g silica gel column) using 2% MeOH in DCM to afford the title compound (3) as an off-white solid (300 mg, 60%). LC-MS: m / z 548.3 [M-tBu+H]+; tR = 2.09 min. LC-MS purity: 88.92%. 'H NMR (400 MHz, DMSO-de) = 5 ppm 7.72-7.70 (d, J =1.6 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).

[0492] Step 2: N-((lr,4r)-4-Aminocyclohexyl) acetamide (4)

[0493] To a stirred solution of tert-butyl ((lr,4r)-4-acetamidocyclohexyl) carbamate (3) (300 mg, 1.86 mmol) in DCM (3 mL) was added TEA (667 mg, 5.85 mmol) at 0 °C, then the reaction mixture was stirred at RT for 6 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude was basified with aq. sat. NaHCOs 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 Na2SC>4, and concentrated under vacuum to afford the title compound (4) as an off-white solid (250 mg, crude, 120%). LC-MS: m / z 157.2 [M+H]+; tR= 0.37 min. LC-MS purity: 93.98%.1H NMR (400 MHz, DMSO-de) = 5 ppm 7.69-7.67 (d, J= 7.6Hz, 1H), 1.76-1.70 (m, 9H), 1.17-1.04 (m, 6H).

[0494] Step 3: N-((lr,4r)-4-((2-(6-Chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2- phenylethyl)amino)cyclohexyl)acetamide (6)

[0495] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]- 2-carbonitrile (5, prepared according to Example 4, Int. 6) (150 mg, 0.35 mmol) in MeOH / DCM (3 mL) were added / V-((lr,4r)-4-aminocyclohexyl)acetamide (4) (82 mg, 0.53 mmol) followed by AcOH (2 drops) at RT. The reaction mixture stirred at the same temperature for 4 h. Then NaCNBEE (66 mg, 1.05 mmol) was added at RT and reaction mixture was stirred at 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 Na2SC>4, and concentrated under vacuum. The crude was purified by com omatography (4 g silica gel column) using 7% MeOH in DCM to afford the title compound (6) as an off-white solid (7 mg, 3.5%). LC-MS: m / z 564.3 [M + H]+; tR = 2.06 min. LC-MS purity: 97.26%.

[0496] Step 4: 5'-(2-(((lr,4r)-4-Acetamidocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide (Example 13)

[0497] To a stirred solution of JV-((lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,T- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)acetamide (6) (7 mg, 0.012 mmol) in EtOH / BLO (5: 1, 1.2 mL) was added Parkins catalyst (7) (1.5 mg, 0.003 mmol ) at RT, then the reaction mixture was heated to 80 °C for 4 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum. The crude product was purified by prep- HPLC [column: Kinetex C18 (250 mm x 21.2 mm; 5.0 pm); mobile phase A: 0.1% TLA in H2O, mobile phase B: MeCN; flow: 15 ml / min; gradient time (min) / %B: 0 / 10, 10 / 60] to afford the trifluoroacetate salt of the title compound (Example 13) as an off-white solid (1.5 mg, 18%). LC-MS: m / z 582.3 [M+H]+; tR = 2.00 min. LC-MS purity: 99.48%, HPLC purity: 96.18%.1H NMR (400 MHz, DMSO-de) = 5 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).

[0498] Example 14.

[0499] Synthesis of 2'-Chloro-5'-(2-(((lr,4r)-4-(((l-(2-(dimethylamino)-2-oxoethyl)-lH-pyrazol-4- yl)methyl)amino)cyclohexyl)amino)-l-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]- 2-carboxamide trifluoroacetate

[0500]

[0501] Step 1: Ethyl 2-(4-formyl-l / / -pyrazol-l-yl)acetate (3)

[0502] To a stirred solution of lH-pyrazole-4-carbaldehyde (1) (2 g, 20.8 mmol) in DMF (15 mL) was added KOtBu (2.8 g, 24.9 mmol) portion wise at 0 °C and stirred for 10 min. Ethyl-2-bromoacetate (2) (3.5 g, 22.8 mmol) was added to the reaction mixture dropwise at 0 °C, and the reaction mixture was stirred at RT for 3 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 30% EtOAc in hexane to afford the title compound (3) as a yellow liquid (1.4 g, 40%). ’H NMR (400 MHz, DMSO-de) = 5 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= 7.2 Hz, 3H). Step 2: benzyl N-[(lr,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]carbamate (6)

[0503] To a stirred solution of tert-butyl ((lr,4r)-4-am y xyl)carbamate (4) (5 g, 23.36 mmol) in DCM (50 mL) was added DIPEA (12.2 mL, 70.08 mmol) and benzyl chloroformate (5) (3.98 g, 23.36 mmol) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After reaction completion (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 Na2SC>4, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (2 x 4 g silica gel column) using 2% of MeOH in DCM to afford the title compound (6) as an off-white solid (6.5 g, 80%). LC-MS: m / z 249.2 [M-Boc+H]+; tR= 2.58 min, LC-MS purity: 96%. 'H NMR (400 MHz, DMSO-de) = 5 ppm 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).

[0504] Step 3: Benzyl ((lr,4r)-4-aminocyclohexyl)carbamate (7)

[0505] To a stirred solution of benzyl N-[(lr,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]carbamate (6) (6.5 g, 18.67 mmol) in DCM (60 mL) was added TFA (7.8 ml, 93.3 mmol) at RT, and the reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude was triturated with pentane to afford trifluoroacetate salt of the title compound (7) as an off-white solid (5 g, 98%). LC-MS: m / z 249.2 [M+H]+; tR= 1.77 min, LC- MS purity: 98.38%. 'HNMR (400 MHz, DMSO-de) = 5 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).

[0506] Step 4: Ethyl 2-(4-((((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)amino)methyl)-lH-pyrazol- l-yl)acetate (8)

[0507] To a stirred solution of ethyl 2-(4-fonnyl- IH-pyrazol- l -yl)acctatc (3) (1.4 g, 7.69 mmol) in MeOH / DCM (20 mL) were added benzyl ((lr,4r)-4-aminocyclohexyl)carbamate (7) (1.9 g, 7.69 mmol) followed by AcOH (0.23 mL, 3.84 mmol) at RT, and the reaction mixture was stirred at RT for 4 h. Then NaCNBHs (1.4 g, 3.84 mmol) was added to the reaction mixture at RT, and the reaction mixture was stirred at RT for 12 h. After reaction completion (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) and dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The obtained crude was purified by combiflash chromatography on (40 g silica gel column) using 20% MeOH in DCM to afford the title compound (8) as a colorless gummy solid (1.3 g, 42%). LC-MS: m / z 415.2 [M+H]+; tR= 1.38, LC-MS purity: 93.9%. 'H NMR (400 MHz, DMSO-de) = 5 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).

[0508] Step 5: Ethyl 2-[4-({[(tert-butoxy)carbonyl] [(lr,4r)-4-{[(benzyloxy)carbonyl]amino}cyclo- hexyl]amino}methyl)-lH-pyrazol-l-yl] acetate (9)

[0509] To a stirred solution of ethyl 2-(4-((((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl) amino)methyl)- IH-pyrazol- 1 -yl [acetate (8) (1.3 g, 3.13 mmol) in THP / H2O (3: 1, 20 mL) were added NaHCOs (0.788 g, 9.39 mmol) followed by (Boc^O (1 3 g 6 27 mmol) at RT then the reaction mixture was stirred at RT for 20 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 100 mL). The co ganic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (4 g silica gel column) using 80% EtOAc in hexane to afford the title compound (9) as a colorless gummy liquid (1.2 g, 75%). LC-MS: m / z 459 [M-tBu+H]+; tR = 2.74 min, LC-MS purity: 88.22%. ’HNMR (400 MHz, DMSO-de) = 5 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).

[0510] Step 6: Methyl 2-(4-((((lr,4r)-4-aminocyclohexyl)(ter / -butoxycarbonyl)amino)methyl)-LH-pyrazol- l-yl)acetate (10)

[0511] To a stirred solution of ethyl 2-(4-((((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl) (tertbutoxycarbonyl)amino)methyl)-lH-pyrazol-l-yl)acetate (9) (1 g, 1.94 mmol) in MeOH (10 mL) was added Pd / C (207 mg, 1.94 mmol) at RT, then the reaction mixture was stirred at RT under H2 balloon pressure for 6 h. After reaction completion (monitored by TLC), the reaction mixture was filtered on a pad of celite, and the filtrate was concentrated under vacuum to afford the title compound (10) as a colorless gummy solid (800 mg, 95%). LC-MS: m / z 366 [M +H]+; tR = 1.85 min. LC-MS purity: 66.03%, 'H NMR (400 MHz, DMSO-de) = 5 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).

[0512] Step 7: Ethyl 2-(4-(((ter / -butoxycarbonyl)((lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2- meth oxyethoxy)- [1 ,1 '-biphenyl] -3-yl)-2-phenylethyl)amino)cyclohexyl)amino) methyl)- LH-pyrazol-

[0513] 1-yl)acetate (12)

[0514] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,T-biphenyl]-

[0515] 2-carbonitrile (11, prepared according to Example 4, Int.6) (400 mg, 0.94 mmol) in MeOH / DCM (8 mL, 1: 1) were added methyl 2-(4-((((lr,4r)-4-aminocyclohexyl)(tert-butoxycarbonyl)amino)methyl)-lH- pyrazol- 1 -yl)acetate (10) (518 mg, 1.41 mmol) followed by AcOH (3 drops) at RT and the reaction mixture was stirred at RT for 4 h. Then NaCNBHs (177 mg, 2.83 mmol) was added and the reaction mixture was stirred at RT for 16 h. After reaction completion (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 washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (24 g silica gel column) using 10% MeOH in DCM to afford the title compound (12) as a white gummy solid (170 mg, 22%). LC-MS: m / z 774.3 [M+H]+; tR = 2.29 min. LC-MS purity: 94.98%.

[0516] Step 8: Ethyl 2-(4-(((ter / -butoxycarbonyl)((lr,4r)-4-((ter / -butoxycarbonyl)(2-(6-chloro-6'-cyano-2'- fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)- l / / -pyrazol-l-yl)acetate (13)

[0517] To a stirred solution of methyl 2-(4-(((tert-butoxycarbonyl)((lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'- (2-methoxyethoxy)-[ 1 , 1 '-biphenyl] -3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)- 1 H-pyrazol- 1 - yl)acetate (12) (170 mg 021 mmol) in THE (2 mL) were added EtsN (63 mg 0 63 mmol) followed by (BOC)2O (71 mg, 0.32 mmol) at RT, and the reaction mixture was stirred at RT for 20 h. After reaction completion (monitored by TLC), the reaction m 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 Na2SC>4, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (4 g silica gel column) using 10% of MeOH in DCM to afford the title compound (13) as an off-white solid (150 mg, 77%). LC-MS: m / z 774.3 [M-Boc+ H]+; tR=3.17 min. LC-MS purity: 74.6%. 'H NMR (400 MHz, DMSO-de) = 5 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,lH), 2.17-2.15 (m, 2H), 1.93-1.88 (m, 2H), 1.38 (s, 18H).

[0518] Step 9: Methyl 2-(4-(((ter / -butoxycarbonyl)((lr,4r)-4-((ter / -butoxycarbonyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl) amino)methyl)-LH-pyrazol-l-yl)acetate (15)

[0519] To a stirred solution of methyl 2-(4-(((tert-butoxycarbonyl)((lr,4r)-4-((tert-butoxycarbonyl)(2-(6-chloro- 6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)amino) cyclohexyl)amino)methyl)-lH-pyrazol-l-yl)acetate (13) (150 mg, 0.17 mmol) in EtOH / H2O (5: 1, 2 mL) was added Parkins catalyst (14) (29.4 mg, 0.06 mmol ) at RT, and the reaction mixture was stirred at 80 °C for 6 h. After reaction completion (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 obtained crude was purified by combiflash chromatography (4 g silica gel column) using 10% of MeOH in DCM) to afford the title compound (15) as a yellow liquid (70 mg, 40%). LC-MS: m / z 792.3 [M-Boc+H]+; tR= 2.95 min, LC-MS purity: 72.99%,1H NMR (400 MHz, DMSO-de) = 5 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).

[0520] Step 10: 2-(4-(((ter / -Butoxycarbonyl)((lr,4r)-4-((ter / -butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'- fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino)methyl)- LH-pyrazol-l-yl)acetic acid (16)

[0521] To a stirred solution of methyl 2-(4-(((tert-butoxycarbonyl)((lr,4r)-4-((tert-butoxycarbonyl)(2-(6'- carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,T-biphenyl]-3-yl)-2- phenylethyl))cyclohexyl)amino)methyl)-lH-pyrazol-l-yl)acetate (15) (60 mg, 0.067 mmol) in THL / MeOH / H2O (1 : 1 : 1, 3 mL) was added LiOH H2O (11 mg, 0.269 mmol) at RT, and the reaction mixture was stirred at RT for 3 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with ice cold H2O (10 mL), acidified with IN HC1 (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 obtained crude was triturated with Et2O (10 mL) to afford the title compound (16) as an off-white solid (55 mg, 93%). LC-MS: m / z 876.4 [M-H]+; tR= 2.82 min. LC-MS purity: 95.39%, HPLC purity: 93.55%, tR= 10.15 min. ’H NMR (400 MHz, DMSO-de and D2O) = 5 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), ( , ), 1.23 (s, 9H), 1.17-1.06 (m, 2H).

[0522] Step 11: tert- Butyl ((lr,4r)-4-(( / e / 7-butoxycarbonyl)((l-(2-(dimethylamino)-2-oxoethyl)-l H-pyrazol- 4-yl)methyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'- biphenyl]-3-yl)-2-phenylethyl)carbamate (18)

[0523] To a stirred solution of 2-(4-(((lert-butoxycarbonyl)((lr,4r)-4-((lert-butoxycarbonyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro3'-(2-methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)amino) methyl) -lH-pyrazol-l-yl)acetic acid (16) (11 mg, 0.012 mmol) and dimethylamine hydrochloride (17) (4 mg, 0.050 mmol) in DMF (1 ml) were added HATU (6 mg, 0.018 mmol) followed by DIPEA (9 mg, 0.072 mmol) at RT, and the reaction mixture was stirred at the RT for 16 h. After completion (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SC>4 and concentrated under vacuum to afford the title compound (18) as brown liquid (11 mg, 100%). LC-MS: m / z 805.4 [M-Boc+H]+; tR= 2.849 min. LC-MS purity: 93.32%.

[0524] Step 12: 2'-Chloro-5'-(2-(((lr,4r)-4-(((l-(2-(dimethylamino)-2-oxoethyl)-lH-pyrazol-4- yl)methyl)amino)cyclohexyl)amino)-l-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]- 2-carboxamide trifluoroacetate (Example 14)

[0525] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)((l-(2-(dimethylamino)-2-oxoethyl)- lH-pyrazol-4-yl)methyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2 -methoxyethoxy)- [l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (18) (11 mg, 0.012 mmol) in DCM (1 ml) was added TFA (4 mg, 0.036 mmol) at 0 °C, then the reaction mixture was stirred at rt for 2 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC [column: Kinetex C18 (250 mm x 21.2 mm, 5.0 pm); Mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow: 15 ml / min; gradient, time (min) / %B: 0 / 20, 10 / 50] to afford the trifluoroacetate salt of the title compound (Example 14) as a white solid (3 mg, 30%). LC-MS: m / z 705.40 [M+H]+; (tR= 1.852 min). LC-MS purity: 99.44%. HPLC purity: 99.64% (tR= 6.482 min, at 210 nm). 'H NMR (400 MHz, DMSO-de and D2O) = 5 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).

[0526] Example 15.

[0527] Synthesis of 2'-chloro-6-fluoro-5'-(2-(((lr,4r)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3- yl)cyclohexyl)amino)-l-phenylethyl)-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0528]

[0529] Step 1: Benzyl ((lr,4r)-4-(oxetan-3-ylamino)cyclohexyl)carbamate (3)

[0530] To a stirred solution of benzyl ((lr,4r)-4-aminocyclohexyl)carbamate (1) (1.00 g, 4.02 mmol) in MeOH / DCM (20 mL) were added oxetan-3-one (2) (870 mg, 12.08 mmol) followed by AcOH (0.05 mL) at RT and the reaction mixture was stirred at RT for 24 h. Then NaCNBtL (760 mg, 12.08 mmol) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at RT for 24 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum to afford the title compound (3) as a brown sticky solid (1.0 g, crude, 83%). LC-MS: m / z 305.20 [M+H]+; tR= 1.32, LC-MS purity: 64.99%.

[0531] Step 2: tert- Butyl ((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (4)

[0532] To a stirred cooled solution ofbenzyl ((lr,4r)-4-(oxetan-3-ylamino)cyclohexyl)carbamate (3) (1.00 g, 3.28 mmol) in THF (20 mL) were added EtsN (1.57 mL, 11.49 mmol) followed by (Boc^O (1.80 g, 8.213 mmol) at RT, then the reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The obtained crude was purified by combiflash chromatography (24 g silica gel column) using 20% EtOAc in hexane to afford the title compound (4) as an off-white solid (0.7 g, 53%). LC-MS: m / z 405.25 [M+H]+; tR= 1.68, LC-MS purity: 96.02%. 'HNMR (400 MHz, DMSO-de) = 5 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).

[0533] Step 3: tert- Butyl ((lr,4r)-4-aminocyclohexyl)(oxetan-3-yl)carbamate (5)

[0534] To a stirred solution of tert-butyl ((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(oxetan-3- yl)carbamate (4) (700 mg, 1.73 mmol) in MeOH (20 mL) was added 10% Pd / C (185 mg) and the reaction mixture was stirred at RT under hydrogen balloon pressure for 48 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with MeOH (20 mL) and filtered on a celite pad. The filtrate was concentrated under reduced pressure. The o ude was triturated with Et2O (20 mL) to afford the title compound (5) as a brown solid (450 mg, crude, 96%). LC-MS: No ionization.

[0535] Step 4: tert- Butyl ((lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3- yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (7)

[0536] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,T-biphenyl]- 2-carbonitrile (6, prepared according to Example 4, Int.6) (150 mg, 0.35 mmol) in MeOH / DCM (1: 1, 3 mL) were added tert-butyl ((lr,4r)-4-aminocyclohexyl)(oxetan-3-yl)carbamate (5) (137 mg, 0.35 mmol) followed by AcOH (10 mg, 0.17 mmol) at RT, and the reaction mixture was stirred at RT for 4 h. Then NaCNBHs (67 mg, 1.06 mmol) was added to the reaction mixture at RT and stirred for 12 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under reduced pressure. The obtained crude was purified by combiflash chromatography (4 g silica gel column) using 2-3% of MeOH in DCM to afford the title compound (7) as a colorless gummy solid (50 mg, 20%). LC-MS: m / z 678 [M+H]+; tR= 1.49, LC-MS purity: 47%.

[0537] Step 5: tert- Butyl ((lr,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (9)

[0538] To a stirred solution of tert-butyl ((lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,T- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (7) (50 mg, 0.07 mmol) in EtOH / tLO (5: 1, 3 mL) was added Parkins catalyst (8) (10 mg, 0.02 mmol) at RT, and the reaction mixture was stirred at 80 °C for 5 h. After reaction completion (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 Na2SC>4, filtered and concentrated under vacuum to afford the title compound (9) as an off-white solid (40 mg, crude, 96%). LC-MS: m / z 640.3 [M-tBu+ H]+; tR = 2.21 min. LC-MS purity: 46.13%.

[0539] Step 6: 2'-Chloro-6-fluoro-5'-(2-(((lr,4r)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3- yl)cyclohexyl)amino)-l-phenylethyl)-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 15)

[0540] To a stirred solution of tert-butyl ((lr,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)- [l,T-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (9) (40 mg, 0.05 mmol) in DCM (1 mL) was added TLA (0. 1 mL) at 0 °C, then the reaction mixture was stirred at RT for 4 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude was purified by prep-HPLC [column: Kinetex Cl 8 (250 x 21.2 x 5 pm); mobile phase A: 0.1% TLA in H2O, mobile phase B: MeCN; flow: 15 mL / min; gradient: time (min) / %B: 0 / 10, 10 / 50] to afford trifluoroacetate salt of the title compound (Example 15) as an off-white solid (3 mg, 7%). LC-MS: m / z 640.3 [M+H]+; tR= 2.02 min. LC-MS purity: 99.05%; HPLC purity: 98.18%, tR= 7.13 min. 'H NMR (400 MHz, DMSO-de) = 5 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).

[0541] Example 16.

[0542] Synthesis of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((lr,4r)-4-(methylamino) cyclohexyl) amino)-l-phenylethyl)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0543] Step 1: (lr,4r)- / Vl-Methylcyclohexane-l,4-diamine (2)

[0544] To a stirred solution of solution of tert-butyl (4-aminocyclohexyl)carbamate (1) (500 mg, 2.33 mmol) in THF (5.0 mL) was added Li AIH4 (443 mg, 11.6 mmol) at 0 °C, then the reaction mixture was stirred at 70 °C for 3 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum to afford the title compound (2) as an off-white solid (400 mg, crude, 130%). ’H NMR (400 MHz, CDCfi) = 5 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).

[0545] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((lr,4r)-4-(methylamino)cyclohexyl)amino)-

[0546] 1-phenylethyl)- [1,1 '-biphenyl] -2-carbonitrile (4)

[0547] To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,r-biphenyl]-

[0548] 2-carbonitrile (3, prepared according to Example 4, Int.6) (200 mg, 0.47 mmol) in MeOH / DCM (1; 1, 4 mL) were added (lr,4r)-Al-methylcyclohexane-l,4-diamine (2) (60 mg, 0.47 mmol) followed by AcOH (2 drops) at RT, and the reaction mixture was stirred at RT for 4 h. Then NaCNBLL (59 mg, 0.94 mmol) was added and the reaction mixture was stirred at RT for 20 h. After reaction 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 brine (20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (4 g silica gel column) using 20% of MeOH in DCM to afford the title compound (4) as a brown liquid (35 mg, 13%). LC-MS: m / z 536.3 [M-H]+; tR= 1.90 min. LC-MS purity: 92.84%. 'H NMR (400 MHz, DMSO-de) = 5 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). Step 3: Zert- Butyl ((lr,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl) (2-(6-chloro-6'-cyano- 2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl) carbamate (5) To stirred a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((lr,4r)-4- (methylamino)cyclohexyl)amino)-l-phenylethy ) [ , phenyl]-2 -carbonitrile (4) (25 mg, 0.046 mmol) in THF (1 mL) were added EtsN (23 mg, 0.230 mmol) followed by (Boc)2O (40 mg, 0. 186 mmol) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 20 mL), washed with brine (10 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under vacuum to afford the title compound (5) as a brown liquid (19 mg, crude, 55%). LC-MS: m / z 536.3 [(M-Boc+H)]+; tR = 3.37 min. LC-MS purity: 92.84%.

[0549] Step 4: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)(methyl)amino)cyclohexyl) (2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (7)

[0550] To a stirred solution of tert-butyl ((lr,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 / lLO (5: 1, 1.2 mL) was added Parkins catalyst (6) (3 mg, 0.007 mmol) at RT, then the reaction mixture was stirred at 80 °C for 6 h. After reaction completion (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 afford the title compound (7) as a yellow liquid (19 mg, crude, 100%). LC-MS: m / z 654.3 [M-Boc+H]+; tR= 3.10 min. LC-MS purity: 59.23%.

[0551] Step 5: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((lr,4r)-4-(methylamino) cyclohexyl)amino)- l-phenylethyl)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 16)

[0552] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(2-(6'- carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)carbamate (7) (19 mg, 0.025 mmol) in DCM (1 mL) was added TFA (8 mg, 0.075 mmol) at 0 °C, and the reaction mixture was stirred at RT for 3 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude was purified by preparative HPLC [column: Kinetex Cl 8 (250 x 21.2 mm; 5.0 pm); mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; flow: 15 mL / min; gradient time (min) / %B: 0 / 10, 2 / 10,10 / 40] to afford the trifluoroacetate salt of the title compound (Example 16) as an off-white solid (2.5 mg, 12%). LC-MS: m / z 554.3 [M+H]+; tR = 1.80 min. LC-MS purity: 97.76%, tR= 6.58 min, HPLC purity: 95.28%, 'H NMR (400 MHz, DMSO-de) = 5 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).

[0553] Example 17.

[0554] Synthesis of 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidin-2-yl)methyl)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate

[0555] Step 1: 2'-Chloro-6-fluoro-5'-(hydroxy(phenyl)methyl)-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2- carbonitrile (2)

[0556] To a stirred cooled solution of 5'-benzoyl-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2- carbonitrile (1, prepared according to Example 4) (150 mg,0.365mmol) in MeOH (4 mL) was added NaBH4(41 mg, 1.09 mmol) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC), the reaction was quenched with aq. NH4CI (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (4 g silica gel column) using 20% EtOAc in hexane to afford the title compound (2) as a colorless liquid (150 mg, 98%). LC-MS: m / z 394.1 [M-OH +H]+; tR= 2.59 min. LC-MS purity: 97.89%. 'H NMR (400MH, DMSO-de) = 5 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).

[0557] Step 2: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(lH-pyrrol-2-yl)methyl) - [1,1 '-biphenyl] - 2-carbonitrile (4)

[0558] To a stirred solution of 2'-chloro-6-fluoro-5'-(hydroxy(phenyl)methyl)-5-(2-methoxyethoxy)-[l,l'- biphenyl] -2-carbonitrile (2) (100 mg, 0.242 mmol) in 20 mL sealed tube were added IH-pyrrole (3) (32 mg, 0.485 mmol) followed by BF3 OEt2 (34 mg, 0.242 mmol), and the reaction mixture was stirred at 1000C for 16h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (4 g silica gel column) using 30% EtOAc in hexane to afford the title compound (4) as a colorless liquid (70 mg, 90%). LC-MS: m / z 461.1 [M +H]+; tR= 2.78 min. LC-MS purity: 95.53%.

[0559] Step 3: 2’-Chloro-6-fluoro-5-(2-methoxyethoxy)-5’-(phenyl(lH-pyrrol-2-yl)methyl)-[l,l’-biphenyl]- 2-carboxamide (10)

[0560] To a stirred solution of2’-chloro-6-fluoro-5-(2-methoxyethoxy)-5’-(phenyl(lH-pyrrol-2-yl)methyl)-[l,l’- biphenyl] -2-carbonitrile (4) (70 mg, 0.152 mmol) in EtOH / FLO (5: 1, 5 mL) was added Parkins’s catalyst (5) (20 mg, 0.045 mmol) at RT, and the reaction mixture was heated at 80 °C for 16 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum to afford the title compound (6) as a yellow liquid (70 mg, crude, 97%). LC- MS: m / z 479.1, tR= 2.61 min. LC-MS purity: 76.45%.

[0561] Step 4: 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidin-2-yl)methyl)-[l,l'-biphenyl]- 2-carboxamide trifluoroacetate (Example 17) To a stirred solution of 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(lH-pyrrol-2-yl)methyl)-[l,l'- biphenyl] -2 -carboxamide (6) (70 mg, 0.146 mm ) H (3.00 mb) were added 1 drop of cone. HC1 followed by PtO2(33 mg, 0.146 mmol) at RT, and the reaction mixture was stirred at RT under hydrogen for 16 h. After reaction completion (monitored by TLC), the reaction mixture was diluted with 10% MeOH / DCM (30 mb), filtered on a celite pad, and concentrated under vacuum. The crude compound was purified by combiflash chromatography (4 g silica gel column) using 15% MeOH in DCM to afford an impure brown solid (17) which was further purified by HPEC [column: buna OMEGA C18 (250 x 21.2 mm; 5 pm); mobile phase A: 0.1% TEA in in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 35, 10 / 50; flow rate:15mb / min] to afford trifluoroacetate salt of stereoisomer 1 (17a) of the title compound (Example 17) (7 mg, 11%) as an off-white solid. EC-MS: m / z 483.1 [M + H]+; tR= 1.96 min. EC-MS purity: 85.72%, tR= 6.95 min; HPLC purity = 97.37%, 'H NMR (400 MHz, DMSO-de and D2O) = 5 ppm 7.48-7.25(m, 10H), 4.44 (bs, 1H), 4.24-4.09 (m, 3H), 3.72-3.71(bs, 2H), 3.3 l(s, 3H), 3.22-3.20 (bs, 2H), 2.05-2.00 (m, 3H), 1.56-1.52 (m, 1H) and trifluoroacetate salt of stereoisomer 2 (17b) ofthe title compound (Example 17): Yield = 7 mg, 11%. LC-MS: m / z 483.1 [M + H]+; tR= 2.10 min. LC-MS purity: 99.44%, tR= 7.14 min; HPLC purity= 86.43%, 'H NMR (400 MHz, DMSO-de and D2O) = 5 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), 3.32-3.3 l(s, 3H), 3.25-3.18 (m, 2H), 1.97- 1.80 (m, 4H), 1.59-1.54 (m, 1H).

[0562] Example 18.

[0563] Synthesis of (lr,4r)-4-((2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3- yl)-2-phenylethyl)amino)cyclohexane-l-carboxylic acid trifluoroacetate

[0564] Step 1: Methyl (lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)- 2-phenylethyl)amino)cyclohexane-l-carboxylate (3) To a stirred solution of methyl (lr,4r)-4-aminocyclohexane-l-carboxylate hydrochloride salt (2) (2.4 g, 5.67 mmol) in MeOH / DCM (1: 1, 25 mL) was ad A (1.9 mL, 11.34 mmol) at RT and the reaction mixture was stirred for 1 h. 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,r- biphenyl] -2 -carbonitrile (1, prepared according to Example 4, Int.6) (2.4 g, 5.671 mmol) followed by AcOH (0.5 mL) were added to the reaction mixture at RT and stirred for 4 h. Then NaCNBHs (0.71g, 11.34 mmol) was added to the reaction mixture and the reaction mixture was stirred at RT for 12 h. After reaction completion (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 Na2SC>4, filtered, and concentrated under reduced pressure. The obtained crude was purified by combiflash chromatography (24 g silica gel column) using 3-5% of MeOH in DCM to afford the title compound (3) as a colorless gummy liquid (0.6 g, 19%). LC-MS: m / z 565.3 [M+H]+; tR= 2.19 min, LC-MS purity: 85.76%.

[0565] Step 2: Methyl (lr,4r)-4-((ter / -butoxycarbonyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2- methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-l-carboxylate (4)

[0566] To a stirred solution of methyl (lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(2-methoxyethoxy)-[l,T- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-l-carboxylate (3) (600 mg, 1.063 mmol) in DCM (10 mL) were added EtsN (0.42 mL, 3.189 mmol ) followed by (Boc^O (348 mg, 1.59 mmol ) at 0 °C, and the reaction mixture was stirred at RT for 4 h. After reaction completion (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 was purified by combiflash chromatography (24 g silica gel column) using 3-5% MeOH in DCM to afford the title compound (4) as an off-white solid (500 mg, 70%). LC-MS: m / z 565.2 [M-Boc+H]+; tR= 3.16 min and 3.20 min. LC-MS Purity: 99%, 'H NMR (400 MHz, DMSO-de) = 5 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).

[0567] Step 3: Methyl (lr,4r)-4-((ter / -butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2- methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-l-carboxylate (6)

[0568] To a stirred solution of methyl (lr,4r)-4-((tert-butoxycarbonyl)(2-(6-chloro-6'-cyano-2'-fluoro-3'-(2- methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-l-carboxylate (4) (500 mg, 0.752 mmol) in EtOH / ILO (5: 1, 9 mL) was added Parkins catalyst (5) (97 mg, 0.225 mmol) at RT, and the reaction mixture was stirred at 80 °C for 5 h. After reaction completion (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 was purified by combiflash chromatography (12 g silica gel column) using 3- 5% MeOH in DCM to afford the title compound (6) as an off-white solid (500 mg, 64%) from two batches. LC-MS: m / z 583.3 [M-Boc+H]+; tR= 2.92 min. LC-MS purity: 70.78%. 'H NMR (400 MHz, DMSO-de) = 5 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 ( , H), 1.33 (s, 9H), 1.22-1.17 (m, 5H).

[0569] Step 4: (lr,4r)-4-(( / e / 7-Butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)- [l,l'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-l-carboxylic acid (7)

[0570] To a stirred solution of methyl (lr,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2- methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-l-carboxylate (6) (350 mg, 0.512 mmol) in THF / MeOH (3: 1, 8 mL) and H2O (1.00 mb) was added LiOH H2O (64.5 mg, 1.537 mmol) and the reaction mixture was stirred at RT for 5 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with ice cold H2O (10 mL), acidified with IN HC1, and the precipitated solid was filtered, and dried under reduced pressure. The obtained crude was triturated with hexane (20 mL) to afford the title compound (7) as an off-white solid (420 mg, 85%) from two batches. LC-MS : m / z 667.3 [M- H]+; tR= 2.66 min. LC-MS purity: 74.87%, HPLC purity: 74.18%, ' H NMR (400 MHz, DMSO-de) = 5 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).

[0571] Step 5: (lr,4r)-4-((2-(6'-Carbamoyl-6-chloro-2'-fluoro-3'-(2-methoxyethoxy)-[l,l'-biphenyl]-3-yl)-2- phenylethyl)amino)cyclohexane-l-carboxylic acid (18)

[0572] To a stirred solution of (lr,4r)-4-((tert-butoxycarbonyl)(2-(6'-carbamoyl-6-chloro-2'-fluoro-3'-(2- methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-l-carboxylic acid (7) (420 mg, 0.628 mmol) in DCM (5 mL) was added TFA (185 mg, 1.88 mmol) at 0 °C, then the reaction mixture was stirred at RT for 4 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude was triturated with Et2O (15 mL) to afford trifluoroacetate salt of the title compound (Example 18) as an off-white solid (365 mg, 67%). LC-MS: m / z 569.25; [M+H]+(tR = 1.47 min), LC-MS purity: 96.82%. HPLC purity: tR= 7.15 min (78.53%). 'H NMR (400 MHz, DMSO-de) = 5 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).

[0573] Synthesis and chiral purification of Example 18

[0574] Comp 7aTFAExample 18a d gBoc. deprotection

[0575] The scale-up of 3.0 g of stereoisomeric mixture of compound (7) was carried out by following the same reaction procedure and 3.0 g of compound (7) was purified by chiral prep-HPLC (1stprep purification: Column: Chiralpak IG (250 x 10; 5pm); Mobile phase A : 0.1% DEA in hexane, mobile phase B: EtOH (100%); Flow: 10 mL / min, Isocratic: 80 (A):20 (B); Dilution: IPA / DCM (90: 10); 2ndprep purification: Column: Chiralpak IA (250 x 20; 5pm ); Mobile Phase A: 0.1% TFA in hexane, mobile phase B: IPA / DCM (90: 10); Flow: 15 mL / min, Isocratic: 85 (A): 15 (B); Dilution: THF (100%) to afford four stereoisomers of compound (7). The first step chiral prep, purification of compound 7 afforded 720 mg of a mixture of compound 7a and 7b and 820 mg of mixture of compound 7c and 7d, respectively. The second step chiral prep, purifications afforded 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%.

[0576] The four stereoisomers of compound 7a-7d each independently subjected for Boc-deprotection with TFA by following step 5 in the synthesis of Example 18, to afford four stereoisomers of Example 18a-18d in enantiomeric excess of >90% - 97%, respectively. The absolute stereochemistry of the stereoisomers of Example 18a-18d has not been determined.

[0577] 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. 'H NMR (400 MHz, DMSO-rC,) 5 ppm 12.21 (bs, 1H), 8.29 (bs, 1H), 8.22 (bs, 1H), 7.59 (bs, 1H), 7.47-7.25 (m, 9H), 7.15 (bs, 1H), 4.36 (t, J= 8.0 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).

[0578] Example 18b (stereoisomer 2): 50 mg used 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. 'H NMR (400 MHz, DMSO-de) 5 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). 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. NMR (400 MHz, DMSO-de) 5 ppm 12.20 (bs, 1H), 8.36 (bs, 1H), 8.31 (bs, 1H), 7.57 (bs, 1H), 7.47-7.25 (m, 10H), 7.10 (bs, 1H), 4.36 (t, J = 8.0 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).

[0579] 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. 'HNMR (400 MHz, DMSO-de) 5 ppm 12.20 (bs, 1H), 8.34 (bs, 2H), 7.57 (bs, 1H), 7.47-7.26 (m, 10H), 7.10 (bs, 1H), 4.36 (t, J= 8.0 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).

[0580] Example 19.

[0581] 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2’-chloro-5,6-difluoro-[l,l’-biphenyl]-2- carboxamide

[0582] Step 1: tert- Butyl ((lr,4r)-4-(( / e / 7-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6’-cyano-2’,3’- difluoro-[l,l’-biphenyl]-3-yl)-2-phenylethyl)carbamate

[0583] To a stirred solution of / m-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(4-chloro-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-phenylethyl)carbamate (1, prepared according to Int. 6, Example 10)) (600 mg, 0.91 mmol) and 2-bromo-3,4-difluorobenzonitrile (2) (238 mg, 1.09 mmol) in toluene / lTO (5: 1, 12.0 mL) were added K3PO4 (609 mg, 2.745 mmol), N-XantPhos (53 mg, 0.091 mmol) and Pd2(dba)s (42 mg, 0.045 mmol) at 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 reaction completion (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 Na2SC>4, filtered, and concentrated under reduced pressure. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 20% EtOAc in hexane to afford the title compound (3) as an off-white solid (400 mg, 60%). LC-MS: m / z 564.2 [M-Boc+H]+; tR= 3.13 min. LC-MS purity: 96.37%.

[0584] Step 2: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro- 2',3'-difluoro-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3)

[0585] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6’- cyano-2’,3’-difluoro-[l,l’-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (100 mg, 0.150 mmol) in EtOH / H2O (5: 1, 3 mL) was added Parkins catalyst (4) (20 mg, 0.045 mmol) at RT then the reaction mixture was heated at 80 °C for 5 h. After reaction co p (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 solution (10 mL), dried over Na2SC>4, filtered, and concentrated under vacuum to afford the title compound (5) as an off-white solid (75 mg, 73%). LC-MS: m / z 584.2 [M-Boc+H]+; tR= 2.91 min. LC-MS purity: 95.92%. 'HNMR (400 MHz, DMSO-de) = 5 ppm 7.79-7.74 (m, 1H), 7.62-7.55 (m, 1H), 7.45 -7.43(m, 2H), 7.35-7.28(m, 7H), 7.22-7.19(m, 1H), 6.66 (d, J= 7.2Hz, 1H), 4.40-4.20 (bs, 1H), 3.77- 3.64 (bs, 2H), 3.05 (bs, 2H), 1.62 -1.50 (bs, 3H), 1.33 (s, 18H), 1.06-1.03 (m, 5H).

[0586] Step 3: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-5,6-difluoro-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 19)

[0587] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl) (2-(6'-carbamoyl-6- chloro-2',3'-difluoro-[l,T-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (75 mg, 0.109 mmol) in DCM (1 mL) was added TLA (0.1 mL) at 0 °C, then the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude was triturated with diethyl ether and purified by prep-HPLC [column: Kinetex C18 (250 x 21.2 mm; 5 pm); mobile phase A: 0.1% TLA in H2O, mobile phase B: MeCN; flow rate: 15 ml / min; gradient time (min) / %B: 0 / 20, 2 / 20, 10 / 50] to afford the trifluoroacetate salt of the title compound (Example 19) as an off-white solid (55 mg, 92%). LC-MS: m / z 484.2 [M+H]+; tR= 1.81 min. LC-MS purity: 99.68%. HPLC :98.42%, tR= 6.59 min. ’HNMR (400 MHz, DMSO-de ) = 5 ppm 8.47 (bs, 1H), 7.86 (bs, 2H), 7.57-7.53 (m, 1H), 7.50-7.44 (m, 3H), 7.40-7.33 (m, 5H), 7.28-7.25 (m, 1H), 7.10 (bs, 1H), 4.44-4.40 (m, 1H), 3.74-3.67 (m, 3H), 3.06-2.94 (m, 2H), 2.12-2.07 (m, 2H), 2.00-1.97 (m, 2H), 1.48-1.24 (m, 4H).

[0588] Example 20.

[0589] Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- hydroxyethoxy)- [1,1 '-biphenyl] -2-carboxamide trifluoroacetate

[0590] Step 1: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro- 3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3)

[0591] To a stirred solution of stirred solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-l-ol (2) (22 mg, 0.105 mmol) in DML (2.0 mL) was added NaH (11 mg, 0.30 mmol) at 0 °C and stirred for 15 min at RT. tert- Butyl (( lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[ 1, T- biphenyl]-3-yl)-2-phenylethyl)carbamate (1, prepared according to Int. 3, Example 19) (60 mg, 0.150 mmol) was added to the reaction mixture at 0 °C and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold H2O (10 mL), and the precipitated solid was filtered through Buchner funnel and dr vacuum. The obtained crude was triturated with hexane (20 mL) to afford the title compound (3) as an off-white solid (60 mg, 53%). LC-MS: m / z 692.3 [M-Boc +H]+; tR= 3.34, LC-MS purity: 92.39%. 1H NMR (400 MHz, DMSO-de) = 5 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).

[0592] Step 2: tert- Butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'- fluoro-3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5)

[0593] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-2'-fluoro-3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[l,l'-biphenyl]-3-yl)-2- phenylethyl)carbamate (3) (60 mg, 0.075 mmol) in EtOH / fLO (5: 1, 3 mL) was added Parkins catalyst (4) (10 mg, 0.022 mmol) at RT, and the reaction mixture was stirred at 80 °C for 5 h. After reaction completion (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 afford the title compound (5) as an off-white solid (60 mg, 97%) which was used in the next step without any further purification.

[0594] Step 3: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- hydroxyethoxy)- [1 ,1 '-biphenyl] -2-carboxamide trifluoroacetate

[0595] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[l,l'-biphenyl]-3-yl)-2- phenylethyl)carbamate (5) (60 mg, 0.074 mmol) in DCM (1 mL) was added TFA (0.1 mL) at 0 °C, and the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude was triturated with diethyl ether to afford trifluoroacetate salt of the title compound (Example 20) as an off-white solid (45 mg, 94%). LC-MS: m / z 526.2 [M+H]+; tR= 1.69 min. LC-MS purity: 99.63%, HPLC purity: 95.51%, tR=5.35 min. 1H NMR (400 MHz, DMSO-de) = 5 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 l(m, 4H), 1.40-1.23 (m, 4H).

[0596] Example 21.

[0597] Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-methoxy- [l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0598] Step 1: tert- Butyl ((lr,4r)-4-(( / e / 7-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro- 3'-methoxy-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3)

[0599] To a stirred solution of / -butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-2',3'-difluoro-[l,T-biphenyl]-3-yl)-2-phenylethyl)carbamate (1, prepared according to Int. 3, Example 19) (100 mg, 0.150 mmol) in MeOH (1.0 mL), was added NaOMe (40 mg, 0.751 mmol) at 0 °C and the reaction mixture was stirred at RT for 24 h. After completion of the reaction (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 Na2SC>4, filtered, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 20% EtOAc in hexane to afford the title compound (3) as an off-white solid (60 mg, 59%). LC-MS: m / z 578.3 [M-Boc+H]+; tR= 3.23, LC-MS purity: 99.46%. 1H NMR (400 MHz, DMSO-de) = 5 ppm 7.86- 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).

[0600] Step 2: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'- fluoro-3'-methoxy-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5)

[0601] To a stirred solution of / -butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-2'-fluoro-3'-methoxy-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (60 mg, 0.075 mmol) in EtOHTLO (5: 1, 3 mL) was added Parkins catalyst (11 mg, 0.024 mmol) at RT, and the reaction mixture was heated at 80 °C for 5 h. After reaction completion (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 afford the title compound (5) as an off-white solid (60 mg, 98%). LC-MS: m / z 596.3 [M-Boc+H]+; tR= 2.85 min. LC- MS purity: 90.72%. ' H NMR (400 MHz, DMSO-de) = 5 ppm 7.62-7.50 (m, 2H), 7.43-7.38 (m, 2H), 7.31- 7.13 (m, 9H), 4.45-4.20 (m, 1H), 3.90 (d, J = 3.6 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).

[0602] Step 3: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-methoxy- [l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 21)

[0603] To a stirred solution of / -butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-methoxy-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.086 mmol) in DCM (1 mL) was added TFA (0 1 mL) at 0°C and the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude was triturated with diethyl ether to afford roacetate salt of the title compound (Example 21) as an off-white solid (48 mg, 90%). LC-MS: m / z 496.2 [M+ H]+; tR = 1.79 min. LC-MS purity: 99.07%. HPLC :98.04%, tR=6.55 min. HNMR (400 MHz, DMSO-de and D2O) = 5 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).

[0604] Example 22.

[0605] Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin- 3-yloxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0606] Step 1: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro- 3'-(pyridin-3-yloxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (3)

[0607] To a stirred solution of pyridin-3-ol (2) (10.0 mg, 0.105 mmol) in DMF (2.0 mL) was added NaH (11 mg, 0.30 mmol) at 0°C and the reaction mixture was stirred for 15 mins at RT. Then tert-butyl ((lr,4r)-4- ((tertbutoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro-[l,T-biphenyl]-3-yl)-2- phenylethyl)carbamate (1, prepared according to Int. 3, Example 19) (lOOmg, 0.150 mmol) was added at 0 °C and the reaction mixture was stirred as RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold H2O (10 mL), the precipitated solid was fdtered with a Buchner funnel and dried under vacuum. The obtained crude was triturated with 10% Et2O in hexane to afford the title compound (3) as an off-white solid (60 mg, 54%). LC-MS: m / zrl \3 [M-H]+; tR= 2.06 min, LC-MS purity: 87.01%. ’HNMR (400 MHz, DMSO-de ) = 5 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).

[0608] Step 2: tert- Butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'- fluoro-3'-(pyridin-3-yloxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5)

[0609] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-2'-fluoro-3'-(pyridin-3-yloxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)carbamate (3) (60 mg, 0.081 mmol) in EtOH / H2O (5: 1, 3 mL) was added Parkins catalyst (11 mg, 0.024 mmol) at RT. Then the reaction mixture was heated at 80 °C for 5h. After reaction completion (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 Na2SC>4 filtered and concentrated under vacuum to afford the title compound (5) as an off-white solid (60 mg, crude, 98%). LC-MS: m / z 759.3 [M+H]+; tR= 2.97 min. LC- MS purity: 74.63%.

[0610] Step 3: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin-3- yloxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 22)

[0611] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-(pyridin-3-yloxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl)carbamate (5) (60 mg, 0.079 mmol) in DCM (1 mL) was added TFA (0. ImL) at 0 °C, and the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude was triturated with diethyl ether and purified by prep-HPLC [column: Kinetex C18 (250 x 21.2 mm; 5 pm); dilution: MeCN+ H2O+ THF; mobile phase A: 0.1%TFA in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10,10 / 50; flow rate: 15 mL / min] to afford the trifluoroacetate salt of the title compound (Example 22) as an off-white solid (12 mg, 23%). LC-MS: m / z 559.2 [M+H]+; tR= 1.82 min. LC-MS purity: 89%, HPLC: 99.39%; tR=6.29 min. 'HNMR (400 MHz, DMSO-de and D2O) = 5 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), 2.1 l(bs, 2H), 2.00-1.98 (m, 2H), 1.43-1.31(m, 4H).

[0612] Example 23.

[0613] Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(((7?)- tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0614] Step 1: tert- Butyl ((lr,4r)-4-((rert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro- 3'-(((7?)-tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate

[0615] To a stirred solution of of ( / ?)-(tctrahydrofuran-2-yl)mcthanol (2) (16.0 mg, 0.105 mmol) in DMF (2.0 mL), was added NaH (11 mg, 0.30 mmol) at 0 °C and the reaction mixture was stirred for 15 mins at RT. Then tert-butyl (( lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2',3'-difluoro- [l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (1, prepared according to Int. 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 completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold H2O (10 mL), the precipitated solid was filtered with a Buchner funnel and dried under vacuum. The obtained crude was triturated with 10% Et2O in hexane (20 mL) to afford the title compound (3) as an off-white solid (60 mg, 53%). LC-MS: m / z 593.15 [M-Boc,-tBu+H]+; tR= 2.06, LC-MS purity: 95.89%,’HNMR (400 MHz, DMSO-de) = 5 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, 1 ), (s, 3H).

[0616] Step 2: tert- Butyl ((1 rArl^-firerr-butoxycarbonyllaminolcyclohexyll^-fb'-carbamoyl-b-chloro^'- fluoroA'-ffi^l-tetrahydrofuran^-yllmethoxyl-ILl '-biphenyll^-yll^-phenylethyllcarbamate (5)

[0617] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-2'-fliioro-3'-((( / ?)-tctrahydrofiiran-2-yl)mctlwxy)-| 1. 1 '-biphenyl |-3-yl)-2-phcnylcthyl)carbam ate

[0618] (3) (60 mg, 0.075 mmol) in EtOH / lLO (5: 1, 3 mb) was added Parkins catalyst (4) (11 mg, 0.024 mmol ) at RT and the reaction mixture was heated at 80 °C for 5h. After reaction completion (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 Na2SC>4, filtered, and concentrated under vacuum to afford the title compound (5) as an off-white solid (60 mg, 97%). LC-MS: m / z 666.3 [M- Boc+H]+; tR = 2.90 min. LC-MS purity: 86.84%.

[0619] Step 3: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(((7?)- tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 23)

[0620] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-(((R)-tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate

[0621] (5) (60 mg, 0.078 mmol) in DCM (1 mL) was added TLA (0.1 mL) at 0 °C, and the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude was triturated with diethyl ether and purified by prep. HPLC [column: Kinetex C18 (250 x 21.2 x 5pm); dilution: MeCN+H2O+THP; mobile phase A: 0.1%TLA in H2O, mobile phase B MeCN; gradient time (min) / %B: 0 / 10,10 / 50; flow rate: 15 mL / min] to afford the trifluoroacetate salt of the title compound (Example 23) as an off-white solid (32 mg, 53%). LC-MS: m / z 566.3 [M +H]+; tR= 1.84 min. LC-MS purity: 99.63%; HPLC purity: 99.65%, tR= 6.61 min. ’HNMR(400 MHz, DMSO-de) = 5 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).

[0622] Example 24.

[0623] Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(((5)- tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0624]

[0625] Step 1: (5)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzonitrile (3)

[0626] To a stirred solution of NaH (60% in mineral oil) (1.00 g, 27.5 mmol) in DMF (40 mL) was added (5)- (tetrahydrofuran-2-yl)methanol (2) (2.108 g, 20.64 mmol) slowly at 0 °C and the reaction mixture was stirred for 0.5 h. To this reaction mixture, 2-bromo-3,4-difluorobenzonitrile (1) (5.00 g, 22.94 mmol) in DMF (10 mL) was added at 0 °C and the reaction mixture was stirred at RT for 1 h. After reaction completion (monitored by TLC), the reaction mixture was quenched with water (150 mL). The obtained solid was filtered, and dried under vacuum to afford the title compound (3) as an off-white solid (4.00 g, 58.1%). 'H NMR (400 MHz, DMSO-de) 5 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).

[0627] Step 2: 5’-Benzoyl-2’-chloro-6-fluoro-5-(((iS)-tetrahydrofuran-2-yl)methoxy)-[l,l’-biphenyl]-2- carbonitrile (5) To a stirred solution of (.S)-2-bromo-3-fluoro-4-((tctrahydrofuran-2-yl)mcthoxy (benzonitrile (3) (3.5 g, 11.66 mmol) and (4-chloro-3-(4,4,5,5-tetramethy , , oxaborolan-2-yl)phenyl)(phenyl)methanone (4, prepared according to the similar reaction procedure for Int.3, Example 2) (5.99 g, 17.49 mmol) in toluene / water (50 mL, 9: 1) was added K3PO4 (7.42 g, 35.0 mmol) at RT and the reaction mixture was degassed with N2 for 10 min. To this solution, N-XantPhos (643 mg, 1.166 mmol) and Pd2(dba)s (534 mg, 0.583 mmol) were added at RT and degassed with N2 for 5 min. The resulting reaction mixture was stirred at 100 °C for 16 h. After reaction completion (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 Na2SC>4and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (80 g silica gel column) using 0-20% EtOAc in hexane to afford the title compound (5) as a yellow sticky solid (3.00 g, 59%). LC-MS: m / z 436.1 [M+H]+. ’H NMR (400 MHz, CDCL) 5 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).

[0628] Step 3: 2'-Chloro-6-fluoro-5'-(2-phenyloxiran-2-yl)-5-(((iS)-tetrahydrofuran-2-yl)methoxy)-[l,l'- biphenyl]-2-carbonitrile (6)

[0629] To a stirred solution of trimethylsulfonium iodide (2.81 g, 13.77 mmol) in THF / DMSO (40 mL, 1: 1) was added NaH (496 mg, 20.65 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. The 5'- benzoyl-2'-chloro-6-fluoro-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[ 1 , 1 '-biphenyl] -2 -carbonitrile (5) (3.00 g, 6.88) was added at 0 °C and the reaction mixture was stirred at RT for 18. After reaction completion (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 afford the title compound (6) as a yellow liquid (3.00 g, 97%) which was used in next reaction without further purification.

[0630] Step 4: 2'-Chloro-6-fluoro-5'-(2-oxo-l-phenylethyl)-5-(((iS)-tetrahydrofuran-2-yl)methoxy)-[l,l'- biphenyl]-2-carbonitrile (7)

[0631] To a stirred solution of 2'-chloro-6-fluoro-5'-(2-phenyloxiran-2-yl)-5-(((S)-tetrahydrofuran-2- yl)methoxy)-[l,l'-biphenyl] -2 -carbonitrile (6) (1.50 g, 3.33 mmol) in Et2O (15 mL) was added BF3 Et2O (1.26 mL, 10.0 mmol) at 0 °C, and the resulting reaction mixture was stirred at 0 °C for 10 min. After reaction completion (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 Na2SC>4 and concentrated under vacuum to afford the title compound (7) as a yellow liquid (1.50 g) which was used in next reaction without further purification. LC-MS: m / z 448.1 [M-H]+.

[0632] Step 5: tert- Butyl ((lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(((iS)-tetrahydrofuran-2-yl)methoxy)- [l,l'-biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)carbamate (9)

[0633] To a stirred solution of 2'-chloro-6-fhioro-5'-(2-oxo-l-phenylethyl)-5-(((S)-tetrahydrofuran-2- yl)methoxy)-[l,l'-biphenyl] -2 -carbonitrile (7) (1.50 g, 3.33 mmol) in MeOH / DCM (30 mL, 1: 1) were added tert-butyl ((lr,4r)-4-aminocyclohexyl)carbamate (8) (1.429 g, 6.67 mmol) followed by AcOH (0.019 mL, 0.33 mmol) at RT After stirring the reaction mixture at RT for 4 h NaCNBHs (629 mg, 10.0 mmol) was added and the reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC) the reaction mixture was diluted with ( mL) and extracted with EtOAc (2 x 120 mL). The combined organic layers were dried overNa2SC>4, and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 40% EtOAc in hexane then 20% MeOH in DCM to afford the title compound (9) as a colorless gummy solid (1.20 g, 55.5%). LC-MS: m / z 648.3 [M+H]+.

[0634] Step 6: tert-butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro- 3'-(((5)-tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (10)

[0635] To a stirred solution of tert-butyl ((lr,4r)-4-((2-(6-chloro-6'-cyano-2'-fluoro-3'-(((S)-tetrahydrofuran-2- yl)methoxy)-[l, T -biphenyl] -3 -yl)-2-phenylethyl)amino)cyclohexyl)carbamate (9) (1.20 g, 1.851 mmol) in DCM (20 mL) were added EtsN (0.77 mL, 5.55 mmol) and BOC2O (0.64 mL, 2.78 mmol) at 0 °C, and the resulting reaction mixture was stirred at RT for 16 h. After reaction completion (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 obtained crude was purified by combiflash chromatography (24 g silica gel column) using 40% EtOAc in hexane to afford the title compound (10) as a colorless gummy solid (1.20 g, 86%). LC-MS: m / z 592.3 [(M-Boc-tBu) + H]+.

[0636] Step 7: tert-butyl ((lr,4r)-4-((ter / -Butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-2'- fluoro-3'-(((5)-tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (11)

[0637] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[l,r-biphenyl]-3-yl)-2-phenylethyl)carbamate

[0638] (10) (1.20 g, 1.604 mmol) in EtOH / water (20 mL, 4: 1) was added Parkins catalyst (275 mg, 0.641 mmol) at RT, then the resulting reaction mixture was stirred at 80 °C for 5 h. After reaction completion (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 obtained crude was purified by combiflash chromatography (12 g silica gel column) using 0-100% EtOAc in hexane to afford the title compound (11) as an off-white gummy solid (1.10 g, 89%). LC-MS: m / z 766.5 [M+H]+; ’HNMR (400 MHz, DMSO-de) 8 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).

[0639] Step 8: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(((5)- tetrahydrofuran-2-yl)methoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 24)

[0640] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6- chloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[l,r-biphenyl]-3-yl)-2-phenylethyl)carbamate

[0641] (11) (50 mg, 0.067 mmol) in DCM (1 mL) was added TFA (0.016 mL, 0.202 mmol) and the resulting reaction mixture was stirred at RT for 4 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The obtained crude was washed with Et2O (10 mL), pentane (10 mL), dried under vacuum and lyophilized to afford the title compound (Example 24) as an off-white solid (30 mg 82%) LC MS: m / z 566 5 [M+H]+; ’H NMR (400 MHz DMSO-de) 8 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),

[0642] 4.37 (t, J= 7.6 Hz, 1H), 4.18-4.10 (m, 4H), 3.79- ( , H), 2.09-1.84 (m, 7H), 1.70-1.68 (m, 1H), 1.37-

[0643] 1.23 (m, 5H).

[0644] Synthesis and chiral purification of four stereoisomers of Example 24:

[0645] TFA

[0646] C 11 E l 24 :190 mg Boc-deprotection : 160 mg

[0647] A stereoisomeric mixture of compound (11, 1.20 g) was purified by chiral SFC (Column: Lux Cellulose- 4-4.4 mm x 250 mm x 21.2 mm; 5 pm; Mobile Phase A: CO2 and mobile phase B: 0.1% HCOOH in IPA / MeOH (1: 1); Flow: 50 mL; Isocratic: 75(A):25(B); Diluents: EtOH / DCM (1: 1), 18 mL; Injection volume: 0.2 mL; Run time: 27 min) purification to afford all four stereoisomers of compound 11 (Halid). Compound Ila: 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 lid: 190 mg; chiral HPLC purity: 95.06%.

[0648] The four steroisomers of compound lla-lld were each independently subjected for Boc-deprotection with TFA by following step 8 in the procedure for Example 24, to afford four stereoisomers of Example 24a- 24d in an enantiomeric excess of >87-98%, respectively. The absolute stereochemistry of stereoisomers of Example 24a-24d has not been determined.

[0649] 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. ’H NMR (400 MHz, DMSO-de) 5 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).

[0650] 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. ’H NMR (400 MHz, DMSO-de) 5 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).

[0651] 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. ’H NMR (400 MHz, DMSO-de) 5 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), (m, 2H), 3.03-2.93 (m, 2H), 2.09-1.84 (m, 7H),

[0652] 1.70-1.67 (m, 1H), 1.44-1.23 (m, 4H).

[0653] 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. ’H NMR (400 MHz, DMSO-de) 5 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),

[0654] 1.70-1.65 (m, 1H), 1.37-1.23 (m, 4H).

[0655] Step 9: (3-Bromo-4-chlorophenyl)(phenyl)methanone (13)

[0656] A solution of 3-bromo-4-chlorobenzoic acid (12) (8.00 g, 34.20 mmol) in SOCI2 (12 m ) was stirred at 80 °C for 4 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The obtained crude was dissolved in benzene (80 m ), then AICI3 (13.5 g, 101.91 mmol) was added to the reaction mixture portion wise at 0 °C. The resulting reaction mixture was stirred at 80 °C for 6 h. After completion reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and diluted with water (50 mb), basified with aq. sat NaHCOs solution (50 mb) and extracted with EtOAc (2 x 100 mb). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under vacuum. The obtained crude was triturated with pentane (100 mL) to afford the title compound (13) as a off white solid (8.78 g, 87%). LC-MS: m / z = 295.85 [M-H]+; 'H NMR (400 MHz, DMSO-d6) 5 ppm 8.02 (s, 1H), 7.81 - 7.70 (m, 5H), 7.58 - 7.57 (m, 2H).

[0657] Step 10: (4-Chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (4)

[0658] To a stirred solution of (3-bromo-4-chlorophenyl)(phenyl)methanone (13) (9.0 g, 30.5 mmol) in 1,4- dioxane (90 mL) were added bis(pinacolato)diboron (11.6 g, 45.7 mmol)) and KOAc (8.97 g, 91.0 mmol) at RT and degassed with N2 for 10 min. Pd(dppf)C12.DCM (2.48 g, 3.05 mmol) was added to the reaction mixture at RT and degassed with N2 for 5 min. The resulting reaction mixture was stirred at 100 °C for 16 h. After completion of reaction (monitored by TLC) the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The obtained crude was purified by combi flash chromatography (80 g silica gel column) using 0-10% EtOAc in hexane to afford the title compound (4) as a brown gummy liquid (10 g, 96%). LC-MS: m / z = 343.2 [M+H]+.

[0659] Example 25.

[0660] Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(pyridin- 2-ylmethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0661]

[0662] Step 1: 2-Bromo-3-fluoro-4-(pyridin-2-ylmethoxy) benzonitrile (3)

[0663] To a stirred cooled (0 °C) solution of pyridin-2-ylmethanol (2) (0.080 g, 0.733 mmol) in DMF (8.00 mL), NaH (0.044 g, 1. 100 mmol) was added and stirred for 15 mins at RT, again cooled to 0 °C then 2-bromo- 3,4-difluorobenzonitrile (1) (0.200 g, 0.917 mmol) in 2 mL of DMF was added and the reaction mixture was stirred at the same temperature for 2h. After completion (monitored by TLC) the reaction mixture was poured into ice cold FLO (50 mL), precipitated solid was filtered through Buchner funnel and dried under vacuum to afford the title compound (3) as off-white solid (0.22 g, 78%) LC-MS : No ionization; ’H NMR (400 MHz, DMSO-de) = 5 ppm 8.60 (s, 1H), 7.89-7.80 (m, 2H), 7.55-7.39 (m, 3H), 5.37(s, 2H).

[0664] Step 2: tert- Butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-2'-fluoro- 3'-(pyridin-2-ylmethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (5)

[0665] To a stirred solution of tert-butyl (( lr,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl) (2-(4-chloro-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl)-2 -phenylethyl) carbamate (4, prepared according to Int.6, Example 10) (100 mg, 0.152 mmol) and 2-bromo-3-fluoro-4-(pyridin-2-ylmethoxy) benzo nitrile (56.0 mg, 0.183 mmol) in tolucnc / FLO (6: 1, 3.5 mL) were added K3PO4 (101 mg, 0.456 mmol), n- XantPhos (9 mg, 0.015 mmol) and Pd2(dba)s (7 mg, 0.0076 mmol) at RT and the reaction mixture was degassed with argon for 5 min. Then the reaction mixture was heated at 100°C for 16 h. After reaction completion (monitored by TLC). reaction mixture was diluted with H2O (30 mL) and organic was extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL) solution, dried over Na2SC>4, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (12 g silica gel column) using 60% of EtOAc in hexane to afford the title compound (5) as an off-white solid (50 mg, 43%). LC-MS: m / z 753.4 [M-H)]+; tR = 3.23 min. LC-MS purity: 97.25%. 'H NMR (400 MHz, DMSO-de) = 5 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).

[0666] Step 3: tert- Butyl ((lr,4r)-4-(( / e / 7-butoxycarbonyl)amino) cyclohexyl) (2-(6'-carbamoyl-6-chloro-2'- fluoro-3'-(pyridin-2-ylmethoxy)-[l,l'-biphenyl]-3-yl)-2-phenylethyl) carbamate (7)

[0667] To a stirred solution of tert-butyl (( lr,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl) (2-(6-chloro-6'- cyano-2'-fluoro-3'-(pyridin-2-ylmethoxy)-[l,T-biphenyl]-3-yl)-2-phenylethyl) carbamate (5) (50 mg, 0.066 mmol) in EtOH / lLO (3 ml) was added Parkins catalyst (6) (9 mg, 0.019 mmol) at RT, then heated the reaction mixture at 80 °C for 5 h. After reaction completion (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 brine solution (50 mL), dried over Na2SC>4 filtered and concentrated under vacuum to afford the title compound (7) as an off-white solid (50 mg, 97%). LC-MS: m / z 773.55 [M +H]+; tR= 1.88 min. LC- MS purity: 92.80%. >HNMR (400 MHz, DMSO-de) = 5 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).

[0668] Step 4: 5’-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2’-chloro-6-fluoro-5-(112yridine- 2-yhnethoxy)-[l,l’-biphenyl]-2-carboxamide trifluoroacetate (Example 25)

[0669] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6’-carbamoyl-6- chloro-2’-fluoro-3’-(l 12yridine-2-ylmethoxy)-[l,r-biphenyl]-3-yl)-2 -phenylethyl) carbamate (7) (50 mg, 0.064 mmol) in DCM (1 mL) was added TFA(0.1 mL ) at 0 °C, then the reaction mixture was stirred at RT for 4 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was triturated with Et2O to afford trifluoroacetate salt of the title compound (Example 25) as an off-white solid (45 mg, 99%). LC-MS: m / z [M+H]+; tR = 3.08 min. LC-MS purity: 97.29%, tR= 6.33 min HPLC purity: 96.32%.1H NMR (400 MHz, DMSO-de and D2O) = 5 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).

[0670] Example 26.

[0671] Synthesis of 5’-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2’-chloro-6-fluoro-5- (pyrimidin-2-ylm ethoxy)- [1,1 ’-biphenyl] -2-carboxamide trifluoroacetate

[0672] 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) To a stirred solution of stirred solution of pyrimidin-2-ylmethanol (2) (16.0 mg, 0.105 mmol) in DMF (1.0 mL), was added NaH (11 mg, 0.30 mmol) at 0 °C and stirred for 15 mins at RT, then tert-butyl ((1r,4r)-4- ((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6 -cyano-2 ,3 -difluoro-[1,1 -biphenyl]-3-yl)-2- phenylethyl)carbamate (1, prepared according to Int.3, 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 completion of the reaction (monitored by TLC), reaction mixture was quenched with ice cold H2O (10 mL), precipitated solid was filtered through Buchner funnel and dried under vacuum, obtained crude was triturated with hexane (20 mL) to afford the title compound (3) as an off-white solid (60 mg, 53%), LC-MS: No ionization.1HNMR (400 MHz, DMSO-d6 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). 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) 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) was added Parkins catalyst (4) (12 mg, 0.027 mmol) at RT then heated the reaction mixture at 80 °C for 5h. After reaction completion (monitored by TLC), 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 afford the title compound (5) as an off-white solid (60 mg, crude, 84%). LC-MS: m / z 674.3 [M-Boc+H]+; tR= 2.89 min. LC-MS purity: 59.2%.1HNMR (400 MHz, DMSO-d6-8.85 (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). 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) 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) was added TFA (0.1 mL) at 0 °C, then the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was triturated with diethyl ether and purified by prep-HPLC [column: Kinetex C18 (250 x 21.2; dilution: MeCN+ H2O+THF; mobile phase A: 0.1% TFA in H2O, mobile phase B: MeCN; gradient time (min) / %B: 0 / 10,10 / 50; flow rate: 15 mL / min] to afford trifluoroacetate salt of the title compound (Example 26) as an off-white solid (16 mg, 32%). LC-MS: m / z 574.2 [M + H]+; tR = 1.78 min. LC-MS purity: 99.77%, HPLC purity: 95.42%, tR=6.44 min.1HNMR (400 MHz, DMSO-d6) 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), 113 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), ( , ), 1.96 -1.94 (bs, 2H), 1.43-1.23(m, 4H).

[0673] Example 27.

[0674] Synthesis of 5-(2-((l-acetylazetidin-3-yl)oxy)ethoxy)-5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l- phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0675] Step 1: Benzyl 3-(2-ethoxy-2-oxoethoxy)azetidine-l-carboxylate (3)

[0676] To a stirred solution of benzyl 3 -hydroxyazetidine- 1 -carboxylate (1) (1 g, 4.83 mmol) in THF (10 m ) was added NaH (0.21 g, 5.314 mmol) at 0 °C and stirred for 30 min at the same temperature. Then added Ethyl bromoacetate (2) (0.8 g, 4.830 mmol) at 0 °C and stirred at RT for 1.5 h. After reaction completion (monitored by TLC), reaction was diluted with aq. sat NH4CI solution (20 m ) and extracted with EtOAc (100 mb). The combined organic layers were washed with brine solution, dried over anhydrous Na2SC>4 and concentrated under vacuum to afford the title compound (3) as an off-white solid (0.8 g, 57%), ’H NMR (400 MHz, CDC13) = 5 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).

[0677] Step 2: Benzyl 3-(2-hydroxyethoxy)azetidine-l-carboxylate (4)

[0678] To a stirred solution of benzyl 3 -(2 -ethoxy-2-oxoethoxy)azetidine-l -carboxylate (3) (800 mg, 2.729 mmol) in THF (10 mb) was added EiAlH4(124 mg, 3.275 mmol) at 0 °C and stirred at RT for 3 h. After reaction completion (monitored by TEC) reaction was diluted with aq sat NH CI solution (10 mb) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SC>4 and concentrated under vacuum. The c ue was purified by combiflash chromatography (12 g silica gel column) using 50% EtOAc in hexane to afford the title compound (4) as an off-white solid (600 mg, 88%). LC-MS: m / z 252.2 [M+H]+tR= 2.04, LC-MS purity: 98.80%.

[0679] Step 3: Benzyl 3-(2-(3-bromo-4-cyano-2-fluorophenoxy)ethoxy)azetidine-l-carboxylate (6)

[0680] To a stirred solution of benzyl 3 -(2 -hydroxy ethoxy) azetidine- 1 -carboxylate (4) (600 mg, 2.390 mmol) in DMF (15 mL) was added NaH (143 mg, 3.585 mmol) at 0°C and stirred at the same temperature for 30 min. and then 2-bromo-3, 4-difluorobenzonitrile (5) (622 mg, 2.868 mmol) in DMF (5 mL) was added at 0 °C and stirred at the same temperature for 1.5 h. After reaction completion (monitored by TLC), reaction was diluted with aq. sat NH4CI solution (20 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, filtered, and concentrated under vacuum. The crude compound was purified by combiflash chromatography (12 g silica gel column) using 50% EtOAc in hexane to afford title compound (6) as a brown liquid (600 mg, 66%). LC-MS: m / z 490.0 [M+MeCN+H]+; tR= 2.74, LC-MS purity: 88.22%. 'H NMR (400 MHz, DMSO-de) = 5 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).

[0681] Step 4: Benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-cyano-2-fluoro-[l,l'- biphenyl]-3-yl)oxy)ethoxy)azetidine-l-carboxylate (8)

[0682] To a stirred solution of benzyl 3 -(2-(3-bromo-4-cyano-2 -fluorophenoxy) ethoxy)azetidine-l -carboxylate (6) (600 mg, 1.339 mmol) and tert-butyl (( lr,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl)(2-(4-chloro- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-phenylethyl) carbamate (7, prepared according to Example 10) (800 mg, 1.339 mmol) in toluene / H2O (9: 1, 12 mL), K3PO4 (850mg, 4.017 mmol) and Pd2dbas (62 mg, 0.066 mmol) and N-XantPhos (73 mg, 0.133 mmol) were added under argon atmosphere and heated the reaction mixture at 100 °C for 16 h. After reaction completion (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 was purified by combiflash chromatography (12 g silica gel column) using 90% EtOAc in hexane to afford the title compound (8) as a sticky brown liquid (400 mg, 33%). LC-MS: m / z 797.3 [M-Boc+H]+; tR= 3.25, LC- MS purity: 48.66%.

[0683] Step 5: Benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)((lr,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl)amino)-l-phenylethyl)-6-carbamoyl-2'-chloro-2-fluoro-[l,l'-biphenyl]-3-yl) oxy)ethoxy)azetidine-l-carboxylate (10)

[0684] To a stirred solution of benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)- 1 -phenylethyl)-2'-chloro-6-cyano-2-fluoro-[ 1 , 1 '-biphenyl] -3- yl) oxy)ethoxy)azetidine-l -carboxylate (8) (400 mg, 0.446 mmol) in EtOH / lLO (9: 1, 8 mL) was added Parkins catalyst (9) (76 mg, 0.178 mmol) at RT and the reaction was heated at 90°C for 16 h. After reaction completion (monitored by TLC), reaction was diluted with H2O (10 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine solution dried over Na2SO4 filtered and concentrated under vacuum. The crude was purified by combiflash chromatography (12 g silica gel column) using 90% EtOAc in hexane to afford t mpound (10) as a yellow liquid (300 mg, 75%). LC-MS: m / z 815.3 [M-Boc+H]+; tR= 3.08, LC-MS purity: 92.31%. ’H NMR (400 MHz, DMSO-de) = 5 ppm 7.62-7.56 (m, 2H), 7.41-7.38 (m, 2H), 7.33-7.24 (m, 12H), 7.21-7.14 (m, 2H), 6.64 (d, J = 8.0 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).

[0685] Step 6: tert- Butyl (2-(3'-(2-(azetidin-3-yloxy)ethoxy)-6'-carbamoyl-6-chloro-2'-fluoro-[l,l'- biphenyl]-3-yl)-2-phenylethyl)((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)carbamate (11)

[0686] To a stirred solution of benzyl 3-(2-((5'-(2-((tert-butoxycarbonyl)((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)- 1 -phenylethyl)-6-carbamoyl-2'-chloro-2-fluoro-[ 1 , 1 '- biphenyl] -3 -yl) oxy)ethoxy)azetidine-l -carboxylate (10) (40 mg, 0.043 mmol) in THF / MeOH (1: 1, 1 mL) was added 10% Pd / C (10 mg) and stirred under H2 atmosphere at RT for 3 h. After reaction completion (monitored by TLC), reaction was filtered through Celite bed, filtrate was concentrated under vacuum to afford the title compound (11) as an off-white solid (40 mg, crude, 110%). LC-MS: m / z 781.3; [M +H]+, tR= 2.30 min. LC-MS purity: 46.17%.

[0687] Step 7: tert- Butyl (2-(3'-(2-((l-acetylazetidin-3-yl)oxy)ethoxy)-6'-carbamoyl-6-chloro-2'-fluoro-[l,l'- biphenyl]-3-yl)-2-phenylethyl)((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl) carbamate (12)

[0688] To a stirred solution of tert-butyl (2-(3'-(2-(azetidin-3-yloxy)ethoxy)-6'-carbamoyl-6-chloro-2'-fluoro- [1,1 '-biphenyl]-3-yl)-2-phenylethyl)(( 1 r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl) carbamate (11) (40 mg, 0.051mmol) in DCM (1 mL) was added EtsN (0.1 ml, 0.102 mmol) and (Ac)2O (0.1 mL, 0.328 mmol) and the reaction was stirred at RT for 3 h. After reaction completion (monitored by TLC), Reaction was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine solution (50 mL) and dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by combiflash chromatography (4 g silica gel column) using 90% EtOAc in hexane to afford the title compound (12) as an off-white solid (30 mg, 71%). LC-MS: m / z 723.3; [M-Boc+H]+; tR= 2.76 min; LC-MS purity: 99.86%.

[0689] Step 8: 5-(2-((l-Acetylazetidin-3-yl)oxy)ethoxy)-5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l- phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 27)

[0690] To a stirred solution of tert-butyl (2-(3'-(2-((l-acetylazetidin-3-yl)oxy)ethoxy)-6'-carbamoyl-6-chloro-2'- fluoro-[ 1 , 1 '-biphenyl] -3 -yl)-2-phenylethyl)(( 1 r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl) carbamate (12) (30 mg, 0.036 mmol) in DCM (0.4 mL) was added TFA (0.1 mL) under nitrogen atmosphere at RT and the reaction was stirred at the same temperature for 3 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude was triturated with pentane and lyophilized for 2 days to afford trifluoroacetate salt of the title compound (Example 27) as an off-white solid (15 mg, 68%). LC-MS: m / z 623.3 [M +H]+; (tR= 1.76 min). LC-MS purity: 98.42%, HPLC purity: 98.81%, tR=6.41 min, 'H NMR (400 MHz, DMSO-de) = 5 ppm 8.40-8.32 (bs, 2H), 7.83 (bs, 3H), 7.65 - 7.62 (m, 1H), 7.48-7.44 (m, 3H), 7.41-7.32 (m, 6H), 7.29-7.12(m, 3H), 4.38-4.22(m, 5H), 4.01-3.93(m, 2H), 3.77-3.73(m, 3H), 3.63-3.61(m, IH), 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).

[0691] Example 28.

[0692] Synthesis of 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-5-(2-(2-

[0693] (dimethylamino)-2-oxoethoxy)ethoxy)-6-fluoro-[l,l'-biphenyl]-2-carboxamide trifluoroacetate

[0694] Step 1: N,N-Dimethyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)acetamide (3)

[0695] To a stirred solution of 2-((tetrahydro-2H-pyran-2-yl) oxy) ethan-l-ol (2) (0.500 g, 3.420 mmol) in THF (10.00 mL), reaction mixture was cooled to 0 °C, NaH (0.164 g, 4.104 mmol) was added and stirred for 15 mins at RT, 2-bromo-N, N-dimethylacetamide (1) (0.681 g, 4.104 mmol) in 5 mL (THF) was added at 0 °C and the reaction mixture was stirred at RT for 2h. After reaction completion (monitored by TLC). reaction mixture was quenched with H2O (100 mL) extracted withl0% MeOH in DCM (2 x 100 mL). The combined organic layers were washed brine solution (100 mL), dried over Na2SC>4 filtered and concentrated under vacuum to afford title compound (3) as colorless gummy liquid (0.7 g, 88%). LC-MS: No ionization; 1HNMR(4OO MHz, DMSO-de) = 5ppm 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).

[0696] Step 2: 2-(2-Hydroxyethoxy)-N, N-dimethylacetamide (4)

[0697] To a stirred solution of N,N-dimethyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acetamide (3) (0.400 g, 1.729 mmol) in MeOH (10.00 mL) at RT, PTSA monohydrate (0.032 g, 0.172 mmol) was added, and the reaction mixture was stirred at RT for Ih. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum to afford the title compound (4) as a colorless gummy liquid (0.2 g, 78%). LC-MS: m / z 148.30 [M+H]+; tR= 0.35 min; LC-MS purity: 88.07%. 'HNMR (400 MHz, DMSO- de) = 5 ppm 7.12-7.10 (d, J= 8Hz, IH), 4.13 (s, 2H), 3.50-3.38 (m, 4H), 2.89 (s, 3H), 2.79(s, 3H).

[0698] Step 3: tert- Butyl ((lr,4r)-4-((ter / -butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'-cyano-3'-(2-(2- (dimethylamine)-2-oxoethoxy)ethoxy)-2'-fluoro-[l,l'-biphenyl]-3-yl)-2-phenylethyl)carbamate (6) To stirred cooled solution of 2-(2-hydroxyethoxy)-N,N-dimethylacetamide (4) (23.0 mg, 0.150 mmol) in DMF (2.0 mL), reaction mixture was cold to 0 ° , ( 2 mg, 0.31 mmol) was added and stirred for 15 mins at RT, tert-butyl (( lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6’-cyano-2’,3’- difluoro-[l,r-biphenyl]-3-yl)-2-phenylethyl)carbamate (6, prepared according to Int. 3, Example 19) (100 mg, 0.150 mmol) was added at 0 °C and the reaction mixture was stirred for 2 h at 0 °C. After reaction completion (monitored by TLC). reaction mixture was quenched with H2O (100 mL) extracted with EtOAc (2 x 100 mL): The combined organic layers were washed brine solution (200 mL), and dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by combiflash chromatography (24 g silica gel column) using 3-6% MeOH in DCM to afford the title compound (6) as an off-white solid (60 mg, 50%). LC-MS: m / z 693.3 [M-Boc+H]+; tR= 3.01 min. LC-MS purity: 85.07%. 'H NMR (400 MHz, DMSO-de) = 5 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).

[0699] Step 4: tert- Butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6-chloro-3'- (2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-2'-fluoro-[l,l'-biphenyl]-3-yl)-2-phenylethyl) carbamate (8)

[0700] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6-chloro-6'- cyano-3'-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-2'-fluoro-[l,l'-biphenyl]-3-yl)-2- phenylethyl)carbamate (6) (60 mg, 0.075 mmol) in EtOH / tLO (3 mL) was added Parkins catalyst (7) (10 mg, 0.022 mmol ) at RT, then heated the reaction mixture heated at 80 °C for 5 h. After reaction completion (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 brine solution (50 mL), dried over Na2SO4 filtered and concentrated under vacuum to afford the title compound (8) as an off-white solid (60 mg, 97%). LC-MS: m / z 811.1 [M +H]+; tR= 1.74 min; LC-MS purity: 81.54%.

[0701] Step 5: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)- 2-oxoethoxy)ethoxy)-6-fluoro-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 28)

[0702] To a stirred solution of tert-butyl ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(6'-carbamoyl-6- chloro-3'-(2-(2-(dimethylamino)-2-oxoethoxy)ethoxy)-2'-fluoro-[l,l'-biphenyl]-3-yl)-2- phenylethyl)carbamate (8) (60 mg, 0.074 mmol) in DCM (1 mL) was added TFA (0.1 mL) at 0 °C, then the reaction mixture was stirred for 4 h at RT. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude product was purified by HPLC [column: Kinetex C18 (250 x 21.2; 5pm), mobile phase: 0.1% TFA in H2O (A) / MeCN (B), flow rate: 15 mL / min, gradient time (min) / %B: 0 / 50 10 / 50] to afford trifluoroacetate salt of the title compound (Example 28) as an off-white solid (42 mg, 70%). LC-MS: m / z 611.3 [M+H]+; tR= 1.76 min; LC-MS purity: 98.63%. HPLC purity: 99.01%; tR= 6.41 min. H NMR (400 MHz, DMSO-de and D2O) = 5 ppm 7.51-7.28 (m, 11H), 4.38-4.22 (m, 5H), 3.95-3.67 (m, 8H), 3.05-2.89 (m, 2H), 2.10-1.97 (m, 4H), 1.40-1.23 (m, 4H).

[0703] Example 29. Synthesis of 5'-(2-(((lr,4r)-4-aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- methoxyethoxy)- [1,1 '-biphenyl] -2-carboxami oacetate

[0704] Step 1: 3-Bromo-4-chloro-5-fluorobenzoic acid (2)

[0705] To a stirred solution of 4-chloro-3-fluorobenzoic acid (1) (10 g, 57.28 mmol) in H2SO4 (80 mL), then added NBS (10.19 g, 57.286 mmol) at RT and the reaction mixture was stirred at the same temperature for 16 h. After reaction completion (monitored by TLC), reaction mixture was diluted with ice H2O and precipitated solid was filtered through Buchner funnel and dried under vacuum. The crude was purified by combiflash chromatography (80 g silica gel column) using 10-15% EtOAc in hexane to afford a mixture of regioisomers of the title compound (2) as an off-white solid (11 g, 75%). LC-MS: m / z 252.9; tR= 2.48 min, LC-MS purity: 54.28%, tR= 2.33 min; LC-MS purity: 34.96%. HPLC purity: 48.96%; tR=10.19 min and 36.26%; 1R=9.76 min. This mixture was used in the next step without separation of regioisomers.

[0706] Step 2: (3-Bromo-4-chloro-5-fluorophenyl)(phenyl)methanone (3)

[0707] To stirred solution of in SOCI2 (80 mL) was added 3-bromo-4-chloro-5-fluorobenzoic acid (mixture of regioisomers) (2) (11 g, 43.401 mmol) at RT, then refluxed the reaction at 80 °C for 3 h. After reaction completion (monitored by TLC), reaction mixture was concentrated under nitrogen atmosphere to get crude compound. The crude compound was dissolved in benzene and cooled to 0 °C then added A1CL (17.36 g, 130.203 mmol) portion wise and heated the reaction at 80 °C for 6 h. After reaction completion (monitored by TLC), reaction mixture was concentrated under reduced pressure, then ice H2O was added to the reaction mixture, and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained crude was purified by combiflash chromatography (80 g silica gel column) using 10-15% EtOAc in hexane. The mixture of regioi f th if d b HPLC [ l X l t CSH, dilution : THF+MeCN+H20, mobile phase A: 0.01 M NH4OAC in H2O, mobile phase B: MeCN; gradient time (min) / %B : 0 / 35,10 / 65; flow rate: 15 mL / min] o afford the title compound (3) as an off-white solid (3.0 g, 22%). LC-MS: m / z 311.1 [M-2H]+; tR= 2.92, LC-MS purity: 99.70%. HPLC purity: 99.37%, tR=10.77 min. 'H NMR (400 MHz, DMSO-de) = 5 ppm 7.89 (s, 1H), 7.81-7.71(m, 4H), 7.61-7.57 (t, J = 7.6 Hz, 2H).

[0708] Step 3: (4-Chloro-3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(phenyl) methanone (4)

[0709] To a stirred solution of (3-bromo-4-chloro-5-fluorophenyl)(phenyl)methanone (3) (3.0 g, 9.567 mmol) in 1,4-dioxane (40 mL) was added bis(pinacolato)diboron (3.1 g, 12.438 mmol) followed by KOAc (2.81 g, 28.703 mmol) at RT and purged with argon for 5 min then added PdC12(dppf) DCM (0.78 g, 0.956 mmol) and reaction mixture was again purged with argon for 10 min, then heated the reaction at 95 °C for 16 h. After reaction completion (monitored by TLC), reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine and dried over Na2SC>4, filtered and concentrated under reduced pressure. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 10-15% EtOAc in hexane to afford the title compound (4) as off-white solid (3 g, 88%). 'H NMR (400 MHz, DMSO-de) = 5 ppm 7.82-7.66 (m, 5H), 7.61-7.56 (m, 2H), 1.12 (s, 12H).

[0710] Step 4: 5'-Benzoyl-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carbonitrile (6)

[0711] To a stirred solution of 2-bromo-3-fluoro-4-(2 -methoxyethoxy )benzonitrile(5) (0.4 g, 1.459 mmol) in toluene / H2O (2: 1, 6 mL) was added (4-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)(phenyl)methanone (0.78 g, 2.189 mmol) followed by K3PO4 (0.92 g, 4.378 mmol), N-XantPhos (0.08 g, 0.145 mmol) at RT and purged with argon for 5 min then added Pd2(dba)s (0.06 g, 0.072 mmol) and reaction mixture was again purged with argon for lOmin then heated the reaction mixture at 100 °C for 16 h. After reaction completion (monitored by TLC), reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 xlOO mL). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by combiflash chromatography (40 g silica gel column) using 30-40% EtOAc in hexane to afford the title compound (6) as a yellow sticky liquid (0.46 g, 71%). 'H NMR (400 MHz, DMSO-de) = 5 ppm 7.96 (dd, J= 2.0 Hz and 9.2 Hz, 1H), 7.88 (dd, J = 1.2 Hz and 8.8 Hz, 1H), 7.83-7.81 (m, 2H), 7.75-7.70 (m, 2H), 7.60-7.56 (m, 2H), 7.51 (t, J= 8.4 Hz, 1H), 4.38-4.34 (m, 2H), 3.72-3.70 (m, 2H), 3.31 (s, 3H).

[0712] Step 5: 2'-Chloro-3',6-difluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,l'-biphenyl]-2- carbonitrile (8)

[0713] To a stirred solution of MesSI (7) (438.8 mg, 2.150 mmol) in THF (2.5 mL) and DMSO (2.5 mL) was added NaH (86 mg, 2.150 mmol), at 0 °C and allowed the reaction to RT, and stirred for 2 h, then added 5'-benzoyl-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2 -carbonitrile (6) (460 mg , 1.075 mmol) in THF / DMSO (5 mL, 1: 1) at 0 °C then allowed the reaction mixture to RT and stirred at RT for 16 h. After reaction completion (monitored by TLC), reaction mixture was diluted with H2O / DMSO (100 mL) and extracted with EtOAc (2 x 200 mL) The combined organic layers were washed with brine and dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by combiflash chromatography (12 g silica gel column) using OAc in hexane to afford the title compound (8) as a yellow gummy solid (260 mg, 54%). LC-MS: m / z 440.0 [M-H]+; tR = 2.92, LC-MS purity: 75.92%.

[0714] Step 6: 2'-Chloro-3',6-difluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2- carbonitrile (9)

[0715] To a stirred solution of 2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,T- biphenyl] -2 -carbonitrile (8) (270 mg, 0.611 mmol) in Ether (3.0 mb) was added BF3 OEt2 (173.4 mg, 1.222 mmol) at 0 °C, then the reaction mixture was stirred at the same temperature for 10 min. After reaction completion (monitored by TLC),the reaction mixture was diluted with H2O and extracted with diethyl ether (2 x 50 mb). The combined organic layers were washed with brine solution, dried over Na2SC>4 , filtered and concentrated under reduced pressure to afford the title compound (9) as a yellow liquid (270 mg, 100%). LC-MS: m / z 440.1 [M-H]+; tR = 2.84 min. LC-MS Purity: 49.75%. The crude was used in the next step without further purification.

[0716] Step 7: tert- Butyl ((lr,4r)-4-((2-(6-chloro-6'-cyano-2',5-difluoro-3'-(2-methoxyethoxy)-[l,l'- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)carbamate (11)

[0717] To a stirred solution of 2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'- biphenyl] -2 -carbonitrile (9) (270 mg, 0.61 mmol) in MeOH / DCM (1: 1, 4 mL) were added tert-butyl ((lr,4r)-4-aminocyclohexyl) carbamate (10) (196.42 mg, 0.91 mmol) followed by AcOH (1 drop) at RT, and stirred at RT for 4 h, then NaCNBHs (114.64 mg, 1.833 mmol) was added and reaction mixture was stirred at RT for 16 h. After reaction completion (monitored by TLC), reaction mixture was diluted with H2O and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated under vacuum. The crude compound was purified by combiflash chromatography (12 g silica gel column) using 100% EtOAc in hexane to afford the title compound (11) as a light brown solid (60 mg, 15%), LC-MS : m / z 640.3 [M+H]+; tR = 2.32 min. LC-MS purity: 62.02%.

[0718] Step 8: tert- Butyl ((lr,4r)-4-((2-(6'-carbamoyl-6-chloro-2',5-difluoro-3'-(2-methoxyethoxy)-[l,l'- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexyl)carbamate (13)

[0719] To a stirred solution of tert-butyl ((lr,4r)-4-((2-(6-chloro-6'-cyano-2',5-difluoro-3'-(2-methoxyethoxy)- [l,T-biphenyl]-3-yl)-2-phenylethyl)amino) cyclohexyl) carbamate (11) (60 mg, 0.09 mmol) in EtOH / lLO (5: 1, 2.4 mL) was added Parkins catalyst (12) (12 mg, 0.04 mmol) at RT, then heated the reaction at 80 °C for 8 h. After reaction completion (monitored by TLC), reaction mixture was diluted with H2O and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layers were washed with brine solution, dried over Na2SC>4, filtered and concentrated under vacuum. The crude was washed twice with diethyl ether to afford the title compound (13) as a light-brown solid (50 mg, crude, 81%). LC-MS: m / z [M+H] = 658.3; tR= 2.27 min. LC-MS purity: 75.55%.

[0720] Step 9: 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 29) To a stirred solution of tert-butyl ((lr,4r)-4-((2-(6'-carbamoyl-6-chloro-2',5-difluoro-3'-(2- methoxyethoxy)-[l,T-biphenyl]-3-yl)-2-phenyle y ) o) cyclohexyl) carbamate (13) (50 mg, 0.07 mmol) in DCM (2 mb) was added TFA (0.5 mL) at 0 °C, then the reaction mixture was stirred at RT for 2 h. After reaction completion (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude compound was purified ...

Claims

Claims 1. A compound, which comprises or essentially consists of (Formula I)wherein: X is selected from CH; CF; N; or C-R1d; A1 is selected from the group consisting of phenyl, wherein said phenyl is optionally substituted with fluoro; and a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N, S, and O; A2 is selected from the group consisting of: phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C3alkoxy, C1-C3alkyl, C1-3-haloalkyl 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 said heteroaromatic ring is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkoxy, C1-C3alkyl, preferably Cl; R1is selected from the group consisting of hydrogen; halogen; C1-C6 haloalkoxy; O(CH2)nO(CH2)mR1a; NR1b(CH2)nO(CH2)m; C1-C6 alkoxy optionally substituted with C3-C6 cycloalkyl, COOH, (O-CH2)m-CONR1bR1c, a 5- or 6-membered heteroaromatic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, or a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and a 5- or 6-membered heteroaryloxy; R1ais selected from the group consisting of hydrogen, C1-C2 alkyl, or a 4-membered heterocyclic ring comprising NCOCH3; R1band R1care independently selected from the group consisting of hydrogen, C 1b 1-C6 alkyl or R and R1ctogether with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring;R1dand R1taken together with the carbon atom to which they are each attached form a 5- or 6- membered aromatic, heteroaromatic, cyclic or heterocyclic ring; R2is selected from the group consisting of hydrogen, C1-C3 alkyl, and halogen; R3is selected from the group consisting of hydrogen, hydroxyC1-C3 alkyl; (CH2)nOCH2CONR9R9, C1-C3 alkyl optionally substituted with a 4-membered heterocyclic ring comprising NCOCH3; R4is selected from the group consisting of hydrogen, C1-C5alkyl optionally substituted with OH or C1-C4alkyl optionally substituted with OH; a 4-, 5-, 6- or 7-membered saturated cyclic or heterocyclic ring optionally substituted with C1-C3 alkyl, NHR9, CONR9R9, NHCO(C1-C3-alkyl), CONR6R6, NH- CH2-R7COOH, CHO, CO(C1-C3-alkyl), or OH, CH2NH2, or C1-C3 alkyl and OH, or CH2OH and =O; or NH-R4forms a 5- or 6-membered saturated heterocyclic ring to the carbon to which NH-R4is attached; R5is selected from hydrogen, OH and fluoro; R6is independently selected from the group consisting of hydrogen, C1-C3 alkyl, or R6R6together form a 5- to 6-membered ring with the nitrogen to which they are attached optionally wherein said 5- to 6-membered ring further comprises oxygen, R7is a 5- or 6-membered aromatic ring comprising at least one NR8; R8is selected from the group consisting of hydrogen and CH2CONR9; R9is independently selected from the group consisting of hydrogen and methyl; each n is individually 1, 2 or 3; each m is individually 0 or 1; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. The compound according to claim 1, wherein said halogen in A2, R1and / or R2is selected from the group consisting of chloro and fluoro.

3. A compound according to any one of claims 1 or 2, wherein X is selected from CH; CF; and N.

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

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

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

7. The compound according to any one of claims 1 to 6, wherein A2 is selected from the group consisting of phenyl substituted with at least one halogen, and a 5-membered heteroaromatic ring; such as wherein A2 is phenyl substituted with at least one halogen.

8. The compound according to any one of claims 1 to 7, wherein R1is selected from the group consisting of hydrogen; halogen; C1-C6 haloalkoxy, O(CH2)nO(CH2)mR1a; NR1b(CH2)nO(CH2)m; C1-C6 alkoxy optionally substituted with C3-C6 cycloalkyl, (O-CH2)m-CONR1bR1c, a 6-membered heteroaromatic ring comprising at least one N, or a 5-membered saturated heterocyclic ring comprising one heteroatom selected from N and O; a 5-membered aromatic heterocyclic ring comprising at least one N; and a 5- or 6-membered heteroaryloxy; R1ais selected from the group consisting of hydrogen, C1-C2 alkyl, and a 4-membered heterocyclic ring comprising NCOCH3; R1band R1care independently selected from the group consisting of hydrogen, C1-C3 alkyl.

9. The compound according to any one of claims 1 to 8, wherein R1is selected from the group consisting of:

10. The compound according to any one of claims 1 to 9, wherein R2is selected from the group consisting of hydrogen and F.

11. The compound according to any one of claims 1 to 10, wherein R3is selected from the group consisting of of hydrogen, (CH2)2OCH2CON(CH3)2, C2-alkyl substituted with a 4-membered heterocyclic ring comprising NCOCH3, such as wherein R3is hydrogen.

12. The compound according to any one of claims 1 to 11, wherein R4is selected from the group consisting of hydrogen; C1-C4alkyl; C2-C4alkyl substituted with OH; a 4-, 5-, 6- or 7-membered saturated cyclic or heterocyclic ring; 6-membered saturated cyclic or heterocyclic ring substituted with C1-C3 alkyl, NHR9, CONR9R9, NHCO(C1-C3-alkyl), CONR6R6, NH-CH2-R7, COOH, or OH, or C1-C3 alkyl and OH, or CH2OH and =O; or NH-R4forms a 5-membered saturated heterocyclic ring to the carbon to which NH-R4is attached.

13. The compound according to any one of claims 1 to 12, wherein R4is selected from the group consisting of hydrogen and a 6-membered saturated ring substituted with CHO, COOH, CONHR6, or NH2.

14. The compound according to any one of claims 1 to 13, wherein R5is hydrogen.

15. The compound according to any one of claims 1 to 14, wherein A2 is bound in Formula I such that the ring bearing X and the carbon to which A1 is attached are positioned 1,3 to each other.

16. The compound according to claim 1, wherein said 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)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl] -2- carboxamide; 5'-(2-amino-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-1-phenylethyl)-[1,1'-biphenyl]-2- carboxamide; 5'-(2-(((S)-azepan-4-yl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide; 2'-chloro-5'-(2-(cyclobutylamino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]- 2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]- 2-carboxamide;5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-5'-(2-(((1r,4r)-4-(((1-(2-(dimethylamino)-2-oxoethyl)-1H-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(pyrrolidin-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-acetylazetidin-3-yl)oxy)ethoxy)-5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1- phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide;5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(2-(dimethylamino)-2- oxoethoxy)ethoxy)-6-fluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-Aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-3',6-difluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5- (2-methoxyethoxy)-[1,1'-biphenyl]-2-carbonitrile; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-5-(2-(dimethylamino)-2- oxoethoxy)-3',6-difluoro-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-3',6-difluoro-5-(2- (methylamino)-2-oxoethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',3'-dichloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2',4'-dichloro-6-fluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2',4'-Dichloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5- (2-methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2'-chloro-6-fluoro-4'-methoxy-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-5-(difluoromethoxy)-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1- phenylethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-1-phenylethyl)-5-(1H- 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-acetylazetidin-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-(morpholine-4-carbonyl)cyclohexyl)amino)-1- phenylethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-(((1r,4r)-4-(piperidine-1- carbonyl)cyclohexyl)amino)ethyl)-[1,1'-biphenyl]-2-carboxamide; 5'-(2-(((1r,4r)-4-acetamidocyclohexyl)amino)-1-phenylethyl)-2'-chloro-4',6-difluoro-5-(2- methoxyethoxy)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5'-(1-hydroxy-2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide ; 2'-chloro-4',6-difluoro-5'-(2-(isopropylamino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide ; 2'-chloro-6-fluoro-5'-(2-((2-hydroxy-2-methylpropyl)amino)-1-phenylethyl)-5-(2-methoxyethoxy)-[1,1'- biphenyl]-2-carboxamide ; 3'-(2-Amino-1-phenylethyl)-6'-chloro-2',6-difluoro-5-(2-methoxyethoxy)-[1,1'-biphenyl]-2- carboxamide ; 4-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-2-chlorophenyl)-5-fluoro-6-(2- methoxyethoxy)nicotinamide; 5'-(2-(((1r,4r)-4-aminocyclohexyl)amino)-1-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-2'- (trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide ; (1r,4r)-4-((2-(6'-carbamoyl-4,6-dichloro-2'-fluoro-3'-(((S)-tetrahydrofuran-2-yl)methoxy)-[1,1'- biphenyl]-3-yl)-2-phenylethyl)amino)cyclohexane-1-carboxylic acid and stereoisomers thereof; (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 stereoisomers thereof; 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 trifluoracetate; (1r,4r) 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; (1r,4r) (1r,4r) (1r,4r) 17. A conjugate, which comprises or essentially consists of Formula II: A-B-C (formula II) wherein A is a compound of Formula I according to any one of claims 1 to 16; with the proviso that one of R1, R3or R4in formula I is or contains a bond to B, or wherein A-B is a condensation product formed from a compound of formula I according to any one of claims 1 to 16 and B; B is a linker that covalently links A to C, and C is a ligase binder.

18. The conjugate according to claim 17, wherein said linker B has the formula: -L1-X1-L2-X2-L3- (B), and wherein the conjugate has a formula: A-L1-X1-L2-X2-L3-C, wherein L1 is selected from the group consisting of a bond, -O-, -NR'-, -C(O)-, C1-C9alkylene, C1- C9heteroalkylene, *C(O)-C1-C6alkylene, *C(O)-C1-C6heteroalkylene, *C1-C6alkylene-C(O), *C1-C6 heteroalkylene-C(O), cyclohexyl and *L1a-C4-C7cycloalkylene, or is cyclohexyl; wherein * denotes the bond of L1 to X1; wherein L1a is selected from the group consisting of C(O), *N H-C(O) and *C1-C6alkylene- NH-C(O) wherein* denotes the bond of L1a to X1;X1 and X2 are each independently selected from the group consisting of a bond, C4- C7cycloalkylene, 4 to 7 membered heterocyclylene comprising 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, and 5 or 6 membered heteroarylene comprising 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; L2 is selected from the group consisting of a bond, -O-, -NR'-, -C(O)-, C1-C6alkylene, -NR'-C1- C9alkylene-NR'-, *C1-C9alkylene-N R'-,*NR'-C1-C9alkylene, *C(O)NR'-C1-C5alkylene, polyethylene glycol , -NR'-polyethylene glycol-NR'-, polyethylene glycol, *NR'-polyethylene glycol and *polyethylene glycol-NR', wherein * denotes the bond of L 2 to X2; or X1-L2-X2 form a 7 to 13 membered spiroheterocyclylene comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; L3 is selected from the group consisting of a bond, C1-C5alkylene, C2-C5alkenylene, C1- C6alkynylene, C1C6heteroalkylene, -C(O)-, -S(O)r, -O-, *C(O)-C1-C6alkylene, *C(O)-C1-C5alkylene- O, *C(O)-C1-C6heteroalkylene, ,*C1-C5alkylene-NH and *NH-C1-C5alkylene wherein* denotes the bond of L3 to X2; and wherein each R' is independently hydrogen or C1-C6alkyl, preferably wherein each R' is hydrogen.

19. The conjugate according to claim 17, wherein said linker B has the formula: -L1-X1-L2-X2-L3-X3-L4- (B), and wherein the conjugate has the formula: A-L1-X1-L2-X2-L3-X3-L4-C, wherein X1, X2 and X3 are each independently selected from the group consisting of a bond, -O-, -CH2-, and -NH-; and wherein L1, L2, L3 and L4 are each individually selected from the group consisting of: a bond; a heterospirocycle or spirocycle having 7-11 ring atoms; a cycle or heterocycle; a bicycle or a biheterocycle, or two cycles or heterocycles being bound to each other via a carbon, a nitrogen or an oxygen; C1-C3alkyl, 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 a bond between A and C in formula II, wherein R1ais selected from the group consisting of hydrogen, C1-C2alkyl; or an aromatic or heteroaromatic ring having 5 to 6 ring atoms; optionally wherein said heteroaromatic ring comprises one or two nitrogen atoms; and wherein said 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: a bond, -CH2-, -C(=O)-, -O-, -NH-, -NH-C1-C3alkyl, -NH-hydroxyC1-C3alkyl,wherein each is an attachment point to A, X1, X2, X3 or C, and wherein L1, L2, L3 and / or L4 is optionally substituted with F, Me, and / or OH.

21. The conjugate according to any one of claims 17 and 19 to 20, wherein said linker is selected from the group consisting ofwherein A is a compound of formula I and wherein C is a ligase binder.

22. The conjugate according to any one of claims 17 and 19 to 21, wherein said linker is selected from the group consisting of:wherein A is a compound of formula I and wherein C is a ligase binder.

23. The conjugate according to any one of claims 17 and 19 to 20, wherein said linker is selected from the group consisting of:, wherein each is an attachment point to A or C.

24. The conjugate according to any one of claims 17 to 23, having from about 2 to about 50 bonds, such as from 3 to about 45 bonds, such as from 3 to about 40 bonds, such as from 3 to about 35 bonds, such as from 3 to about 30 bonds, such as from 4 to about 23 bonds, such as 4 to 23 bonds between A and C; 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 said ligase binder comprises two or three 5- or 6-membered cyclic or heterocyclic rings, wherein at least one of said cyclic heterocyclic rings is aromatic.

26. The conjugate according to any one of claims 17 to 25, wherein said ligase binder comprises a 6-membered heterocyclic group comprising one or two nitrogen atoms in the ring and / or and two oxo substituents.

27. The conjugate according to any one of claims 17 to 26, wherein said ligase binder is selected from the group consisting of:wherein is an attachment point to a linker or is a bond to a linker, and wherein R is H, F, Cl, methyl or methoxy.

28. The conjugate according to any one of claims 17 to 27, wherein said ligase binder is selected from the group consisting of29. The conjugate according to any one of claims 17 to 28, wherein said ligase binder is selected from the group consisting of:,wherein is an attachment point to a linker.

30. The conjugate according to any one of claims 17 to 29, wherein said ligase binder is selected from the group consisting of; wherein is an attachment point to a linker (B).

31. The conjugate according to claim 17, wherein said conjugate is selected from the group consisting of: 2'-chloro-6-fluoro-5-{[(2S)-oxolan-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)-oxolan-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)-oxolan-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}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}octanamido)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}propanamido)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]piperidine-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)propanamido]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-diazinan-1-yl)-4- methoxyphenyl]formamido}ethoxy)ethoxy]ethoxy}propanamido)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- diazinan-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)piperidine-1- carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{4-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazine-1-carbonyl}piperidine-1- carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[2-(2-{[2-(2,6- 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'-bipiperidine]-1-carbonyl}cyclohexyl]amino}ethyl)- [1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[4-({1-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}oxy)piperidine-1- carbonyl]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-(4-{[1-(2-{[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]oxy}piperidine- 1-carbonyl)cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-({2-[1-(2-{[2-(2,6- 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]piperazine-1-carbonyl}cyclohexyl]amino}ethyl)-[1,1'- biphenyl]-2-carboxamide; 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(1-phenyl-2-{[(1r,4r)-4-[({1-[2-(2,6-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]azetidin-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]azetidin-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]piperazine-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]azetidin-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)azetidin-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)propanoyl]azetidin-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]piperazine-1-carbonyl}piperidin-1-yl)acetyl]azetidin-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]piperidine-4-carbonyl}azetidin-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)azetidin-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 (1r,4r) (1r,4r)- carboxamide; carboxamide; carboxamide; carboxamide; carboxamide;carboxamide; (1r,4r) e;carboxamide;(1r,4r)-2'-Chloro-6-fluoro-5-{[(2S)-oxolan-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}piperidin-1- yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide; - (1r,4r) ; and .

32. The conjugate according to claim 17, wherein said 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)- oxolan-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)-oxolan-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}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]piperazine-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)-oxolan-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]azetidin-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]piperazine-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)azetidin-3-yl]oxy}ethoxy)-6-fluoro-5'-(1-phenyl-2-{[(1r,4r)-4- aminocyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide and 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 said conjugate is selected from the group consisting of 2'-chloro-6-fluoro-5-{[(2S)-oxolan-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}piperidin-1- yl)acetamido]cyclohexyl]amino}ethyl)-[1,1'-biphenyl]-2-carboxamide;2'-chloro-6-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-5'-(1-phenyl-2-{[(1r,4r)-4-{2-[4-({4-[2-(2,6- 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 said conjugate is selected from the group consisting of: ; ; ; and .

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

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

37. A compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35; for use in the treatment of a disease or a disorder wherein the Hippo pathway is hyper-activated; optionally wherein said Hippopathway is hyper-activated due to any of overexpression of YAP, mutations or deletion of LATS2 or neurofibromatosis type 2 (NF2), or hypermethylation of the LATS2 promoter.

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

39. The compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35; for use according to claim 38, wherein said 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. The compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35; for use according to any one of claims 36 or 39, wherein the administration is in combination 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-alpha inhibitors; ABL1 inhibitors; and XPO1 inhibitors.

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

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

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

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

45. The method according to claim 44, wherein said 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.

46. The method according to any one of claims 44 or 45, wherein the administration is in combination 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-alpha inhibitors; ABL1 inhibitors; and XPO1 inhibitors.

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

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

49. The method according to any one of claims 47 to 48, wherein said fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.

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

51. The use according to claim 50, wherein said 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 a compound according to any one of claims 1 to 16, or a conjugate according to any one of claims 17 to 34, or a pharmaceutical composition according to claim 35; for the manufacture of a medicament for use in the treatment of fibrosis.

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

54. Method of preparing of a conjugate according to formula II, the method comprising: - reacting a ligase binder according to any one of claims 25 to 30 with a linker according to any one of claims 18 to 24, thereby forming an intermediate; - reacting said intermediate with a compound of formula I according to any one of claims 1 to 16, thereby forming a conjugate of formula II according to any one of claims 17 to 34.

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