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WO2024240840A1 - Amides aromatiques et conjugués de ceux-ci utilisés en tant que liants à tead - Google Patents

Amides aromatiques et conjugués de ceux-ci utilisés en tant que liants à tead Download PDF

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Publication number
WO2024240840A1
WO2024240840A1 PCT/EP2024/064137 EP2024064137W WO2024240840A1 WO 2024240840 A1 WO2024240840 A1 WO 2024240840A1 EP 2024064137 W EP2024064137 W EP 2024064137W WO 2024240840 A1 WO2024240840 A1 WO 2024240840A1
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amino
biphenyl
chloro
fluoro
carboxamide
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Peter Brandt
Rajiv T. SAWANT
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Beactica Therapeutics AB
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Beactica Therapeutics AB
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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • 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.
  • 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].
  • 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.
  • YAP and TAZ remain unphosphorylated. This allows them to move into the nucleus where they can co-activate TEAD-mediated transcription [7],
  • 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].
  • 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 [10] and myeloid-derived suppressor cells (MDSCs) to the tumor [11]
  • MDSCs myeloid-derived suppressor cells
  • 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 [14]. 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) [15].
  • 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.
  • 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.
  • YAP/TAZ adopt a loop-like structure that interacts with TEAD.
  • 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.
  • 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.
  • a fewer number of inhibitors that bind to the external interface #2 or #3 have also been reported.
  • 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.
  • a compound which comprises, essentially consists of or is (Formula I) wherein: X is selected from CH; CF; and N, or X is C-R 1d ; 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; C 1 -C 3 alkoxy; 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
  • R 1d and R 1 taken 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.
  • 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; C 1 -C 3 alkyl; C 1-3 -haloalkyl, such as CF 3 ; 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, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, preferably Cl
  • 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.
  • 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 R 1 , R 3 or R 4 in formula I is or contains a point of attachment to the linker or the second compound.
  • said halogen is selected from the group consisting of chloro and fluoro.
  • X is CF, CH or N. In some embodiments, X is CH or N.
  • X is CH.
  • A1 is phenyl or a 6-membered heteroaromatic.
  • A1 is phenyl or pyridine.
  • A1 is phenyl.
  • A2 is phenyl substituted with at least one halogen.
  • A2 is phenyl substituted with one or two chlorine(s) and/or at one or two flourine(s).
  • A2 is selected from the group consisting of phenyl substituted with at least one halogen and a 5-membered heteroaromatic ring.
  • A2 binds the remaining part of the molecule orto, meta, or para.
  • 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.
  • A2 binds the remaining general part of the molecule orto.
  • A2 binds the remaining general part of the molecule meta.
  • A2 binds the remaining general part of the molecule para.
  • R 1 is selected from the group consisting of hydrogen; halogen; C 1 -C 6 haloalkoxy, O(CH 2 ) n O(CH 2 ) m R 1a ; NR 1b (CH 2 ) n O(CH 2 ) m; C 1 -C 6 alkoxy optionally substituted with C 3 -C 6 cycloalkyl, (O-CH 2 ) m -CONR 1b R 1c , 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; R 1a is selected from the group consisting of hydrogen, C 1 -C 2 alkyl, and a 4-membered heteroaliphatic ring comprising NCOCH 3; R 1b and R 1c are independently selected from the group consisting of hydrogen,
  • R 1 is selected from the group consisting of hydrogen; halogen; C 1 -C 6 haloalkoxy, O(CH 2 ) n O(CH 2 ) m R 1a ; C 1 -C 6 alkoxy optionally substituted with C 3 -C 6 cycloalkyl, (O-CH 2 ) m - CONR 1b R 1c , 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; R 1a is selected from the group consisting of hydrogen, C 1 -C 2 alkyl, and a 4-membered heteroaliphatic ring comprising NCOCH 3; R 1b and R 1c are independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl. In some embodiments, R 1b and R
  • R 1 is 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.
  • R 2 is selected from the group consisting of hydrogen and F.
  • R 3 is selected from the group consisting of hydrogen, (CH 2 ) 2 OCH 2 CON(CH 3 ) 2 , C 2 alkyl substituted with a 4-membered heteroaliphatic ring comprising NCOCH 3 . In some embodiments, R 3 is hydrogen.
  • NH-R 4 forms a 6-membered saturated heterocyclic ring to the carbon to which NH-R 4 is attached.
  • NH-R 4 forms a 6-membered saturated heterocyclic ring to the carbon to which NH-R 4 is attached.
  • R 4 is selected from the group consisting of hydrogen and a 6-membered saturated ring substituted with CHO, COOH, CONHR 6 , or NH2.
  • R 4 is selected from the group consisting of hydrogen and a 6- membered saturated ring substituted with NH2.
  • R 5 is hydrogen.
  • 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.
  • 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
  • a conjugate that comprises a compound of formula I and a ligase binder may recruit TEAD to E3 Ubiquitin ligase for degradation.
  • 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 R 1 , R 3 or R 4 in formula I is or contains a bond to B.
  • the proviso includes that one of R 1 , R 3 or R 4 in formula I is or contains a point of attachment to B.
  • A-B is a condensation product formed from a compound of formula I according to the first aspect and the linker B.
  • a condensation product requires the removal of water in the reaction forming said product.
  • 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).
  • -COOH carboxylic acid
  • -NHR or -NH2 an amine
  • amide bond -CONR- or -CONH-
  • water H2O
  • 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.
  • the linker is group that covalently links the compound of Formula I (A) to the ligase binder (C).
  • the linker may have a number of rotatable bonds between 1 and 13, preferably below 10.
  • the linker may have a number of non- hydrogen atoms between 5 and 30, preferably below 26.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • said heteroaromatic ring comprises one or two nitrogen atoms.
  • said linker is optionally substituted with F, Me, OH.
  • the skilled person understands which positions are suitable for such substitutions.
  • each is an attachment point to A, X1, X2, or C.
  • 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.
  • 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.
  • said linker is selected from the group consisting of
  • A is a compound of formula I and wherein C is a ligase binder.
  • said linker is selected from the group consisting of: wherein A is a compound of formula I and wherein C is a ligase binder.
  • R 4 in formula I is the part of A that is or contains a bond to B.
  • this group of linkers is particularly suitable for attachment at a position in R 4 in formula I.
  • said linker is selected from the group consisting of:
  • A is a compound of formula I and wherein C is a ligase binder.
  • R 4 in formula I is the part of A that is or contains a bond to B.
  • this group of linkers is particularly suitable for attachment at a position in R 4 in formula I.
  • said linker is selected from the group consisting of:
  • A is a compound of formula I and wherein C is a ligase binder.
  • R 1 or R 3 in formula I is the part of A that is or contains a bond to B.
  • this group of linkers is particularly suitable for attachment at a position in R 1 or R 3 in formula I.
  • said linker is selected from the group consisting of:
  • each > is an attachment point to A or C.
  • 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.
  • 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.
  • R 4 formula I is the part of A that is or contains a bond to B.
  • this group of linkers is particularly suitable for attachment at a position in R 4 in formula I.
  • R 4 in formula I is cyclohexyl-4-amine or cyclohexyl -4-formyl .
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of: In some embodiments, said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • said linker is selected from the group consisting of:
  • 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.
  • 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.
  • 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.
  • the ligase binder includes two rings, one of the rings may be phenyl, or phenyl substituted with alkoxy such as methoxy.
  • the second ring is glutarimide or dihydrouracil.
  • the ligase binder 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.
  • 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.
  • the ligase binder comprises a glutarimide or a dihydrouracil group, or a similar group.
  • said ligase binder is selected from the group consisting of:
  • said ligase binder is selected from the group consisting of:
  • R is H, F, Cl, methyl or methoxy.
  • R is H.
  • R is F.
  • R is Cl.
  • R is methoxy.
  • R is methyl.
  • 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.
  • 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.
  • 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.
  • the conjugate according to the present disclosure can prepared as laid out in the examples.
  • 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.
  • the intermediate may be represented by B-C.
  • 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;
  • said conjugate is selected from the group consisting of:
  • Said intermediate may be in the form of a salt, such as a trifluoroacetate salt.
  • 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 ;
  • said conjugate is selected from the list consisting of:
  • the conjugate is selected from the group consisting of
  • said conjugate is selected from the group consisting of:
  • 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.
  • 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.
  • 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.
  • 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 ⁇ M, such as below 400 ⁇ M , such as below 300 ⁇ M , such as below 200 ⁇ M , such as below 100 ⁇ M , such as below 50 ⁇ M, such as below 40 ⁇ M, such as below 30 ⁇ M, such as below 20 ⁇ M, such as below 15 ⁇ M, such as below 10 ⁇ M, such as below 7.5 ⁇ M, or preferably below 5 ⁇ M, such as below 4 ⁇ M, such as below 3 ⁇ M.
  • affinities of a KD value below 500 ⁇ M such as below 400 ⁇ M , such as below 300 ⁇ M , such as below 200 ⁇ M , such as below 100 ⁇ M , such as below 50 ⁇ M, such as below 40 ⁇ M, such as below 30 ⁇ M, such as below 20 ⁇ M, such as below 15 ⁇ M, such as below 10 ⁇ M, such as below 7.5 ⁇ M, or preferably
  • compositions 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.
  • 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.
  • 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.
  • NF2 deficient tumors includes schwannoma and meningioma
  • 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.
  • 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.
  • 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.
  • AKT inhibitors such as afuresertib,
  • 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.
  • AKT inhibitors such as afuresertib, capivasertib, ipatasertib, miransertib, perifosine, and uprosertib
  • CDK4/6 inhibitors such as abemaciclib, palbociclib,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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; m
  • AKT inhibitors such as afuresertib, capivasertib, ipatasertib, miransertib, perifosine, and uprosertib
  • CDK4/6 inhibitors such as abemac
  • 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.
  • AKT inhibitors such as afuresertib, capivasertib, ipatasertib, miransertib, perifosine, and uprosertib
  • CDK4/6 inhibitors such as abemaciclib, palbociclib,
  • 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.
  • 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.
  • said fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.
  • 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.
  • 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.
  • 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.
  • 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.
  • the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and scleroderma.
  • conjugates according to the second aspect of the present invention may be prepared in accordance with the examples presented below.
  • a method for preparing of a conjugate according to formula II comprises:
  • the method further comprises:
  • 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.
  • 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.
  • Suitable salts according to the invention include those formed with organic or inorganic acids or bases.
  • 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.
  • 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.
  • 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.
  • organic bases for example dicyclohexylamine N methyl D glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or tri lower alkylamine, for example ethyl, ter
  • Corresponding internal salts of the compounds of the present invention may furthermore be formed.
  • the compounds of the present invention may also be isotopically labelled.
  • 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 as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively.
  • 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 as 2 H, 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.
  • 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.
  • halogen means fluorine, chlorine, bromine or iodine.
  • halo means fluoro, chloro, bromo or iodo.
  • Ci-C2alkyl means saturated hydrocarbon groups with 1 or 2 carbon atoms.
  • Examples of ”Ci-C2alkyl” groups are methyl and ethyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • halomethyl groups include, but are not limited to, difluoromethyl, trifluoromethyl, dichloromethyl and trichloromethyl.
  • CHO aldehyde.
  • 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.
  • 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.
  • Examples of monocyclic heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl.
  • 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.
  • C 3 -C 6 cycloalkyl means a cyclic saturated hydrocarbon group, with 3 to 6 carbon atoms.
  • Examples of C 3 -C 6 cycloalkyl 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.
  • heterocyclyl groups and heterocyclic rings examples include oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetedinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxanyl.
  • TEAD means TEA domain transcription factor and includes all four TEAD orthologs designated TEAD1, TEAD2, TEAD3, and TEAD4.
  • the term “excipient” encompasses adjuvants and diluents.
  • 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 pharmaceutical composition may be adapted to be suitable for the desired administered dose.
  • 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.
  • treat 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.
  • Figure 1 shows a western blot probed for panTEAD for representative examples after 4 h incubation with example compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • Step 4 2-(3-Bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-2-phenylethan-1-amine (7)
  • 2-(3-bromo-4-chlorophenyl)-2-phenylacetaldehyde (5) 1.0 g, 3.23 mmol
  • MeOH/DCM MeOH/DCM
  • 4-methoxyphenyl)methanamine (6) 1.3 g, 9.69 mmol
  • AcOH (0.01 mL)
  • 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)
  • 2-(3-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-2-phenylethan-1-amine (7) 800 mg, 1.85 mmol
  • 1,4-dioxane 8 mL
  • KOAc 546 mg, 5.57 mmol
  • bis(pinacolato)diboron (8) (613 mg, 2.41 mmol
  • Step 6 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2- carbonitrile (11)
  • 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/H 2 O (5:1, 10 mL) were added K 3 PO 4 (799 mg, 3.76 mmol), N-XantPhos (69 mg, 0.12 mmol) and Pd 2 (dba) 3 (57 mg, 0.06mmol) at RT and the reaction mixture was degassed with argon for 5 min
  • Step 7 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'-biphenyl]-2- carboxamide (13)
  • 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'- biphenyl]-2-carbonitrile (11) 250 mg, 0.53 mmol
  • EtOH/H2O 5:1, 8 mL
  • Parkins catalyst (12) 68 mg, 0.15 mmol
  • Step 8 5'-(2-Amino-1-phenylethyl)-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carboxamide trifluoroacetate (Example 1)
  • 2'-chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-1-phenylethyl)-[1,1'- biphenyl]-2-carboxamide (13) 50 mg, 0.08 mmol
  • MeCN/H 2 O 1 mL
  • ceric ammonium nitrate 179 mg, 0.32 mmol
  • Step 1 (4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (3)
  • (3-bromo-4-chlorophenyl)(phenyl)methanone (1) 1.0 g, 3.38 mmol
  • 1,4-dioxane 20.0 mL
  • bis(pinacolato)diboron (2) 1.288 g, 5.07 mmol
  • KOAc 0.95 g, 10.1 mmol
  • Step 2 5'-Benzoyl-2'-chloro-6-fluoro-[1,1'-biphenyl]-2-carbonitrile (5)
  • 2-bromo-3-fluorobenzonitrile (4) (0.400 g, 1.999 mmol) and (4-chloro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (3) (0.685 g, 1.999 mmol) in DME/H2O (4:1, 15 mL), K2CO3 (0.829 g, 5.999 mmol) was added.
  • 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%).
  • Step 3 2'-Chloro-6-fluoro-5'-(2-phenyloxiran-2-yl)-[1,1'-biphenyl]-2-carbonitrile (7)
  • Me3SI (6) 0.790 g, 3.871 mmol
  • DMSO DMSO
  • NaH 0.15g, 3.871 mmol, 60% dispersion in mineral oil
  • 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.
  • Step 4 2'-Chloro-6-fluoro-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2-carbonitrile (8)
  • 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)
  • 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)
  • Step 7 5'-(2-(((7?)-Azepan-4-yl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl]-2- carboxamide trifluoroacetate (Example 2)
  • 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] + ; t R 1.77 min.
  • 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)
  • 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)
  • Step 3 5'-(2-(((5)-Azepan-4-yl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-[l,l'-biphenyl] -2- carboxamide
  • 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.
  • Step 2 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,l'-biphenyl]-2- carbonitrile (5):
  • Step 3 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2- carbonitrile (6)
  • 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%.
  • Step 4 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-l-phenylethyl)-5-(2-methoxyethoxy)- [1 ,1 '-biphenyl] -2-carbonitrile (8)
  • Step 5 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)amino)-l-phenylethyl)-5-(2-methoxyethoxy)- [1,1 '-biphenyl] -2-carboxamide (10)
  • Step 6 5'-(2-Amino-l-phenylethyl)-2'-chloro-6-fluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2- carboxamide trifluoroacetate (Example 4)
  • Step 2 2'-Chloro-6-fluoro-5'-(2-((4-methoxybenzyl)(methyl)amino)-l-phenylethyl)-5-(2- methoxyethoxy)- [1 ,1 '-biphenyl] -2-carboxamide (5)
  • Step 3 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(methylamino)-l-phenylethyl)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 5)
  • 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)
  • 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 was added (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.
  • 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)
  • 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
  • DCM 1, 0.078 mmol
  • TFA 26 mg, 0.23 mmol
  • Step 1 2'-Chloro-5'-(2-(cyclobutylamino)-l-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carbonitrile (3)
  • Step 2 2'-Chloro-5'-(2-(cyclobutylamino)-l-phenylethyl)-6-fluoro-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 7)
  • 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)
  • 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)
  • Step 1 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2- carbonitrile
  • Step 2 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-l-phenylethyl)-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carbonitrile (3)
  • Step 3 2'-Chloro-6-fluoro-5'-(2-(isopropylamino)-l-phenylethyl)-5-(2-methoxyethoxy)-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 9)
  • 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%).
  • Step 1 tert- Butyl ((lr,4r)-4-((2-(3-bromo-4-chlorophenyl)-2-phenylethyl)amino)cyclo hexyl)carbamate (3)
  • Step 2 Zert- Butyl (2-(3-bromo-4-chlorophenyl)-2-phenylethyl)((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)carbamate (4)
  • 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.
  • 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)
  • 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)
  • 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)
  • EtOH/EEO 5: 1, 12 mb
  • 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)
  • Example 10 The chiral separation of Example 10 was performed by using chiral HPLC (see Example 11 and Example 12).
  • Example 10 was separated to afford two pairs of stereoisomers, Example 11 and Example 12.
  • Step 1 tert- Butyl ((lr,4r)-4-acetamidocyclohexyl)carbamate (3)
  • 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)
  • 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)
  • Step 4 Ethyl 2-(4-((((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)amino)methyl)-lH-pyrazol- l-yl)acetate (8)
  • Step 5 Ethyl 2-[4-( ⁇ [(tert-butoxy)carbonyl] [(lr,4r)-4- ⁇ [(benzyloxy)carbonyl]amino ⁇ cyclo- hexyl]amino ⁇ methyl)-lH-pyrazol-l-yl] acetate (9)
  • Step 6 Methyl 2-(4-((((lr,4r)-4-aminocyclohexyl)(ter/-butoxycarbonyl)amino)methyl)-LH-pyrazol- l-yl)acetate (10)
  • 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-
  • 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)
  • 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)
  • reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na 2 SO4, 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%).
  • 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)
  • 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)
  • 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)
  • Step 1 Benzyl ((lr,4r)-4-(oxetan-3-ylamino)cyclohexyl)carbamate (3)
  • Step 2 tert- Butyl ((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)(oxetan-3-yl)carbamate (4)
  • Step 3 tert- Butyl ((lr,4r)-4-aminocyclohexyl)(oxetan-3-yl)carbamate (5)
  • 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)
  • 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)
  • 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)
  • Step 2 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(2-(((lr,4r)-4-(methylamino)cyclohexyl)amino)-
  • 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)
  • a 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.
  • 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)
  • 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)
  • Step 1 2'-Chloro-6-fluoro-5'-(hydroxy(phenyl)methyl)-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2- carbonitrile (2)
  • Step 2 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(lH-pyrrol-2-yl)methyl) - [1,1 '-biphenyl] - 2-carbonitrile (4)
  • Step 4 2'-Chloro-6-fluoro-5-(2-methoxyethoxy)-5'-(phenyl(pyrrolidin-2-yl)methyl)-[l,l'-biphenyl]- 2-carboxamide trifluoroacetate (Example 17)
  • 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.
  • 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.
  • 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)
  • MeOH/DCM MeOH/DCM
  • 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)
  • 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)
  • 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)
  • 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)
  • 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.
  • 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
  • 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)
  • Step 3 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-5,6-difluoro-[l,l'- biphenyl]-2-carboxamide trifluoroacetate (Example 19)
  • 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)
  • 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] + ; t R 3.34, LC-MS purity: 92.39%.
  • 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)
  • 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.
  • Step 3 5'-(2-(((lr,4r)-4-Aminocyclohexyl)amino)-l-phenylethyl)-2'-chloro-6-fluoro-5-(2- hydroxyethoxy)- [1 ,1 '-biphenyl] -2-carboxamide trifluoroacetate
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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
  • 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%).
  • Step 2 tert- Butyl ((1 rArl ⁇ -firerr-butoxycarbonyllaminolcyclohexyll ⁇ -fb'-carbamoyl-b-chloro ⁇ '- fluoroA'-ffi ⁇ l-tetrahydrofuran ⁇ -yllmethoxyl-ILl '-biphenyll ⁇ -yll ⁇ -phenylethyllcarbamate (5)
  • 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)
  • Step 1 (5)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzonitrile (3)
  • Step 2 5’-Benzoyl-2’-chloro-6-fluoro-5-(((iS)-tetrahydrofuran-2-yl)methoxy)-[l,l’-biphenyl]-2- carbonitrile (5)
  • (.S)-2-bromo-3-fluoro-4-((tctrahydrofuran-2-yl)mcthoxy (benzonitrile (3) (3.5 g, 11.66 mmol)
  • (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.
  • Step 3 2'-Chloro-6-fluoro-5'-(2-phenyloxiran-2-yl)-5-(((iS)-tetrahydrofuran-2-yl)methoxy)-[l,l'- biphenyl]-2-carbonitrile (6)
  • 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.
  • Step 4 2'-Chloro-6-fluoro-5'-(2-oxo-l-phenylethyl)-5-(((iS)-tetrahydrofuran-2-yl)methoxy)-[l,l'- biphenyl]-2-carbonitrile (7)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • Step 10 (4-Chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methanone (4)
  • 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)
  • 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 purity 97.25%.
  • 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)
  • 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)
  • 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)
  • pyrimidin-2-ylmethanol (2) (16.0 mg, 0.105 mmol) in DMF (1.0 mL)
  • NaH 11 mg, 0.30 mmol
  • 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)
  • 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)
  • Step 1 Benzyl 3-(2-ethoxy-2-oxoethoxy)azetidine-l-carboxylate (3)
  • 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)
  • 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)
  • 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%).
  • 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)
  • 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)
  • 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)
  • 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
  • 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 Na 2 SO4, 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%).
  • 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)
  • 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)
  • 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.
  • Step 3 (4-Chloro-3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(phenyl) methanone (4)
  • 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).
  • Step 4 5'-Benzoyl-2'-chloro-3',6-difluoro-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carbonitrile (6)
  • 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%).
  • Step 5 2'-Chloro-3',6-difluoro-5-(2-methoxyethoxy)-5'-(2-phenyloxiran-2-yl)-[l,l'-biphenyl]-2- carbonitrile (8)
  • 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%.
  • Step 6 2'-Chloro-3',6-difluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2- carbonitrile (9)
  • 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)
  • 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)
  • 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%).
  • 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)
  • Step 1 2'-Chloro-3',6-difluoro-5-(2-methoxyethoxy)-5'-(2-oxo-l-phenylethyl)-[l,l'-biphenyl]-2- carbonitrile (2)
  • Step 2 2'-Chloro-3',6-difluoro-5'-(2-(((lr,4r)-4-hydroxy-4-methylcyclohexyl) amino)-l- phenylethyl)-5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carbonitrile (4)
  • Step 3 2'-Chloro-3',6-difluoro-5'-(2-(((lr,4r)-4-hydroxy-4-methylcyclohexyl)amino)-l-phenylethyl)- 5-(2-methoxyethoxy)-[l,l'-biphenyl]-2-carboxamide trifluoroacetate (Example 30)
  • Step 5 tert- Butyl ((lr,4r)-4-((2-(3-bromo-4-chloro-5-fluorophenyl)-2- phenylethyl)amino)cyclohexyl)carbamate (8)
  • Step 6 tert- Butyl (2-(3-bromo-4-chloro-5-fluorophenyl)-2-phenylethyl) ((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)carbamate (9)
  • reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under vacuum. The obtained crude was purified by combiflash chromatography (12 g silica gel column) using 90% EtOAc in hexane to afford the title compound (9) as an off-white solid (0.8 g, 67%).
  • LC-MS purity 99.14%.
  • Step 7 tert- Butyl ((lr,4r)-4-((ter/-butoxycarbonyl)amino) cyclohexyl) (2-(4-chloro-3-fluoro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl)-2-phenylethyl) carbamate (10)

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Abstract

L'invention concerne de nouveaux composés de liaison de formule (I), des conjugués comprenant un composé de formule (I), des compositions pharmaceutiques contenant de tels composés et des procédés d'utilisation de tels composés dans le traitement d'une maladie, ainsi que des procédés de préparation de tels conjugués ; (I) R1, R2, R3, R4 et R5 étant tels que définis dans la description.
PCT/EP2024/064137 2023-05-24 2024-05-22 Amides aromatiques et conjugués de ceux-ci utilisés en tant que liants à tead Pending WO2024240840A1 (fr)

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