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NL2037411B1 - Protac compounds - Google Patents

Protac compounds

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Publication number
NL2037411B1
NL2037411B1 NL2037411A NL2037411A NL2037411B1 NL 2037411 B1 NL2037411 B1 NL 2037411B1 NL 2037411 A NL2037411 A NL 2037411A NL 2037411 A NL2037411 A NL 2037411A NL 2037411 B1 NL2037411 B1 NL 2037411B1
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Netherlands
Prior art keywords
chloro
ethoxy
pharmaceutically acceptable
numbered paragraph
acceptable salt
Prior art date
Application number
NL2037411A
Other languages
Dutch (nl)
Inventor
Heitman Laura
Van Der Es Daan
Essa Khaled
Original Assignee
Univ Leiden
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Publication date
Application filed by Univ Leiden filed Critical Univ Leiden
Priority to NL2037411A priority Critical patent/NL2037411B1/en
Priority to PCT/NL2025/050163 priority patent/WO2025216628A1/en
Application granted granted Critical
Publication of NL2037411B1 publication Critical patent/NL2037411B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D207/10—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 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to certain compounds of Formula (I) that function as a proteolysis targeting chimera (PROTAC) against CCR2: ç ‚IYI a O=S|=O NH x—L—E3 Formula (|) wherein X, L, E3, ring A, integer a, Y, ring B, integer b and Z are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which CCR2 activity is implicated.

Description

PROTAC COMPOUNDS
INTRODUCTION
[001] The present invention relates to certain compounds that function as a proteolysis targeting chimera (PROTAC) against CCR2. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which CCR2 activity is implicated.
BACKGROUND OF THE INVENTION
[002] Trafficking of leukocytes, such as lymphocytes, monocytes, and macrophages, to inflammatory sites is a crucial event in immunohomeostasis and immune responses. One of the modulators of this event is the CC chemokine receptor (CCR2)*, where it is expressed on the aforementioned leukocytes.2° Belonging to the class G protein coupled receptor (GPCR) family, COR2 exhibits characteristic seven transmembrane (TM) domains, three extracellular loops and three intracellular loops.® Activation of CCR2 is achieved upon binding to its cognate endogenous chemokines, mainly chemokine ligand 2 (CCL2).” Activation of CCR2 is among the driving events responsible for leukocyte migration to inflammatory sites.®
Dysregulation of CCR2/CCL2 signaling and/or expression is implicated in the pathophysiology of numerous immunoinflammatory pathologies.®'° It has been shown that aberrant CCR2 activation is involved in tumorigenesis and metastasis of several cancers®, atherosclerosis'!, neuropathic pain'?, hepatic fibrosis'®, and rheumatoid arthritis*4. Several
CCR2 selective and dual functioning (CCR2 and CCRS binders) antagonists have progressed to clinical trials.'® However, to date, none of the candidates have cleared phase [Il trials due to a lack of efficacy, resulting in a failure to meet clinical endpoints in the CCR2 trials. 3-13 Accordingly, novel therapeutic modalities are sought after to target the so far undruggable CCR2.
[003] Targeted protein degradation (TPD) using proteolysis targeting chimera (PROTAC) has been rapidly emerging as a novel targeting modality. By recruiting the
Ubiquitin-proteasome pathway, PROTACs enable the degradation of a selected protein of interest (POI). PROTACs employ a POI ligand and an E3 ubiquitin ligase ligand tethered by a linker. Simultaneous binding of the PROTAC to the POI and E3 ligase enables the formation of a so-called ternary complex. Upon forming a ternary complex, a polyubiquitin chain is conjugated to the POI leading to its degradation by the 26S proteasome®®. The event-driven and catalytic mode of action of PROTACS, coupled with their observed improvement in target selectivity, led to opening of new avenues in drug discovery where certain targets were deemed undruggable. The promise of PROTACSs as a novel pharmaceutical modality has been evident by the development of several pre-clinical and clinical candidates targeting proteins involved in various cancers as well as immune disorders.2° Furthermore, PROTACSs can be employed as a chemical biology tool to probe the cellular and molecular consequences of target degradation. According to the PROTAC-
DB (http://cadd.zju.edu.cn/protacdb/), to date, -5000 PROTACSs targeting ~250 targets have been developed.?! Strikingly, only three of these targets are GPCRs despite the fact that
GPCRs are rich drug targets (targeted by ~37% of approved drugs).22 This observation further highlights the need to develop PROTACSs targeting GPCRs, such as CCR2.
[004] The present invention has been devised with the foregoing in mind.
SUMMARY OF THE INVENTION
[005] According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[006] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
[007] According to a further aspect of the present invention, there is provided a method of treating a proliferative condition, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[008] According to a further aspect of the present invention, there is provided a method of treating a disease or condition in which CCR2 activity is implicated, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[009] According to a further aspect of the present invention, there is provided a method of treating immunoinflammatory pathologies, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[0010] According to a further aspect of the present invention, there is provided a method of treating cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g.,
Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neurone disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease and spinal muscular atrophy), hepatic fibrosis and/or rheumatoid arthritis, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[0011] According to a further aspect of the present invention, there is provided a method of treating cancer, in particular tumorigenesis and metastasis, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[0012] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[0013] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.
[0014] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or condition in which CCR2 activity is implicated.
[0015] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of immunoinflammatory pathologies.
[0016] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g., Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neurone disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis,
Lewy body disease and spinal muscular atrophy), hepatic fibrosis and/or rheumatoid arthritis.
[0017] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of cancer, in particular tumorigenesis and metastasis.
[0018] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.
[0019] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or condition in which CCR2 activity is implicated.
[0020] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of immunoinflammatory pathologies.
[0021] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g., Alzheimer's disease, ataxia, Huntington's disease,
Parkinson's disease, motor neurone disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease and spinal muscular atrophy}, hepatic fibrosis and/or rheumatoid arthritis.
[0022] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer, in particular tumorigenesis and metastasis.
[0023] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[0024] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
[0025] According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.
[0026] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention.
DETAILED DESCRIPTION OF THE INVENTION Definitions
[0027] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. 5 [0028] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
[0029] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
[0030] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For example, “(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and t-butyl.
[0031] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.
[0032] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH:-), ethylene (-
CH2CHaz-), propylene (-CH2CH2CH:2-}, 2-methylpropylene (-CH>CH(CH3)CH>-), pentylene (-
CH2CH2CH>CH2CH3-), and the like.
[0033] The term “alkenyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl and but-2,3-enyl and includes all possible geometric (E/Z) isomers.
[0034] The term “alkynyl” refers to straight and branched chain alkyl groups comprising
2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.
[0035] “cycloalkyl” means a hydrocarbon ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.
[0036] The term “alkoxy” refers to O-linked straight and branched chain alkyl groups.
Examples of alkoxy groups include methoxy, ethoxy and f-butoxy.
[0037] The term “haloalkyl” is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g., fluorine} atoms. Examples of haloalkyl groups include -CH2F, -CHF: and -CF:.
[0038] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.
[0039] The term “carbocyclyl”, “carbocyclic” or “carbocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon- containing ring system(s). Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.
[0040] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro oxathiolyl, tetrahydro oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro oxathiazolyl, hexahydrotriazinyl, tetrahydro oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO. groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Heterocycles may comprise 1 or 2 oxo (=O) or thioxo (=S) substituents. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2- thioxopyrrolidinyl, 2-0xoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5- dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,8-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidine or morpholino refers to a piperidin-1- yl or morpholin-4-yl ring that is linked via the ring nitrogen.
[0041] By “bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition,
Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-0xa-5-azabicyclo[2.2.1]heptane, aza- bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.
[0042] By “spiro bi-cyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e., the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2- azaspiro[3.3]heptanes, 2-0xa-6-azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa- 2-azaspiro[3.4]octane, 2-0x4a-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.
[0043] The term “heteroaryl” or “heteroaromatic” means an aromatic mono, bi, or polycyclic ring incorporating one or more (for example 1 4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
[0044] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5 triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3 b]furanyl, 2H furo[3,2 b] pyranyl, 5H pyrido[2,3 d] o oxazinyl, 1H pyrazolo[4,3 d] oxazolyl, 4H imidazo[4,5 d]thiazolyl, pyrazino[2,3 d]pyridazinyl, imidazo[2,1 b]thiazolyl, imidazo[1,2 b][1,2,4]triazinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non- aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro 1,8-naphthyridinyl, 1,2,3,4- tetrahydropyrido[2,3 b]pyrazinyl and 3,4-dihydro 2H pyrido[3,2 b][1,4]oxazinyl.
[0045] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
[0046] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0047] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 8-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.
[0048] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
[0049] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
[0050] The term “aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species.
Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
[0051] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example (3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by (3- 6C)cycloalkyl.
[0052] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term “substituted” suitably means that (any) one of the hydrogen radicals of the relevant group is substituted by a relevant stipulated group. Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
[0053] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically (e.g., compounds having the structural
Formula (I), and any sub-formulae thereof, or the structural Formula (ll), and any sub- formulae thereof).
Compounds of the invention
[0054] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (1}, shown below:
oe" 0=8=0
NH X—L—E;3
GD
0
Formula (I) wherein
X is selected from -C(O)NRx- or -O-, wherein Rx is selected from hydrogen or (1-4C)alkyl;
L is a linker;
Ez is an E3 ubiquitin ligase-binding moiety; ring A is phenyl or a 5- or 6-membered heteroaryl; integer a is 0, 1 or 2; each Y is independently selected from halo or (1-4C)haloalkyl; ring B is phenyl or a 6-membered heteroaryl; integer b is 0, 1, 2 or 3; and each Z is independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, cyano and SO:{(1- 4C)alkyl.
[0055] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (ll), shown below:
EF CI
0 0=8=0
CI Cra 0
Formula (II) wherein
X is selected from -C(O)NRx- or -O-, wherein Rx is selected from hydrogen or (1-4C)alkyl;
L is a linker; and
Ez is an E3 ubiquitin ligase-binding moiety.
[0056] Particular compounds of Formula (I) and Formula (Il) include, for example,
compounds of the Formula (I) and Formula (ll), or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of X, L, Es, ring A, integer a, Y, ring B, integer b and Z, and any associated substituent groups has any of the meanings defined hereinbefore or in any of numbered paragraphs (1) to (59) hereinafter:
X
(1) Xis selected from -C(O)NRx- or -O-; (2) X is -C(O)NRx-; (3) Xis-O-; (4) Ry is selected from hydrogen, methyl or ethyl; (5) Rx is selected from hydrogen or methyl; (6) Xis selected from -C(O)NRx- or -O-, wherein Ry is selected from hydrogen or methyl; (7) Xis selected from -C(O)NRx- or -O-, wherein Ry is hydrogen;
[0057] Suitably, X is as defined in any one of numbered paragraphs (1) to (7) above.
More suitably, X is as defined in any one of numbered paragraphs (6) or (7) above. Most suitably, X is as defined in numbered paragraph (7) above.
[0058] Suitably, X is as defined in numbered paragraph (1) above. More suitably, X is as defined in numbered paragraph (3) above. Even more suitably, X is as defined in numbered paragraph (6) above. Most suitably, X is as defined in numbered paragraph (7) above.
The linker group L
[0059] The linker L is a group that serves to link X to Es. Suitable linkers are well known in the PROTAC field for this purpose. Accordingly, any suitable linker known in the PROTAC field could be used in the compounds of the present invention.
[0060] It will be appreciated that the term “chain atom” will be understood to mean the atoms which space apart X and Es (i.e., bridging atoms between X and Es). It will be understood that the number of bond lengths in the “chain atom” moiety will be n+1, wherein n is the number of “chain atoms”. It will be appreciated that L can be defined in terms of “bond lengths” and “chain atoms”.
[0061] The L group of Formula (I) and Formula (ll) is either as defined hereinbefore or has one of the definitions set out in numbered paragraphs (8) to (27) below: (8) Lis a linker comprising: (iy 31to 40 chain atoms; (i) 3 to 30 chain atoms; (ii) 3 to 20 chain atoms; (iv) 3to 15 chain atoms;
(v) 31to 10 chain atoms; or (vi) 3 to 8 chain atoms; (9) Lis a linker comprising 3 to 40 chain atoms; (10) L is a linker comprising 3 to 30 chain atoms; (11) L is a linker comprising 3 to 20 chain atoms; (12) L is a linker comprising 3 to 15 chain atoms; (13) L is a linker comprising 3 to 10 chain atoms; (14) L is a linker comprising 3 to 8 chain atoms; (15) L is a linker comprising: 0 3 to 40 chain atoms; (ii) 3 to 30 chain atoms; (iii) 3 to 20 chain atoms; (iv) 3 to 15 chain atoms; (v) 3 to 10 chain atoms; or (vi) 3 to 8 chain atoms; and wherein: (a) the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -N{CHs)-, - —N N——
CO-, -CONH-, -NHCO-, -C(O)O-, -OC(Q)-, triazole, \_/
OO
‚ or : (b) the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -N(CHs)-, -
CONH-, -NHCO-, -C{O)O-, -OC(Q)-, or triazole; ©) the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -CONH-, -
NHCO-, -C(O)O-, -OC{(O)-, or triazole; (d) the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -CONH-, -
NHCO- or triazole; (16) L is a linker as defined in any one of numbered paragraphs (8) to (14) comprising an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -N(CH3)-, -CO-, -CONH-, -NHCO-, -C(O)O-, -OC(O}-, triazole,
—N N—— —N —N X N— (17) L is a linker as defined in any one of numbered paragraphs (8) to (14) comprising an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -N(CHz3)-, -CONH-, -NHCO-, -C(O)O-, -OC(O)-, or triazole; (18) L is a linker as defined in any one of numbered paragraphs (8) to (14) comprising an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -CONH-, -NHCO-, -C(0O)O-, -OC{O)-, or triazole; (19) Lis a linker as defined in any one of numbered paragraphs (8) to (14) comprising an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -CONH-, -NHCO- or triazole; (20) L is a linker of the formula: “Air X2- Aro Ats-Ats Kia" wherein: *denotes the point of attachment to X; ** denotes the point of attachment to Es;
Aus is (1-15C)alkylene, (2-8C)alkenylene, (2-8C)alkynylene, -(CH2)a:-[O-CH2CH2le2- or - [O-CH2CH2la2-(CHz}a:-;
Xt is either absent or selected from -O-, NRx2, -C(O)-, -C(O)NRx2, -NRx.2C(O}-, -
C(O)O-, -OC(O)- or triazole; wherein Rx2 is hydrogen or methyl;
Arz is absent or (1-15C)alkylene, -[CH2CH2OJas-(CH2)as- or -(CHz}a3-[OCH2CH2las;
Xs is absent or -O-, NRxu3, -C(O)-, -C(O)NRx13-, -NRx13C{(O)- or triazole; wherein Rx‚ is hydrogen or methyl;
Aus is absent or (1-15C)alkylene, -[CH2CH2O]as-(CH2)as- or -(CHz}as-[OCH2CHz]as;
Xu is absent or -O-, -C(O)-, -C(O)NRxws-, -NRx.4C(O)- or triazole; wherein RxLs is hydrogen or methyl; integers a1, a3 and a5 are each independently 1 to 4; and integers a2, a4 and a6 are each independently 1 to 7; (21) L is a linker of the formula: *-Api-Xiz-A-Xuz-As-Xia-** wherein: *denotes the point of attachment to X;
** denotes the point of attachment to Es;
Artis (1-8C)alkylene or -(CHz}a1-[O-CH2CH:2l-;
Xt is either absent or selected from -O-, NRx2, -C(O)-, -C(O)NRx2, -NRx.2C(O)-, -
C(O)O-, -OC(O)- or triazole; wherein Rx.2 is hydrogen or methyl;
Atz is absent or (1-8C)alkylene or -[CH2CH20]as-(CH2)as-;
Xs is absent or -O-, NRx13, -C(O)-, -C(O)NRx3- or -NRx.3C(O)- or (2-4C)alkynyl; wherein Rx3 is hydrogen or methyl;
Aus is absent or (1-8C)alkylene, -[CH2CHz2O]ss-(CHz)as- or -(CH2}as-[OCH2CHzlas;
Xa is absent or -O-, -C{O)-, -C(O)NRx4-, -NRx4C{(O)- or triazole; wherein Rxua is hydrogen or methyl; integers a1, a3 and a5 are each independently 1 to 4; and integers a2, a4 and a6 are each independently 1 to 4; (22) L is a linker of the formula: *-Ar-Xi2-Ave-Xis-Xua-** wherein: *denotes the point of attachment to X; ** denotes the point of attachment to Es;
Aus is (1-7C)alkylene or -(CHa)a1-[O-CH2CH3Jaz-;
Xz is either absent or selected from -O-, NRx2, -C(O)-, -C(O)NRxLz, -NRx.2C(O)-, -
C(O)O-, -OC(0)- or triazole; wherein Rx2 is hydrogen or methyl;
At is absent or (1-7C)alkylene or -[CH2CH20]as-(CH2)as-;
Xs is absent or -O-, NRx13, -C(O)-, -C(O)NRxv3- or -NRx3C(O)- or (2-4C)alkynyl; wherein RxL3 is hydrogen or methyl;
Ais is absent or (1-8C)alkylene, -[CH2CHz2O]ae-(CH2)as- or -(CH2)as-[OCH2CHslas;
Xu is absent or -O-, -C{O)-, -C(O)NRxws-, -NRx.4C(O)- or triazole; wherein RxLs is hydrogen or methyl, integers a1, a3 and a5 are each independently 1 to 4; and integers a2, a4 and ab are each independently 1 to 4; (23) L is a linker of the formula: *-AL-Xi-A-Xis-* wherein: *denotes the point of attachment to X; ** denotes the point of attachment to Es;
Aus is (1-6C)alkylene or -(CHa)a1-[O-CH2CH3Jaz-;
X12 is either absent or selected from -O-, NRx.2, -C(O)-, -C{(O)NRxi2, -NRx.2C(O)-, -
C(0O)0O-, -OC(O)- or triazole; wherein Rx.2 is hydrogen or methyl;
Arzis absent or (1-6C)alkylene or -[CH2CH2O]a4-(CH2)a3-;
Xia is absent or -O-, NRu3, -C(O)-, -C(O)NRx.3- or -NRx.sC(O)- or (2-4C)alkynyl; wherein RxL3 is hydrogen or methyl; integers a1 and a3 are each independently 1 to 3; and integers a2 and a4 are each independently 1 to 4; (24) L is a linker of the formula: *-AL-Xea-** wherein: *denotes the point of attachment to X; ** denotes the point of attachment to Es;
Au: is (1-6C)alkylene or -{(CHs}a1-[O-CH2CH2la2-;
Xt2 is either absent or selected from -O-, NRx‚2, -C(O)-, -C(O)NRxLz2, or -NRx.2C(O)-, wherein RxL2 is hydrogen or methyl; integers a1 and a3 are each independently 1 to 3; and integers a2 and a4 are each independently 1 to 4; or *-Ar-Xi-Ar- Xs wherein: *denotes the point of attachment to X; ** denotes the point of attachment to Es;
Au is (1-4C)alkylene or -(CHz)as-[O-CH2CHzlaz-;
Xu is triazole;
Aris (1-4C)alkylene or -[CH2CH2O]la4-(CHz)a3-;
Xs is absent or -O-, NRxt3, -C(O)-, -C(O)NRx3- or -NRx:C(O)-; wherein Rx is hydrogen or methyl; integers a1 and a3 are each independently 1 to 3; and integers a2 and a4 are each independently 1 to 3; (25) L is a linker of the formula: *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-X2-**; *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-0-CH2-CH2-XL2-**; *-CHz-CHz2-CH2-CHs-X2-**; *-CH2-CH2-CH2-CHs-CH2-CH2-X2-**; *-CHz-[triazole]-CH2-CH2-0-CH2-X,3-**; *-CHz-[triazole]-CH2-CH2-0-CHz2-CH2-0-CH2-XL3-**; *-CHz-[triazole]-CHz-CH2-O-CH2-CH2-O- CH2-CH2-O0-CH2-X3-**; wherein: * denotes the point of attachment to X; ** denotes the point of attachment to Es;
X12 is selected from -O-, NRxt2, -C(O)-, -C(O)NRxL2, or -NRx.2C(O)-, wherein Rx.z is hydrogen or methyl; and
Xs is selected from -O-, NRx 3, -C(O)-, -C(O)NRx3- or -NRx.3C(O)-; wherein Rx.z is hydrogen or methyl, (26) L is a linker of the formula: *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-X2-**; *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-0-CH2-CH2-XL2-**; *-CHz-CH2-CH2-CH2-X2-**; *-CH2-CH2-CH2-CH2-CH2-CH2-X2-** *-CHz-[triazole]-CH2-CH2-O0-CH2-X3-**; *-CHz-[triazole]-CH2-CH2-0-CH2-CH2-O0-CH2-X3-**; *-CHz-[triazole]-CH2-CH2-0-CH2-CH2-O- CH2-CH2-0-CH2-X3-**; wherein: * denotes the point of attachment to X; ** denotes the point of attachment to Es;
Xz is selected from -O-, NRx2, -C(O)-, -C{O)NRs2, or -NRx2C(O)-, wherein Rx2 is hydrogen; and
Xs is -C(O)NRx3-; wherein Rxt3 is hydrogen. (27)L is a linker of the formula: *-CH2-CHz-O-CH2-CH2-O-CHz-CH2-NHC(O)-**; *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-0-CH2-CH2-NHC{O)-**; *-CH2-CH2-CH2-CH2-NH-**; *-CH2-CH2-CH2-CH2-CH2-CH2-NH-**: *-CHz-[triazole]-CH2-CH2-0-CH2-C(O)NH-**: *-CHz-[triazole]-CH2-CH2-0-CH2-CH2-O0-CH2-C{O)NH-**; *-CHs-[triazole]-CH2-CH2-0-CH2-CH2-0- CH2-CHs-O0-CH2-C(O)NH-**; *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-0-CH2-CH2-0-**; *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-O-**; *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-0-CH2-CH2-NH-**: *-CH2-CH2-0-CH2-CH2-0-CH2-CHs-NH-**; *-CH2-CH2-0-CH2-CH2-0-CH2-C(O)NH-**: *-CH2-CH2-0-CH2-CH2-0-CH2-CH2-O0-CH2-CH2C(O)NH-**: wherein: * denotes the point of attachment to X; and ** denotes the point of attachment to Es;
[0062] Suitably, L is as defined in any one of numbered paragraphs (8) to (27) above.
More suitably, L is as defined in any one of numbered paragraphs (15) to (27) above. Even more suitably, L is as defined in any one of numbered paragraphs (20) to (27) above. Yet even more suitably, L is as defined in any one of numbered paragraphs (24) to (27) above.
Yet still even more suitably, L is as defined in any one of numbered paragraphs (26) or (27) above. Most suitably, L is as defined in numbered paragraph (27) above.
[0063] Suitably, L is as defined in numbered paragraph (8) above. More suitably, L is as defined in numbered paragraph (15) above. Even more suitably, L is as defined in numbered paragraph (20) above. Yet even more suitably, L is as defined in numbered paragraph (24) above. Yet still even more suitably, L is as defined in numbered paragraph (26) above. Most suitably, L is as defined in numbered paragraph (27) above.
The E3 ubiquitin ligase-binding moiety E;
[0064] The E3 ubiquitin ligase-binding moiety E3 may be any suitable E3 ubiquitin ligase-binding moiety known in the art.
[0065] The Es group of Formula (1) and Formula (Il) is either as defined hereinbefore or has one of the definitions set out in paragraphs (28) to (40) below: (28) Ez is a small molecule or peptide E3 ubiquitin ligase-binding moiety; (29) Ez is a small molecule E3 ubiquitin ligase-binding moiety. (30) Es is an E3 ubiquitin ligase-binding moiety capable of binding an £3 ubiquitin ligase selected from the group consisting of von Hippel-Lindau {VHL}, cereblon, AIAP, E3A;
MDMZ; Anaphase-promoting complex, EIBRS (EDD, SOCS/BL-boy eloBG/ CULE RING,
LNXp80 CEXE CBLLY, HACE HELTD1, HECTDZ, HECTDRS, HECW, HECWZ; HERCH;
HERCZ, HERCE, HERO4 HUWET ITOH; NERDY; NEDDdL PRILZ; PRPF1D; PIAST,
PIAS2; PIAS, PIAS4, BANBP2; RNF4; REX, SMURF 1, SMURFZ, STURT, TOPORS,
TRIP 12; UBE2A, UREZR, UBE2C: UBRE4A; UBE4R, UBOKXS, UBRS, WWRT, WWRZ, Parkin;
A2OTNFAIP3; AMFR/gp78, ARAS4 beta-TrCRVBTRE, BRCAT, CBL: CHIP/STUB 1, £5;
ESARMIBESA, F-box protein 15/FBA01S5; FBAW//0dc4, GR AI/RNF 128; HOIB/RNF31;
CIAR-HIAR-2, ClAR-2/HIAR-I CIAR (pan), ITCH/AIPL, KART, MARCHE, Mind Bomb 1/MIB1;
Mind Bomb 2/MIB2; MuRF 1 /TRIMOS; NDEIP], NEDD4, Niel, Parkin; RNF2; RNF4; RNFg;
RNF188; RNF43; SART1; Skp2; SMURF2 TRAF-L TRAF-2; TRAF-3, TRAF-4, TRAF-5;
TRAF-G; TRIMS, TRIM21, TRIMS2; UBRS; and INRF3; (31) Es is an E3 ubiquitin ligase-binding moiety capable of binding an E3 biet ligase selected from the group consisting of von Hippel-Lindau (VHL) or cereblon; (32) Ez is an E3 ubiquitin ligase-binding moiety capable of binding to von Hippel-Lindau (VHL); (33) Es is an E3 ubiquitin ligase-binding moiety capable of binding to cerebion; (34) Es is selected from thalidomide, pomalidomide, lenalidomide, VHL ligand, methyl- bestatin, nutlin or a nutlin derivative (e.g., idasanutlin);
(35) Eis selected from thalidomide, pomalidomide, lenalidomide, VHL ligand, nutlin or idasanutlin; (36) Es is selected from: (i) 0
VU
X9 NH \
N Oo
Rq
Oo : (ii) 0
SU
XxX NH \
N Oo
Rq . (iii)
Oo 2 ~ 5% X, NH \
N ©
Rq © : (iv) 0 2 po X, NH
TT
N Oo
Rq . (v)
=< s
TOP
Ss “HOH
N
© ; (vi)
HS
Ia A, >= 0 ; (vii)
OT
H HN F
2 N mw mm Cl 3 I .
F “N 5 Cl ‚or (viii)
— Y 0 SF
NH HN— 4 N Cl
Oi ON
F = N 9 ® wherein: 3 denotes the point of attachment to L;
R4 is hydrogen or fluoro; and
Xz is selected from -CHz- or -C(O)-; (37) Es is selected from: (i) 0
SU
X9 NH
N\
N 0
Rq © ; (ii)
Oo 2 ~ 5 X, NH
AN
N Oo
Rq 0 : (iii)
ie
Ss
TOP
Ss “HOH
N
© ; (iv)
SK
Ia A, >= © : (v)
OT
H HN F
2 N mw mm CI 3 I .
F “N ; CI or (vi)
— Y 0 SF
NH HN— 4 N Cl
Oi ON
F = N 9 ® wherein: 3 denotes the point of attachment to L;
R4 is hydrogen or fluoro; and
Xz is selected from -CHz- or -C(O)-; (38) Es is selected from: (i) 0
SU
X9 NH
N\
N 0
Rq © ; (ii)
Oo 2 ~ 5 X, NH
AN
N Oo
Rq 0 : (iii)
ie
Ss
TOP
Ss “HOH
N
© ; (iv)
SK
Ia A, >= © : (v)
OT
H HN F
2 N mw mm CI 3 I .
F “N ; CI or (vi)
OY
H SF
HN— 4 N Cl
Oi NX
F = N 9 ® wherein: 3 denotes the point of attachment to L;
R4 is hydrogen; and
Xz is -C(O)-; (39) Es is selected from: (i) 0
SU
X9 NH
AN
N 0
Rq o ; (ii) 0 2 ~ 5 X, NH \
N 0
Rq 0 : (iii)
Ng
J
N © N
Ss “HOH
H
N
© ; (iv) ( H HN "
A, Ore a N
O \
F NN
Cl or (v) 7 H mf
ORT ©
EN
FA. N
A wherein: : denotes the point of attachment to L;
R4 is hydrogen; and
Xz is -C(O)-;
(40) Es is selected from: (i)
I 2 \
N Oo
Rq
O ‚or (ii)
Oo 2
OG -
AN
N ©
Rq o : wherein: 2 : denotes the point of attachment to L;
R4 is hydrogen; and
Xz is -C(O)-;
[0066] Suitably, Es is as defined in any one of numbered paragraphs (28) to (40) above.
More suitably, Es is as defined in any one of numbered paragraphs (30) to (40) above. Even more suitably, Es is as defined in any one of numbered paragraphs (34) to (40) above. Yet even more suitably, Es is as defined in any one of numbered paragraphs (36) to (40) above.
Yet still even more suitably, E; is as defined in any one of numbered paragraphs (38), (39) or (40) above. Most suitably, E; is as defined in numbered paragraph (40) above.
[0067] Suitably, Es is as defined in numbered paragraph (28) above. More suitably, Es is as defined in numbered paragraph (30) above. Even more suitably, Es is as defined in numbered paragraph (34) above. Yet even more suitably, E; is as defined in numbered paragraph (36) above. Yet still even more suitably, Es is as defined in numbered paragraph (38) above. Yet still even more suitably, Es is as defined in numbered paragraph (39) above.
Most suitably, E; is as defined in numbered paragraph (40) above.
Ring A, integer a, Y, ring B, integer b and Z (41) Ring A is phenyl, a 5-membered sulphur-containing heteroaryl or a 6-membered nitrogen-containing heteroaryl; (42) Ring A is phenyl, thiophene or pyridine; (43) Ring A is phenyl; (44) Integer a is 1 or 2; (45) Integer a is 1; (46) Integer a is 2; (47) Each Y is independently selected from fluoro, chloro, bromo, (1-2C)haloalkyl; (48) Each Y is independently selected from fluoro, chloro, CFs, CF2H and CFHy; (49) Each Y is independently selected from chloro or CF3; (50) Ring B is phenyl or a nitrogen-containing 6-membered heteroaryl; (51) Ring B is phenyl or pyridine; (52) Ring B is phenyl; (63) Integerb is 1,2 or 3; (54) Integer b is 1; (55) Integer b is 2; (56) Each Z is independently selected from methyl, ethyl, propyl, fluoro, chloro, bromo, (1- 2C)haloalkyl, cyano and SO:(1-2C)alkyl; (57) Each Z is independently selected from methyl, ethyl, fluoro, chloro, CFs, CF:H and
CFHz, cyano and SO:Me; (58) Each Z is independently selected from methyl, fluoro, chloro, cyano and SO:Me; (59) Each Z is chloro.
[0068] Suitably, ring A is as defined in any one of numbered paragraphs (41) to (43) above. More suitably, ring A is as defined in numbered paragraph (42) or (43) above. Even more suitably, ring A is as defined in numbered paragraph (43) above.
[0069] Suitably, ring A is as defined in numbered paragraph (41) above. More suitably, ring A is as defined in numbered paragraph (42) above. Even more suitably, ring A is as defined in numbered paragraph (43) above.
[0070] Suitably, integer a is as defined in any one of numbered paragraphs (44) to (46) above. More suitably, integer a is as defined in numbered paragraph (45) or (46) above.
Even more suitably, integer a is as defined in numbered paragraph (46) above.
[0071] Suitably, integer a is as defined in numbered paragraph (44) above. More suitably, integer a is as defined in numbered paragraph (45) above. Even more suitably, integer a is as defined in numbered paragraph (46) above.
[0072] Suitably, each Y is as defined in any one of numbered paragraphs (47) to (49) above. More suitably, each Y is as defined in numbered paragraph (48) or (49) above. Even more suitably, each Y is as defined in numbered paragraph (49) above.
[0073] Suitably, each Y is as defined in numbered paragraph (47) above. More suitably,
each Y is as defined in numbered paragraph (48) above. Even more suitably, each Y is as defined in numbered paragraph (49) above.
[0074] Suitably, ring B is as defined in any one of numbered paragraphs (50) to (52) above. More suitably, ring B is as defined in numbered paragraph (51) or (52) above. Even more suitably, ring B is as defined in numbered paragraph (52) above.
[0075] Suitably, ring B is as defined in numbered paragraph (50) above. More suitably, ring B is as defined in numbered paragraph (51) above. Even more suitably, ring B is as defined in numbered paragraph (52) above.
[0076] Suitably, integer b is as defined in any one of numbered paragraphs (53) to (55) above. More suitably, integer b is as defined in numbered paragraph (54) or (55) above.
Even more suitably, integer b is as defined in numbered paragraph (54) above.
[0077] Suitably, integer b is as defined in numbered paragraph (53) above. More suitably, integer b is as defined in numbered paragraph (55) above. Even more suitably, integer b is as defined in numbered paragraph (54) above.
[0078] Suitably, each Z is as defined in any one of numbered paragraphs (56) to (59) above. More suitably, each Z is as defined in any one of numbered paragraphs (57) to (59) above. Even more suitably, each Z is as defined in numbered paragraph (58) or (59) above.
Yet even more suitably, each Z is as defined in numbered paragraph (59) above.
[0079] Suitably, each Z is as defined in numbered paragraph (56) above. More suitably, each Z is as defined in numbered paragraph (57) above. Even more suitably, each Z is as defined in numbered paragraph (58) above. Yet even more suitably, each Z is as defined in numbered paragraph (59) above.
Particular embodiments of Formula (I)
[0080] Compounds of the invention include those in which X is selected from -C(O)NRx- or -O- and Rx, L, Es, Ring A, integer a, Y, ring B, integer b and Z are as defined herein. Such compounds have the Formula (I-1) or (I-1I) shown below: z IY], 0=5=0 0
NH N7 L—E3
GO
0 (II)
0=8=0 6D b 0 (I-11) wherein Ry, L, Es, ring A, integer a, Y, ring B, integer b and Z are each as defined anywhere herein.
[0081] Suitably, the compound is a compound of the Formula (I-I) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0082] Suitably, the compound is a compound of the Formula (I-Il) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0083] In an embodiment of the compounds of Formula (I-1) or (I-11):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (8) to (27) above;
Es is as defined in any one of numbered paragraphs (28) to (40) above;
Ring A is as defined in any one of numbered paragraphs (41) to (43) above;
Integer a is as defined in any one of numbered paragraphs (44) to (46) above;
Y is as defined in any one of numbered paragraphs (47) to (49) above;
Ring B is as defined in any one of numbered paragraphs (50) to (52) above;
Integer b is as defined in any one of numbered paragraphs (53) to (55) above; and
Z is as defined in any one of numbered paragraphs (56) to (59) above.
[0084] In an embodiment of the compounds of Formula (I-1} or (I-11):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (15) to (27) above;
Ez is as defined in any one of numbered paragraphs (30) to (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above,
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in any one of numbered paragraphs (57) to (59) above.
[0085] In an embodiment of the compounds of Formula (I-1) or (I-11):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (20) to (27) above;
Es is as defined in any one of numbered paragraphs (34) to (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[0086] In an embodiment of the compounds of Formula (I-1} or (I-11):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (24) to (27) above;
Ez is as defined in any one of numbered paragraphs (36) to (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above,
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[0087] In an embodiment of the compounds of Formula (I-1} or (I-11):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in numbered paragraph (26) or (27) above;
Ez is as defined in any one of numbered paragraphs (38), (39) or (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[0088] In an embodiment of the compounds of Formula (I-1) or (I-11):
Rx, when present, is as defined in numbered paragraph (4) above;
L is as defined in numbered paragraph (8) above;
Es is as defined in numbered paragraph (28) above;
Ring A is as defined in numbered paragraph (41) above;
Integer a is as defined in numbered paragraph (44) above;
Y is as defined in numbered paragraph (47) above;
Ring B is as defined in numbered paragraph (50) above;
Integer b is as defined in numbered paragraph (53) above; and
Z is as defined in numbered paragraph (58) above.
[0089] In an embodiment of the compounds of Formula (I-1} or (I-11):
Rx, when present, is as defined in numbered paragraph (4) above;
L is as defined in numbered paragraph (15) above;
Ez is as defined in numbered paragraph (30) above;
Ring A is as defined in numbered paragraph (42) above;
Integer a is as defined in numbered paragraph (44) above;
Y is as defined in numbered paragraph (48) above;
Ring B is as defined in numbered paragraph (51) above;
Integer b is as defined in numbered paragraph (53) above; and
Z is as defined in numbered paragraph (57) above.
[0090] In an embodiment of the compounds of Formula (I-1) or (I-11):
Rx, when present, is as defined in numbered paragraph (4) above;
L is as defined in numbered paragraph (20) above;
Es is as defined in numbered paragraph (34) above;
Ring A is as defined in numbered paragraph (42) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (51) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (58) above.
[0091] In an embodiment of the compounds of Formula (I-1) or (I-11):
Rx, when present, is as defined in numbered paragraph (5) above;
L is as defined in numbered paragraph (24) above;
Es is as defined in numbered paragraph (36) above;
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (48) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[0092] In an embodiment of the compounds of Formula (I-1) or (I-1l):
Rx, when present, is as defined in numbered paragraph (5) above;
L is as defined in numbered paragraph (26) above;
Es is as defined in numbered paragraph (38) above;
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[0093] In an embodiment of the compounds of Formula (I-1) or (I-11):
Rx, when present, is as defined in numbered paragraph (5) above;
L is as defined in numbered paragraph (27) above;
Es is as defined in numbered paragraph (40) above
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (48) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[0094] Compounds of the invention include those in which L is as defined in numbered paragraph (27) above and X, Rx, Es, ring A, integer a, Y, ring B, integer b and Z are as defined herein. Such compounds have the Formulae (I-11I) to (I-XV) shown below: z IY, 0=8=0
NH Xo Bs tel IDT 0 (1-111) > a 0=8=0
NH Aa Bs el OT o (I-IV)
HN~E,
Y], SN / o~ =F 0=S=0 N=N 0 ae 0 (IV)
Oo E ‚F3
Vl, NH ~~ ° 0=S=0 N=N 0
NH x IN ets 1) 0 (I-VI)
Y] a
HN~E, 0=5=0 N=N, ea
NH x AN es 1) 0 (I-VI) > 0=8=0 H
NH XN AO A~N Es
EY
0 0 (I-VIII)
z vl,
O=S=0 0
NH X 0 J
Zr B H
Oo (I-1X) z vl, 0=8=0
NH Ae OO,
Zr B
Oo (I-X) >" 0=8=0
NH Xoo dE
ZIT B
Oo (XN) z Iv, 0=8=0 H
NH KT IN,
ZT B
Oo (1-1) >" 0=8=0
NH Xoo On Be
ZT B H
Oo
(I-XI11) 2 AY] a 0=8=0 0
NH X oN „E
SO oy ~ No N 3 0 (I-XIV) > 0=8=0 0 ets Ù oOo b 0 (I-XV) wherein X, Rx, Ez, ring A, integer a, Y, ring B, integer b and Z are each as defined anywhere herein.
[0095] Suitably, the compound is a compound of the Formula (I-III) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0096] Suitably, the compound is a compound of the Formula (I-IV) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0097] Suitably, the compound is a compound of the Formula (I-V) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0098] Suitably, the compound is a compound of the Formula (I-VI) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0099] Suitably, the compound is a compound of the Formula (I-VIl) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00100] Suitably, the compound is a compound of the Formula (I-VIIl) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00101] Suitably, the compound is a compound of the Formula (I-IX) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00102] Suitably, the compound is a compound of the Formula (I-X) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00103] Suitably, the compound is a compound of the Formula (I-XI) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00104] Suitably, the compound is a compound of the Formula (I-XIlI) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00105] Suitably, the compound is a compound of the Formula (I-XIIl) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00106] Suitably, the compound is a compound of the Formula (I-XIV) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00107] Suitably, the compound is a compound of the Formula (I-XV) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00108] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (6) or (7) above;
Es is as defined in any one of numbered paragraphs (28) to (40) above;
Ring A is as defined in any one of numbered paragraphs (41) to (43) above;
Integer a is as defined in any one of numbered paragraphs (44) to (48) above;
Y is as defined in any one of numbered paragraphs (47) to (49) above;
Ring B is as defined in any one of numbered paragraphs (50) to (52) above;
Integer b is as defined in any one of numbered paragraphs (53) to (55) above; and
Z is as defined in any one of numbered paragraphs (56) to (59) above.
[00109] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (6) or (7) above;
Es is as defined in any one of numbered paragraphs (30) to (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in any one of numbered paragraphs (57) to (59) above.
[00110] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (6) or (7) above;
Ez is as defined in any one of numbered paragraphs (34) to (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[00111] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (6) or (7) above;
Ez is as defined in any one of numbered paragraphs (36) to (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[00112] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (6) or (7) above;
Es is as defined in any one of numbered paragraphs (38), (39) or (40) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (58) above.
[00113] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (6) above;
Es is as defined in numbered paragraph (28) above;
Ring A is as defined in numbered paragraph (41) above;
Integer a is as defined in numbered paragraph (44) above;
Y is as defined in numbered paragraph (47) above;
Ring B is as defined in numbered paragraph (50) above;
Integer b is as defined in numbered paragraph (53) above; and
Z is as defined in numbered paragraph (56) above.
[00114] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (8) above;
Es is as defined in numbered paragraph (30) above;
Ring A is as defined in numbered paragraph (42) above;
Integer a is as defined in numbered paragraph (44) above;
Y is as defined in numbered paragraph (48) above;
Ring B is as defined in numbered paragraph (51) above;
Integer b is as defined in numbered paragraph (53) above; and
Z is as defined in numbered paragraph (57) above.
[00115] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (8) above;
Es is as defined in numbered paragraph (34) above;
Ring A is as defined in numbered paragraph (42) above;
Integer a is as defined in numbered paragraph (48) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (51) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (58) above.
[00116] In an embodiment of the compounds of Formulae (I-11) to {I-XV):
X is as defined in numbered paragraph (7) above;
Es is as defined in numbered paragraph (36) above;
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[00117] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (7) above;
Es is as defined in numbered paragraph (38) above;
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[00118] In an embodiment of the compounds of Formulae (I-III) to (I-XV):
X is as defined in numbered paragraph (7) above;
Es is as defined in numbered paragraph (40) above
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (468) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[00119] Compounds of the invention include those in which Es is as defined in numbered paragraph (39) above and X, Rx, L, ring A, integer a, Y, ring B, integer b and Z are as defined herein. Such compounds have the Formulae (I-XVI) to (I-XX) shown below:
0
HN
BM © ‚N
Xo O 0=8=0
NH X—L es] (DJ b 0 Rq (I-XVI)
Oo
HN
0 ‚N
Sn HA a 0=8=0
NH X-L Rq ae CT
Oo (I-XVI1)
OH
Y],
N
0=5=0 Oo
NH X—L O HN ets IT
Oo
STN
SN
(1-XVI11)
z NY],
OT F oo H HN 0=5=0 NO a
NH Or VINA
SAT LS
0
Cl (I-XIX)
Y
Ce dk Hun 0=S=0 N Cl
CT DT GN
ID
CI
(I-XX) wherein X, Rx, L, ring A, integer a, Y, ring B, integer b and Z are each as defined anywhere herein.
[00120] Suitably, the compound is a compound of the Formula (I-XVI} shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00121] Suitably, the compound is a compound of the Formula (I-XVII) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00122] Suitably, the compound is a compound of the Formula (I-XVIII) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00123] Suitably, the compound is a compound of the Formula (I-XIX) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00124] Suitably, the compound is a compound of the Formula (I-XX) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00125] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) or (7) above;
L is as defined in any one of numbered paragraphs (8) to (27) above;
Ring A is as defined in any one of numbered paragraphs (41) to (43) above;
Integer a is as defined in any one of numbered paragraphs (44) to (48) above;
Y is as defined in any one of numbered paragraphs (47) to (49) above;
Ring B is as defined in any one of numbered paragraphs (50) to (52) above;
Integer b is as defined in any one of numbered paragraphs (53) to (55) above; and
Z is as defined in any one of numbered paragraphs (56) to (59) above.
[00126] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) or (7) above;
L is as defined in any one of numbered paragraphs (15) to (27) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in any one of numbered paragraphs (57) to (59) above.
[00127] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) or (7) above;
L is as defined in any one of numbered paragraphs (20) to (27) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[00128] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) or (7) above;
L is as defined in any one of numbered paragraphs (24) to (27) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[00129] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) or (7) above;
L is as defined in numbered paragraph (26) or (27) above;
Ring A is as defined in numbered paragraph (42) or (43) above;
Integer a is as defined in numbered paragraph (45) or (46) above;
Y is as defined in numbered paragraph (48) or (49) above;
Ring B is as defined in numbered paragraph (51) or (52) above;
Integer b is as defined in numbered paragraph (54) or (55) above; and
Z is as defined in numbered paragraph (58) or (59) above.
[00130] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) above;
L is as defined in numbered paragraph (8) above;
Ring A is as defined in numbered paragraph (41) above;
Integer a is as defined in numbered paragraph (44) above;
Y is as defined in numbered paragraph (47) above;
Ring B is as defined in numbered paragraph (50) above;
Integer b is as defined in numbered paragraph (53) above; and
Z is as defined in numbered paragraph (58) above.
[00131] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) above;
L is as defined in numbered paragraph (15) above;
Ring A is as defined in numbered paragraph (42) above;
Integer a is as defined in numbered paragraph (44) above;
Y is as defined in numbered paragraph (48) above;
Ring B is as defined in numbered paragraph (51) above;
Integer b is as defined in numbered paragraph (53) above; and
Z is as defined in numbered paragraph (57) above.
[00132] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (6) above;
L is as defined in numbered paragraph (20) above;
Ring A is as defined in numbered paragraph (42) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (51) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (58) above.
[00133] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (7) above;
L is as defined in numbered paragraph (24) above;
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[00134] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (7) above;
L is as defined in numbered paragraph (26) above;
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
[00135] In an embodiment of the compounds of Formulae (I-XVI) to (I-XX):
X is as defined in numbered paragraph (7) above;
L is as defined in numbered paragraph (27) above;
Ring A is as defined in numbered paragraph (43) above;
Integer a is as defined in numbered paragraph (46) above;
Y is as defined in numbered paragraph (49) above;
Ring B is as defined in numbered paragraph (52) above;
Integer b is as defined in numbered paragraph (54) above; and
Z is as defined in numbered paragraph (59) above.
Particular embodiments of Formula (ll)
[00136] Compounds of the invention include those in which X is selected from -C(O)NRx- or -O-, ring A is as defined in numbered paragraph (43) above, integer a is as defined in numbered paragraph (46) above, Y is as defined in numbered paragraph (49) above, ring B is as defined in numbered paragraph (52) above, integer b is as defined in numbered paragraph (54) above, Z is as defined in numbered paragraph (59) above and Rx, L and Es are as defined herein. Such compounds have the Formula (II-1) or (lI-I) shown below:
EF CI
2e 0=8=0 0
CI Cra 0 Rx (11-1)
EF CI
0 0=8=0
Cl ore” LE,
Oo (11-11) wherein Ry, L and Ez are each as defined anywhere herein.
[00137] Suitably, the compound is a compound of the Formula (lI-I) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00138] Suitably, the compound is a compound of the Formula (lI-Il) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00139] In an embodiment of the compounds of Formula (II-1) or (III):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (8) to (27) above; and
Ez is as defined in any one of numbered paragraphs (28) to (40) above.
[00140] In an embodiment of the compounds of Formula (II-1) or (I1-1I):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (15) to (27) above; and
Es is as defined in any one of numbered paragraphs (30) to (40) above.
[00141] In an embodiment of the compounds of Formula (II-1) or (II-1I):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (20) to (27) above; and
Ez is as defined in any one of numbered paragraphs (34) to (40) above.
[00142] In an embodiment of the compounds of Formula (II-1) or (11-11):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in any one of numbered paragraphs (24) to (27) above; and
Es is as defined in any one of numbered paragraphs (36) to (40) above.
[00143] In an embodiment of the compounds of Formula (II-1) or (II-1I):
Rx, when present, is as defined in numbered paragraph (4) or (5) above;
L is as defined in numbered paragraph (26) or (27) above; and
Ez is as defined in any one of numbered paragraphs (38), (39) or (40) above.
[00144] In an embodiment of the compounds of Formula (II-1) or (11-11):
Rx, when present, is as defined in numbered paragraph (4) above;
L is as defined in numbered paragraph (8) above; and
Es is as defined in numbered paragraph (28) above.
[00145] In an embodiment of the compounds of Formula (II-1) or (III):
Rx, when present, is as defined in numbered paragraph (4) above;
L is as defined in numbered paragraph (15) above; and
Es is as defined in numbered paragraph (30) above.
[00146] In an embodiment of the compounds of Formula (II-1) or (III):
Rx, when present, is as defined in numbered paragraph (4) above;
L is as defined in numbered paragraph (20) above; and
Es is as defined in numbered paragraph (34) above.
[00147] In an embodiment of the compounds of Formula (II-1) or (III):
Rx, when present, is as defined in numbered paragraph (5) above;
L is as defined in numbered paragraph (24) above; and
Es is as defined in numbered paragraph (36) above.
[00148] In an embodiment of the compounds of Formula (II-1) or (III):
Rx, when present, is as defined in numbered paragraph (5) above;
L is as defined in numbered paragraph (26) above; and
Es is as defined in numbered paragraph (38) above.
[00149] In an embodiment of the compounds of Formula (II-1) or (III):
Rx, when present, is as defined in numbered paragraph (5) above;
L is as defined in numbered paragraph (27) above; and
Ez is as defined in numbered paragraph (40) above.
[00150] Compounds of the invention include those in which L is as defined in numbered paragraph (27) above, ring A is as defined in numbered paragraph (43) above, integer a is as defined in numbered paragraph (46) above, Y is as defined in numbered paragraph (49) above, ring B is as defined in numbered paragraph (52) above, integer b is as defined in numbered paragraph (54) above, Z is as defined in numbered paragraph (59) above and X,
Rx and Es are as defined herein. Such compounds have the Formulae (lI-111) to (II-XV) shown below: = F Cl 0=8=0
Cl NH Xa SSN „E3
N
CLT : o
(1-111) =F Cl ae 0=5=0
Cl CO eN „Es
H
0 (11-1) =F Cl HN-E,
F gs ~~ oP 0=S=0 N=N 0 0 (11-V)
F Cl i QA Es
NH
~~ ° 0=S=0 N=N 0 oy 0 (11-V1) =F Cl
F
HN-E, 0=5=0 N=N, ea
Orr 0 (11-VI1)
= FCI
Tl 0=8=0 H
OO
0 Oo (II-VIII) = FC
U
O=S=0 0
CI NH x 0 J cies 0 (11-1X) = F CI ge 0=8=0
OCO
0 (11-X) = FC ae 0=8=0
OCO
0 (11-X1)
E F CI
0 0=3=0 H
OLY Te
O
(1-X11)
E F CI
U
0=8=0
OCO
H
O
(H-XI111)
E F CI ae 0=8=0 O
OYE
H
O
(-XIV)
E F CI ae 0=8=0 O
COC
O
(l-XV) wherein X, Rx and Ez are each as defined anywhere herein.
[00151] Suitably, the compound is a compound of the Formula (I-III) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00152] Suitably, the compound is a compound of the Formula (lI-IV) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00153] Suitably, the compound is a compound of the Formula {lI-V} shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00154] Suitably, the compound is a compound of the Formula (II-VI) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00155] Suitably, the compound is a compound of the Formula (lI-VII) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00156] Suitably, the compound is a compound of the Formula (lI-VIII) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00157] Suitably, the compound is a compound of the Formula (lI-IX) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00158] Suitably, the compound is a compound of the Formula (lI-X) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00159] Suitably, the compound is a compound of the Formula (lI-XI) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00160] Suitably, the compound is a compound of the Formula (lI-XII) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00161] Suitably, the compound is a compound of the Formula (lI-XIll) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00162] Suitably, the compound is a compound of the Formula (lI-XIV) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00163] Suitably, the compound is a compound of the Formula (lI-XV) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00164] In an embodiment of the compounds of Formulae (II-lII} to (1I-XV):
X is as defined in numbered paragraph (6) or (7) above; and
Ez is as defined in any one of numbered paragraphs (28) to (40) above.
[00165] In an embodiment of the compounds of Formulae (I-III) to (1I-XV):
X is as defined in numbered paragraph (8) or (7) above; and
Es is as defined in any one of numbered paragraphs (30) to (40) above.
[00166] In an embodiment of the compounds of Formulae (I-III) to (1I-XV):
X is as defined in numbered paragraph (6) or (7) above; and
Es is as defined in any one of numbered paragraphs (34) to (40) above.
[00167] In an embodiment of the compounds of Formulae (II-lII} to (1I-XV):
X is as defined in numbered paragraph (6) or (7) above; and
Es is as defined in any one of numbered paragraphs (36) to (40) above.
[00168] In an embodiment of the compounds of Formulae (II-lII} to (1I-XV):
X is as defined in numbered paragraph (6) or (7) above; and
Ez is as defined in any one of numbered paragraphs (38), (39) or (40) above.
[00169] In an embodiment of the compounds of Formulae (I-III) to (1I-XV):
X is as defined in numbered paragraph (6) above; and
Es is as defined in numbered paragraph (28) above.
[00170] In an embodiment of the compounds of Formulae (I-III) to (1I-XV):
X is as defined in numbered paragraph (6) above; and
Es is as defined in numbered paragraph (30) above.
[00171] In an embodiment of the compounds of Formulae (lI-111) to (1I-XV):
X is as defined in numbered paragraph (6) above; and
Es is as defined in numbered paragraph (34) above.
[00172] In an embodiment of the compounds of Formulae (II-111) to (lI-XV):
X is as defined in numbered paragraph (7) above; and
Es is as defined in numbered paragraph (38) above.
[00173] In an embodiment of the compounds of Formulae (I-III) to (1I-XV):
X is as defined in numbered paragraph (7) above; and
Es is as defined in numbered paragraph (38) above.
[00174] In an embodiment of the compounds of Formulae (lI-111) to (1I-XV):
X is as defined in numbered paragraph (7) above; and
Es is as defined in numbered paragraph (40) above.
[00175] Compounds of the invention include those in which Es is as defined in numbered paragraph (39) above, ring A is as defined in numbered paragraph (43) above, integer a is as defined in numbered paragraph (46) above, Y is as defined in numbered paragraph (49) above, ring B is as defined in numbered paragraph (52) above, integer b is as defined in numbered paragraph (54) above, Z is as defined in numbered paragraph (59) above and X,
Rx and L are as defined herein. Such compounds have the Formulae (I1-XVI) to (lI-XX) shown below:
O
E F Cl HN
AG
‚N
Xo 0 0=8=0
LO
Oo Rq (XVI)
O
7)
Oo
E F Cl ! > > . Oo
F Xs 0=5=0
COO *
Oo (XVID
F Cl
F OH
F :
N
0=5=0 Oo ry O HN
Oo
SN
Sh (XVII)
= F Cl 0
Oo” dè H HN F 0=5=0 N_ Cl
CI NH Wes 7 LO)
F N
0
Cl (I-XIX) = F Cl
DO >
Oo” —q=— oO) HN—" F
CI NH X—L ,
LT LN
ID
CI
(11-XX) wherein X, Rx and L are each as defined anywhere herein.
[00176] Suitably, the compound is a compound of the Formula (lI-XVI) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00177] Suitably, the compound is a compound of the Formula (lI-XVII) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00178] Suitably, the compound is a compound of the Formula (lI-XVIII) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00179] Suitably, the compound is a compound of the Formula {lI-XIX) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00180] Suitably, the compound is a compound of the Formula (lI-XX) shown above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[00181] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (8) or (7) above; and
L is as defined in any one of numbered paragraphs (8) to (27) above.
[00182] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (6) or (7) above; and
L is as defined in any one of numbered paragraphs (15) to (27) above.
[00183] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (6) or (7) above; and
L is as defined in any one of numbered paragraphs (20) to (27) above.
[00184] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (8) or (7) above; and
L is as defined in any one of numbered paragraphs (24) to (27) above.
[00185] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (6) or (7) above; and
L is as defined in numbered paragraph (26) or (27) above.
[00186] In an embodiment of the compounds of Formulae (II-XVI) to (11-XX):
X is as defined in numbered paragraph (6) above; and
L is as defined in numbered paragraph (8) above.
[00187] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (6) above; and
L is as defined in numbered paragraph (15) above.
[00188] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (6) above; and
L is as defined in numbered paragraph (20) above.
[00189] In an embodiment of the compounds of Formulae (II-XVI) to (11-XX):
X is as defined in numbered paragraph (7) above; and
L is as defined in numbered paragraph (24) above.
[00190] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (7) above; and
L is as defined in numbered paragraph (26) above.
[00191] In an embodiment of the compounds of Formulae (II-XVI) to (lI-XX):
X is as defined in numbered paragraph (7) above; and
L is as defined in numbered paragraph (27) above.
[00192] Particular compounds of the invention (i.e., those of Formula (I) and Formula (I1)), or a pharmaceutically acceptable salt, hydrate or solvate thereof, include any of the following:
Oo
HN
Oo
Oo
N
Oo Oo ; TL
NT HN cl
H
Oo 0=8=0 i
CI F F
4-(4-chloro-2-({4-chloro-3-(trifluoromethyl) phenyl)sulfonamido) phenoxy)-N-(6-((2-(2,6- dioxopiperidin-3-yl}-1,3-dioxoiscindolin-4-yl)amino)hexylibenzamide
Oo
HN
Oo ©
N
Oo Oo
J TL
NO HN Cl
H Oo O0=8=0
CI F F
4-{4-chloro-2-({4-chloro-3-{trifluoromethyl}phenyl)sulfonamido)phenoxy)-N-{4-{{2-{2,8- dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4-yl)amino}butyhbenzamide
Cl EF
F 0
Q cl HN 0 HN-S ©
Oo Oo
NN! 0 N 0 o O 4-(4-chloro-2-({4-chloro-3-(trifluoromethyl)phenyl)sulfonamido}phenoxy)-N-((1-(2-(2-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yljamino)-2-oxoethoxy)ethoxy)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methyl)benzamide
©
HN
RF 7
Cl
F ij N
Ny N o
NN oY
Cl Ox 7 Oo “So
Or NH NH
AIA, 4-(4-chloro-2-({4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-((1-(2- (2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylyamino)-2-oxoethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-ylymethyl)benzamide cl EF
F 0
Q Cl HN
Oo HN-$ 0 © ©
N=N N
FAN N 0 0 © 4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-((1-(2-(2-((2-(2,6- dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethoxy)ethyl)-1H-1,2, 3-triazol-4- yhimethyl)benzamide
Cl
FE
NS, >
LNH ct Fg
F
FO” NH
Cl o pd 0 0=8=0 0 AN °
AO N ry
Oo“ N 0
H
(2R,3S,4R,5S)-N-(4-((1-{(4-(4-chloro-2-({(4-chloro-3- (trifluoromethyl) phenyl)sulfonamido)phenoxy)phenyl)-1-oxo-5,8,11-trioxa-2-azatridecan-13- ylhcarbamoyl)-2-methoxyphenyl)-3-(3-chloro-2-flucrophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamide
Rat a cl cl Ft
F F F
N uO
H HN
H O 0=$=0
SY
Ö H
Oo (2R,3S,4R,55)-N-(4-((2-(2-(2-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl)sulfonamido)phenoxy) benzamido)ethoxy)ethoxy)ethyl)carbamoyl)-2- methoxyphenyl)-3-(3-chloro-2-flucrophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamide
Oo
HN
Oo
Oo
N
Ort O
Oo oN
F3C Sí
Te
Cl Cl 4-chloro-N-(5-chloro-2-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4- ylhoxy)ethoxy)ethoxy)ethoxy)ethoxy)phenoxy)phenyl)-3-(trifluoromethyl)benzenesulfonamide pq TOT
HN
N. 4
Ss CF; ò Cl 4-chloro-N-(5-chloro-2-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4- yhoxy)ethoxy)ethoxy)ethoxy)phenoxy)phenyl)-3-(trifluoromethyljbenzenesulfonamide
Oo
HN >
CI F
©
F
Oo 0=8=0 0 HN i
OLY We
H
Oo 4-(5-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl) sulfonamido)phenoxy)-N-(2-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethaxy)ethoxy)et hyl)benzamide
Cl F E 0
F HN
© © 0=8=0 Oo H N
ROHN Raa 0
H
© 4-(4-chloro-2-{(4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4-yhamino}ethoxy)ethoxy)ethyl)benzamide
N
LY
S
Q F
HN. F 0 NH o F
N AO
N Oo N Oo re < ©
HO
(2S,4R)-1-((S)-12-(tert-butyl)-1-(4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl) sulfonamido)phenoxy)phenyl)-1,10-dioxo-5,8-dioxa-2,11-diazatridecan-13-oyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
N
> Cl
J ? HN. HF #7 0 NH, ; o oC
N Oo Oo
Sry TT No >N o
HO
(28,4R)-1-((S)-16-(tert-butyl)-1-(4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)phenyl)-1,14-dioxo-5,8,11-trioxa-2, 15-diazaheptadecan-17-oyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.
Salts, isomers and prodrugs
[00193] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phospharic, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[00194] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the
R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture”.
[00195] The compounds of this invention may possess one or more asymmetric centres;
such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers).
[00196] It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.
[00197] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.
[00198] It is also to be understood that certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.
[00199] It is also to be understood that certain compounds of invention may exhibit polymorphism, and that the invention encompasses all such farms that possess antiproliferative activity.
[00200] Compounds of the invention may exist in a number of different tautomeric forms and references to compounds of the invention include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by the compounds of the invention. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
Ho \ OH HH Oo
TA == STe = = keto enol enolate
[00201] Compounds of the invention containing an amine function may also form N- oxides. A reference herein to a compound of the invention that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a fertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid), see for example
Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
[00202] The compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the invention, and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the invention.
[00203] Accordingly, the present invention includes those compounds of the invention as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the invention that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the invention may be a synthetically-produced compound or a metabolically-produced compound.
[00204] A suitable pharmaceutically acceptable pro-drug of a compound of the invention is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
[00205] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. {Academic
Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);
fy N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium
Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
[00206] A suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the invention containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3- phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-0x0-1,3- dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and (1- 6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
[00207] A suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
An in vivo cleavable ester or ether of a compound of the invention containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1- 10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C).carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-{1-4C)alkylpiperazin-1- ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
[00208] A suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1-4C)alkylamine such as methylamine, a [{1-4C)alkyll2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1- 4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
[00209] A suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1-4C)alkyl)piperazin-1- ylmethyl.
[00210] The in vivo effects of a compound of the invention may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the invention. As stated hereinbefore, the in vivo effects of a compound of the invention may also be exerted by way of metabolism of a precursor compound (a pro-drug).
[00211] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
[00212] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.
Synthesis
[00213] The present invention provides a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[00214] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
[00215] The present invention also provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.
[00216] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
[00217] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.
[00218] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.
[00219] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.
[00220] For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
[00221] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
[00222] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a fert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
[00223] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
[00224] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
[00225] Resins may also be used as a protecting group.
[00226] Once a compound of invention has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the invention into another compound of the invention; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.
[00227] An example of (ii) above is when a compound of the invention is synthesised and then one or more of the groups may be further reacted to change the nature of the group and provide an alternative compound of the invention.
[00228] The resultant compounds of the invention can be isolated and purified using techniques well known in the art.
[00229] The compounds of the invention may be synthesised by the general synthetic routes shown in the Examples section below, specific examples of which are described in more detail in the Examples.
Biological Activity
[00230] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.
[00231] Although the pharmacological properties of the compounds of the invention vary with structural change, as expected, the compounds of the invention were found to be active in the assays described in the Examples section.
Pharmaceutical Compositions
[00232] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
[00233] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol}, for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
[00234] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
[00235] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
[00236] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
[00237] The size of the dose for therapeutic or prophylactic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
[00238] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
Therapeutic Uses and Applications
[00239] The present invention provides a method of treating a proliferative condition, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[00240] The present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[00241] The present invention provides a method of treating a disease or condition in which CCR2 activity is implicated, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[00242] The present invention provides a method of inhibiting CCR2 activity, in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[00243] The present invention provides a method of treating immunoinflammatory pathologies, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[00244] The present invention provides a method of treating cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g., Alzheimer's disease, ataxia,
Huntington's disease, Parkinson's disease, motor neurone disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease and spinal muscular atrophy), hepatic fibrosis and/or rheumatoid arthritis, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[00245] The present invention provides a method of treating cancer, in particular tumorigenesis and metastasis, said method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.
[00246] In an embodiment, the subject is warm-blooded animal, such as man.
[00247] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[00248] The present invention provides a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.
[00249] The present invention provides a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in inhibiting cell proliferation.
[00250] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or condition in which CCR2 activity is implicated.
[00251] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in inhibiting CCR2 activity.
[00252] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of immunoinflammatory pathologies.
[00253] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g., Alzheimer's disease, ataxia, Huntington's disease,
Parkinson's disease, motor neurone disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease and spinal muscular atrophy), hepatic fibrosis and/or rheumatoid arthritis.
[00254] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of cancer, in particular tumorigenesis and metastasis.
[00255] The present invention provides the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.
[00256] The present invention provides the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for inhibiting cell proliferation.
[00257] The present invention provides the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or condition in which CCR2 activity is implicated.
[00258] The present invention provides the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in inhibiting CCR2 activity.
[00259] The present invention provides the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of immunoinflammatory pathologies.
[00260] The present invention provides the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g., Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neurone disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease and spinal muscular atrophy), hepatic fibrosis and/or rheumatoid arthritis.
[00261] The present invention provides the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer, in particular tumorigenesis and metastasis.
[00262] The term "proliferative disorder" and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers (including breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary), lymphomas (including diffuse large B-cell lymphoma (DLBCL),
B-cell acute lymphoblastic lymphoma (B-ALL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), which includes T-cell acute lymphoblastic leukaemia (T-
ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)), multiple myeloma lymphomas (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lymphatic, blood, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.
[00263] Particular proliferative disorders of interest are haematological cancers, such as, for example, lymphomas (including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), which includes T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)) and multiple myeloma.
Diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), angioimmunoblastic T-cell lymphoma (AITL), T-cell acute lymphoblastic leukaemia (T-ALL), and acute myeloid leukaemia (AML) are of particular interest.
[00264] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
Routes of Administration
[00265] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e, at the site of desired action).
[00266] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
Combination Therapies
[00267] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlarambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea), antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists {for example goserelin, leuprorelin and buserelin), steroid hormones, including progestogens (for example megestrol acetate) and corticosteroids (for example dexamethasone, prednisone and prednisolone), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; (iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino}-7-[2-(4-methylpiperazin-1-yhethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2-chloro-6- methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5- carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-806), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase); (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro- 4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI
1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-2006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, PIt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152,
PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; (v)} antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-8-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin)); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
[00268] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti- tumour agents selected from cyclophosphamide, epirubicin, fluorouracil, methotrexate, mitomycin C, doxorubicin, gemcitabine, docetaxel, carbazitaxel and radium-223 dichloride.
[00269] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti- hormonal agents selected from a selective estrogen receptor modulator (SERM) (e.g., tamoxifen or toremifene), an aromatase inhibitor (Al) {e.g., anastrozole, fadrozole, letrozole or exemestane), a selective estrogen receptor degrader (SERD) (e.g., fulvestrant, elacestrant or GDC-0810), a luteinising hormone (LH) blocker (e.g., goserelin), direct androgen receptor (AR) antagonist (e.g., bicalutamide, enzalutamide, apalutamide, darolutamide, cyproterone acetate or flutamide), a non-competitive AR antagonist (e.g.., ralaniten acetate), an androgen steroid synthesis inhibitor (e.g., abiraterone acetate), a gonadotropin-releasing hormone (GNRH) modulator (e.g., leuprorelin, goserelin, buserelin, triptorelin, degarelix).
[00270] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or cell-cycle agents selected from a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor (e.g., palbociclib, ribociclib or abemaciclib).
[00271] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or DNA damage response agents selected from a poly ADP ribose polymerase (PARP) inhibitor (e.g., olaparib, veliparib, rucaparib or niraparib).
[00272] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more cell signalling agent(s) selected from a phosphatidylinositol 3 kinase (PI3K) inhibitor, (e.g., buparlisib, apitolisib, azd8186, omipalisib, duvelisib, gedatolisib, copanlisib, pictilisib, alpelisib, idelalisib, acalisib, serabelisib, pilaralisib or taselisib), an AKT inhibitor (e.g.,
MK2206, AZD5363, afuresertib, AT13148, miransertib or ipatasertib); a (mTOR) signaling pathway inhibitor {e.g., everolimus, sirolimus, temsirolimus, vistusertib, sapanisertib or ridaforolimus), a Fibroblast growth factor (FGF) signalling inhibitor (e.g., AZD4547 or dovitinib).
[00273] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti- tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
[00274] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more chemotherapeutic agents selected from a BCL-2 family inhibitor (e.g., Venetoclax and/or navitoclax), a BTK inhibitor (e.g., Ibrutinib, Acalabrutinib, Tirabrutinib (ONO/GS-4059), BGB- 3111 or Spebrutinib (CC-292) or a TNF inhibitor (e.g., Lenalidomide).
[00275] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
[00276] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, and another anti-tumour agent.
[00277] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, and any one of the anti-tumour agents listed herein above.
[00278] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
[00279] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
[00280] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, in combination with an anti- tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
EXAMPLES
[00281] One or more examples of the invention will now be described, for the purpose of illustration only, with reference to the accompanying figures, in which:
Fig.1 shows (A) the chemical structure of CCR2 allosteric ligand; (B) the chemical structure of employed E3 ligase ligands; and (C) the proposed design of CCR2 PROTACS;
Fig. 2 shows xCELLigence assay demonstrates varying permeability of the synthesized
CCR2 PROTACs. PROTACSs displaying equal to or less than 50% response demonstrated sufficient enough permeability to bind and inhibit CCR2;
Fig. 3 shows HiBit assays demonstrate a rapid dose-dependent degradation of CCR2;
Fig. 4 shows HiBit assays demonstrate a reduced degradation of CCR2 by the control
PROTACs LUF8138 and 8139. The parent ligand LUF8064 did not display any degradation of CCR2; and
Fig. 5 shows CellTiter Glo cell viability assay demonstrated that the active and control CCR2
PROTACSs do not significantly reduce cell viability.
Results and discussion
Design and synthesis of CCR2 PROTACSs
[00282] Previous work on discovering novel intracellular CCR2 ligands identified 1 (Figure 1A) as a potent CCR2 ligand. By examining the binding mode of 1 it was observed that the carboxylic acid moiety is solvent exposed rendering it a suitable exit vector for CCR2
PROTACSs. The synthesis and SAR of 1 has been previously disclosed and will not be addressed further. Regarding E3 ligase recruiters, the majority of current PROTACs employ
VHL, CRBN and to a lesser extent MDM2. This choice of E3 ligase is attributed to their ubiquitous expression in many cell lines and commercial availability of potent and selective small molecule binders that target them. Moreover, designing PROTACSs recruiting different
E3 ligases improves the chances of discovering a degrader due to the formation of a different ternary complex with each E3 ligase. Accordingly, thalidomide derivatives, 2a and Idasanutlin 2b (Figure 1B) were selected as recruiters for CRBN, VHL and MDM2, respectively. It is noteworthy that the majority of the designed CCR2 PROTACSs recruit CRBN due to its highest rate of success in PROTAC campaigns. Based on the mentioned ligands, CCR2
PROTACs comprised of 1 tethered by a linker to the different E3 ligase ligands (Figure 1C) were designed. Multiple series of CCR2 PROTACSs based on the recruited E3 ligase were synthesised.
[00283] The initial HaloTag results demonstrated that VHL is capable of degrading
CCR2. Thus, series 1 of CCR2 PROTACs employed VHL ligand 2a. Synthesis of series 1 (Scheme 1) was achieved by an initial Fmoc deprotection of Fmoc and t-butyl protected 2a followed by amide coupling with the corresponding Fmoc protected PEG-diamine linkers to obtain 3 and 4. Fmoc deprotection followed by PyBOP-mediated amide coupling followed by a TFA deprotection of the t-butyl group gave PROTAC 5 (XIN-103) and 6 (XIN-108) in moderate yields.
S
N
Y oF s ab NH 0 NH Oo Fmoc ° i H
N 0 0 ‚F
SE Abert \ 0 x 3 n,=0, n2=0 4 n,=1, n2=1
N
} S Cl s 9 F acd HN. F 0 NH Ó F ? nH cl
N 0 A Je
Oer
HO
6 n,=0, ny=0 (XIN-103) 6n,=1, ny=1 (XIN-108) 2Scheme 1. Synthesis of CCR2 PROTACSs series 1
Reagents and conditions: (a) 50% Diethylamine/ACN, (v/v); rt, 3h; (b) Fmoc-PEG:»-
CH:COOH or Fmoc-PEG3-COOH, HCTU, DIPEA, DMF, rt, 18h; 3 84%, 4 86% yield; (c)
PyBOP, DIPEA, DMF, rt, 18h; (d) TFA, tt, 1h, § 43%, 6 38% yield
[00284] Series 2-5 focused on CRBN recruiters and varied in linker composition, length, and functional group of linker attachment point. Series 2 (Scheme 2) employed alkyl chain linkers of 4 and 6 methylene units. Nucleophilic aromatic substitution of Boc-protected diamino alkanes and F-thalidomide yielded intermediates 9 and 10. Boc-deprotection followed by HATU-enabled amide coupling with 1 resulted in PROTAC 13 (LUF7995) and 14 (LUF7996) in moderate to excellent yields.
0 oo F CS d rj n=1 9 n=1 n=2 10 n=2 o FF 2 NH (Co ed b Cf c NN Cb $ - tn od
LEA N PA LT a 0 11 n=1 13 n=1 (LUF7995) 12 n=2 14 n=2 (LUF7996)
Scheme 2. Synthesis of CCR2 PROTACSs series 2
Reagents and conditions: (a) DIPEA, DMF, 90 °C, 18h, 9 19% yield, 10, crude; (b) TFA, rt, 1h, 11 crude, 12 46% (over two steps) yield; (c) 1, HATU, DIPEA, DMF, rt, 2h, 13 quant, 14 55% yield
[00285] The effect of including a rigid linkage moiety in the CCR2 PROTACs was evaluated. Series 3 (Scheme 3) was designed and employed a triazole ring in the central region of the linker. This was achieved through a modular synthetic approach. 1 was initially equipped with an alkyne moiety through EDC amide coupling to obtain 15. The left-hand side required the synthesis of a functionalized PEG linker. Tetra-, tri-, and di-ethylene glycol were first selectively tosylated to furnish 16-18 followed by their azidation to obtain 19-21 using sodium azide in refluxing acetonitrile. Jones oxidation of the intermediates provided linkers 22-24 in moderate yields. Converting the carboxylic acids into acid chlorides followed by their amide coupling reaction with pomalidomide resulted in building blocks 25-27. Azide-alkyne click reaction of 15 with 25-27 gave PROTACs 28-30 (LUF8001, LUF8004 and LUF8005) in good yields.
oO
Hof kon + Th oo > ne on 4, nh of Hou n=1 16 n=1 19 n=1 22 n=1 n=2 17 n=2 20 n=2 23 n=2 n=3 18 n=3 21 n=3 24 n=3
E F Cl E F Cl o “0 “0 nh oA 0 Q a " NH o=s=0 Q o=$=0 0 + CI
OY COS na y n= © 0 26 n=2 15 27 n=3
RF ml cl
Cl
Os
Ss
Od ° 0
Oo HN 0 a 0
HN 0 2
A Lot A Ao
N AT
28 n=1 (LUF8001) 29 n=2 (LUF8005) 30 n=3 (LUF8004)
Scheme 3. Synthesis of CCR2 PROTACSs series 3
Reagents and conditions: (a) EDC-HCI, HOBt, propargylamine, DIPEA, DMF, 0 °C-rt, 18h, 92% yield; (b) TsCl, TEA, DCM, 0 °C-rt, 18h, 73-83% yield; (c) NaN3, MeCN, reflux, 18h, 70- 83% yield; (d) Jones reagent, Acetone, 0 °C-rt, 18h, 41-69% yield; (e) (i) SOCI,, 65°C, 1h; (ii)
Pomalidomide, dry THF, reflux, 18h, 51-86% yield; (f) CuSO:.5H20, (+)-Na L-ascorbate,
H:O, tBuOH, DCM, rt, 1h, 49-53% yield
[00286] Series 4 (Scheme 4) aimed at employing PEG linkers that are connected to pomalidomide by a secondary amine. This modification would allow for evaluation of the effect of amide and amine-connecting functionalities on the CCR2 PROTAC permeability.
This was achieved by amide coupling of Boc-protected 2- and 3-PEG diamine linkers 31-32 to 1, yielding 33-34. Boc deprotection (35-36) followed by a SNAr achieved 37 (LUF8056) and 38 (LUF8055) in low yields. This was attributed to formation of multiple side products that led to purification difficulties during the final step.
rf 9 mi 2 a She ER
LF a UT
EN = ~ o:$:0 ©
SENN ò wo he gi ©
Scheme 4. Synthesis of CCR2 PROTACSs series 4
Reagents and conditions: (a) Boc2O, DCM, 0°C-rt, 18h, 31 49%, 32 64% yield; (b) HATU,
DIPEA, DMF, rt, 2h, 33 45%, 34 52% yield; (c) 4N HCI in dioxane, MeOH, rt, 3h. 98% yield; (d) DIPEA, DMSO, 90 °C,3-18h,37 6%, 38 2% yield
[00287] Substituting the linker-connecting functional groups from amides to esters has been shown to lead to an improvement in PROTAC permeability as a result of increased lipophilicity. An improvement in PROTAC permeability can thus be advantageous to successful PROTAC development. Accordingly, series 5 (Scheme 5) was designed and connects to the POI and ES ligase ligand through an ether linkage. The synthetic route starts with a Williamson etherification between hydroquinone and 39 to achieve 40 in good yields.
A second etherification step between 40 and 17-18 yielded 41-42 in moderate to good yields.
Tosylation of the PEG linker (43-44) followed by reaction with O-thalidomide under basic conditions to obtain 45-46. Reduction of the Nitro group using Tin chloride afforded 47-48.
The final sulfonamide forming step was done using Pyridine and catalytic DMAP that yielded 49 (LUF8062) and 50 (LUF8063) in moderate yields.
2 NO, NO, et . 0 a ee TaghOing, Be AO Co = a HOT >” aS Sey " aS Mofo 39 40 1 ni 41n=2 ’ 42 n=3 0
NK
OK} cl
NO, OH OQ o, Jee 0:8:0 aS AGI os Sey Nt OT voor Y XY ° we n Oo os” SF 3 ì 43 n=2 RL cl ns ï » 45 R= NO, n=2 47 R= NH n=2< 1°
GSI
0
HN-4 0% è
ON
CYS EU 49 n=2(LUF8062) a Yr 50 n=3 (LUF8063)
CF, al
Scheme 5. Synthesis of CCR2 PROTACS series 5
Reagents and conditions: (a) K2CO3, DMF, 110 °C, 2h, 86% yield; (b) K2CO3, Kl (cat), DMF, 60 °C, 24h, 41 74%, 42 44% yield; (c) TSC, TEA, DMAP (cat), DCM, rt 43 86%, 44 55% yield; (d) K2CO3, DMF, 40-60 °C, 18h, 46 31%, 47 41% yield; (e) SnClz.2H20, EtOAc, 40 °C, 18h; (f) DMAP (cat), Py, rt, 2h, 49 37%, 50 30% (over two steps)
[00288] The effect of recruiting MDM2 on CCR2 targeted degradation was investigated.
Idasanutlin is a potent {ICss= 6nM) inhibitor of MDM2 currently being evaluated in clinical trials for different cancers. Thus, it can be advantageous as an E3 recruiter in CCR2
PROTAC:s where a dual effect (CCR2 degradation and MDM2 inhibition) can be useful in the context of CCR2-related cancer indications. This led to the design of series 6 (Scheme 8) which was achieved by Boc deprotection of 35-36 followed by a HATU-mediated amide coupling to yield 51 (LUF8014) and 52 (LUF8013).
Ef Cl! M Ea Ch o H. 3
Ay DE TN, SNS 97 me H al a Ao ~~ oi A wf Ta osss0 © * NE B! SN oo Hi ? J J TN
Or Sr HA A EO Ho. A. Ao OE >= FN For N
Sg ó 1 a 7 raf ore 35n=2 51 n=2 (LUF8014) 36n=3 52 n=3 (LUF8013)
Scheme 6. Synthesis of CCR2 PROTACSs series 6
Reagents and conditions: (a) HATU, DIPEA, DMF, tt, 1h, 51 45%, 52 47% yield
Binding affinity of CCR2 PROTACs. CCR2 PROTACSs exhibit reduced yet sufficient binding to CCR2
[00289] The binding affinity of the synthesized CCR2 PROTACs to CCR2 was evaluated in a radioligand binding assay. This was carried out to assess the effect of incorporating 1 into a PROTAC on CCR2 binding. The assay utilized isolated membranes from U20S cells that stably express hCCR2b. Tritiated CCR2-RA-[R] was used as the radioligand probe based on the previously characterized allosteric CCR2 antagonist, CCR2-RA-[R].
Competition of CCR2 PROTACs at 10 pM with [°H]-CCR2-RA-[R] was measured. The parent ligand (1, LUF8084) displaced CCR2-RA-[R] with a binding affinity of K= 7 nM displaying strong affinity to CCR2. VHL- and CRBN-recruiting CCR2 PROTACSs displayed reduced yet moderate affinity to CCR2 (Kirange= 130-780 nM) in comparison to the parent ligand.
LUF8004 and 7995 displayed the highest affinity to CCR2 with K; of 130 and 138, respectively. XIN-103 (K=780) and LUF7996 (Ki=560) displayed the lowest affinities in the
VHL- and CRBN-recruiting series. MDM2-recruiting CCR2 PROTACs displayed lower in affinities to CCR2 with linkers of similar length to the VHL and CRBN-recruiting PROTACSs. © Compound pK: SEM (Ki, nM)? or displacement at 10 uM (%)° © LUFsoe4 ~~ 82x010(n
XIN-103 6.1 £0.01 (780)
XIN-108 6.6 £ 0.03 (274)
LUF7995 6.9 + 0.07 (138)
LUF7996 6.3 £0.11 (560)
LUF8001 6.7 t 0.05 (203)
LUF8004 6.9 + 0.03 (130)
LUF8005 8.7 £0.10 (219)
LUF8055 6.4 +£0.09 (474)
LUF8056 6.4 £0.03 (417)
LUF8062 6.5 + 0.10 (339)
LUF8063 6.5 + 0.09 (344)
LUF8131 6.8 + 0.04 (165)
LUF8013 14% (12, 17)
LUF8014 18% (18, 17)
LUF8138 6.4 £0.02 (427)
LUF8139 6.7 £0.03 (197)
Table 1. Binding affinities determined in [*H]-CCR2-RA-[R] displacement assays in
U20S-CCR2 membranes “Data are presented as mean pK; + standard error of the mean (SEM) and mean K; (in nM) of at least three individual experiments performed in duplicate. *Values represent mean percentage displacement of [FH]-CCR2-RA-[R] by 10 uM of compound obtained in two individual experiments. Data from individual experiments are shown in brackets
General methods and synthesis
[00290] All solvents and reagents were purchased from commercial sources and were used without further purification. *H and '3C NMR spectra were recorded on a Bruker AV 400
MHz liquid, Bruker AV 400 MHz wide bore, Bruker AV 500 MHz, and Bruker AV 600 MHz at room temperature (rt) using CDCls, MeOD, or DMSO as a solvent. Chemical shifts are reported in ppm relative to internal standard tetramethylsilane (TMS) or solvent resonance.
Purity of the compounds was determined by HPLC with a C18 column (50 x 4.6 mm, 3 Hm), flow rate = 1.3 mL/min, using a gradient of 10-90% MeCN/HzO (0.1% FA) and measuring UV absorbance at 254 nm. Purity of all final compounds used in biological assays was at least 95%. Reactions were monitored by TLC using Merck TLC Silica gel 60 F254 aluminum sheets. Compounds were visualized by UV irradiation or by staining with a KMnO, solution in
H2O. For the flash chromatography, Davisil silica gel (40-63 um) was used. The automatic flash chromatography was performed on an Isolera One Automatic Flash Chromatography
System by Biotage with pre-packed flash cartridges (Biotage Sfar D). Automated reverse phase chromatography was performed using HPL-grade acetonitrile and demi water, both containing 0.1% TFA as the eluent system. Mass spectra were measured using a Shimadzu
Prominence LC-MS-2020 system and a Gemini C18 Phenomenex column (50 x 3 mm, 3
Um). tert-butyl (6-((2-(2,8-dioxopiperidin-3-y1-1,3-dioxoisoindolin-4-ylamino)hexyl)carbamate ©
Ce
Oo
N 9 H Oo gek
[00291] In a round bottom flask, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (12) (150 mg, 0.54 mmol, 1.00 eq.) and tert-butyl (6-aminchexyl)carbamate (130 mg, 0.60 mmol, 1.10 eq.) were dissolved in 7.5 mL DMF. Subsequently, DIPEA (0.14 mL, 0.60 mmol, 1.10 eq.) was added. The mixture was allowed to stir at 90°C overnight. Upon completion, the reaction mixture concentrated in vacuo, re-dissolved in 10 mL EtOAc and poured into 50 mL H2O. The product was extracted with EtOAc (4x50 mL). The combined organic layers were washed with H2O (3x10 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was used in the next step without further purification.
[00292] LC-MS ((ESD) [M + H]+ calculated: 473.24; Found: 473.15 (M+H), 373.05 (M+H-
Boc). tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yamino)butyl)carbamate
Oo
CF
Oo
N 9 Oo
AL nnd
H
[00293] In a round bottom flask, 2-{2,8-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (12) (150 mg, 0.54 mmol, 1.00 eq.) and tert-butyl (4-aminobutyl)carbamate (113 mg, 0.60 mmol, 1.10 eq.) were dissolved in 7.5 mL DMF. Subsequently, DIPEA (0.19 mL, 1.09 mmol, 2.00 eq.) was added. The mixture was allowed to stir at 90°C overnight. Upon completion, the reaction mixture was concentrated in vacuo, re-dissolved in 10 mL EtOAc and poured into 50 mL HzO. The product was extracted with EtOAc (4x50 mL). The combined organic layers were washed with H2O (3x10 mL) and brine (1x50 mL}, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography (1-3% MeOH/DCM) to tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl}amino)butylhcarbamate as a bright green oil.
[00294] Yield: 46 mg, 0.10 mmol, 19%. 'H NMR (400 MHz, MeOD) ò 7.96 (s, 1H), 7.51 (dd, J=8.5,7.2 Hz, 1H), 7.01 (dd, J = 7.8, 4.7 Hz, 2H), 6.62 (t, 1H), 6.42 (t, J = 5.8 Hz, 1H), 5.04 (dd, J = 12.5, 5.4 Hz, 1H), 3.35 —- 3.30 (m, J = 4.2, 3.0 Hz, 2H), 3.12-3.01 (m, J = 12.4, 5.7 Hz, 2H), 2.90 — 2.61 (m, 3H), 2.16 — 2.03 (m, 1H), 1.70 — 1.50 (m, 4H), 1.41 (s, 9H); LC-
MS (ESI) m/z [M + Na]* calculated for C22H2sN4Os: 467.20; found: 467.10. tert-butyl (6-((2-(2,6-dioxopiperidin-3-yl-1,3-dioxoisoindolin-4-yl}amino}hexylcarbamate 0)
CF
Oo
N Oo
Ann
NH,
[00295] 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14b) In a round bottom flask, tert-butyl (6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yhamino}hexyhcarbamate (13b) (139 mg, 0.29 mmol, 1.00 eq.) was dissolved in 10 mL TFA.
The mixture was allowed to stir at RT for 1h. Upon completion, the reaction mixture was diluted with 20 mL DCM and concentrated in vacuo. The crude was purified by silica gel column chromatography (15-18% MeOH/DCM) to obtain tert-butyl (6-((2-(2,6-dioxopiperidin- 3-yh-1,3-dioxoisoindolin-4-yhamino)hexyl)carbamate as a green oil.
[00296] Yield: 104 mg, 0.28 mmol, 46% over two steps. ’H NMR (400 MHz, MeOD) ò 7.54 (t, J= 7.8 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 7.02 (s, 1H), 5.05 (dd, J = 12.5, 5.4 Hz, 1H), 3.36 — 3.32 (m, 2H), 2.92 (t, 2H), 2.89 — 2.62 (m, 3H), 2.16 — 2.06 (m, 1H), 1.73 —1.63 (m, 4H), 1.45 (dd, J = 15.2, 12.1 Hz, 4H); LC-MS (ESI) m/z [M + H]" calculated for C19H24N4O:: 373.18; found: 373.05. 4-{(4-aminobutyhamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ©
CF
©
N ©
NH,
[00297] In a round bottom flask, tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl}amino}butylhcarbamate (13a) (46 mg, 0.10 mmol, 1.00 eq.) was dissolved in 3 mL TFA. The mixture was allowed to stir at RT for 1h. Upon completion, the reaction mixture was diluted with 6 mL DCM and concentrated in vacuo to obtain the 4-((4- aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound as an TFA salt.
The crude product was used in the next step without further purification. 4-{4-chloro-2-({4-chloro-3-(trifluoromethylyphenyl)sulfonamido) phenoxy)-N-(6-((2-(2,6- dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4-ylJamino)hexyl\benzamide
© 27
Oo
Oo
N
Oo Oo
Ca
N HN Cl
Oo O=8=0
Cl F F
[00298] In a round bottom flask, 4-{(6-aminohexyl}amino)-2-(2,6-dioxopiperidin-3- yhisoindoline-1,3-dione (34 mg, 0.09 mmol, 1.00 eq.) was dissolved in 10 mL DMF followed by the addition of HATU (51 mg, 0.18 mmol, 1.50 eq.), DIPEA (0.05 mL, 0.27 mmol, 3.00 ed.) and 4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)phenoxy)benzoic acid (51 mg, 0.18 mmol, 1.50 eq.) (dissolved in 10 mL DMF). The mixture was allowed to stir at
RT for 2h. Upon completion, the reaction mixture was concentrated in vacuo, redissolved in 20 mL EtOAc, and poured into 100 mL H2O and the product was extracted with EtOAc (4x20 mL). The combined organic layers were washed with) H2O (5x20 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography (0-6% MeOH/DCM) to obtain 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)}phenoxy)-N-(6-((2-(2,8-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl}amino)hexyl}benzamide as a green oil.
[00299] Yield: 39.5 mg, 0.05 mmol, 51. ’H NMR (500 MHz, CDCls) ò 8.38 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.4, 2.2 Hz, 1H), 7.69 (d, J = 5.6 Hz, 1H), 7.63 (dt, 2H), 7.55 (s, 1H), 7.53 — 7.46 (m, 2H), 7.11 - 7.02 (m, 2H), 6.87 (d, J = 8.6 Hz, 1H), 8.71 (d, J = 8.0
Hz, 1H), 6.61 (dt, 2H), 6.23 (t, J = 4.9 Hz, 2H), 4.95 - 4.84 (m, 1H), 3.44 (q, J = 13.4, 6.5 Hz, 2H), 3.27 (q, J = 12.5, 6.7 Hz, 2H), 2.90 — 2.67 (m, 3H), 2.15-2.08 (m, J = 7.8, 6.4, 4.0 Hz, 1H), 1.71 (s, 2H), 1.70 — 1.59 (m, J = 24.5, 14.1, 7.0 Hz, 4H), 1.52 — 1.40 (m, 4H), 13C NMR (101 MHz, CDCls) 8 171.3, 169.6, 168.7, 167.6, 166.4, 158.2, 147.0, 145.5, 138.2, 137.7, 136.2, 132.4, 132.4, 131.4, 130.5, 130.1, 129.5, 129.0, 128.5, 126.8, 126.5, 123.8, 123.2, 120.4, 120.2, 117.2, 116.7, 111.5, 109.8, 48.9, 42.5, 40.0, 38.6, 36.5, 31.4, 29.5, 29.0, 26.6, 22.8; LC-MS (ESI) m/z [M + H]* calculated for C39H34Cl2F3Ns5OsS: 860.15; found: 860.10. 4-{4-chloro-2-({4-chloro-3-{trifluoromethyl}phenyl)sulfonamido)phenoxy)-N-{4-({2-(2,6- dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4-yl}amino)butyl)benzamide
Oo 2
Oo
Oo &
Oo Oo
OE
KD Cl
Oo O0=8=0
Cl F F
[00300] In a round bottom flask, 4-{(4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3- yhisoindoline-1,3-dione (34 mg, 0.10 mmol, 1.00 eq.) was in dissolved in 10 mL DMF followed by addition of HATU (45 mg, 0.15 mmol, 1.50 eq.), DIPEA (0.05 mL, 0.30 mmol, 3.00 eq.) and 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl) phenylsulfonamido)phenoxy)benzoic acid (76 mg, 0.15 mmol, 1.50 eq.) (dissolved in 10 mL DMF). The mixture was allowed to stir at RT for 2h. Upon completion, the reaction mixture was concentrated in vacuo, redissolved in 20 mL EtOAc, and poured into 100 mL H2O and the product was extracted with EtOAc (4x20 mL). The combined organic layers were washed with 5x20 mL H.O (5X20 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography (1-6% MeOH/DCM) to obtain 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl)sulfonamido}phenoxy)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl}amino)butyl)benzamide as a green oil.
[00301] Yield over 2 steps: 84.7 mg, 0.10 mmol, 100%. 'H NMR (500 MHz, CDCl) d 8.63 (s, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 8.4, 2.2 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.64 (dt, J =8.7 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.3, 7.3 Hz, 1H), 7.09 (dd, J = 7.1, 3.6 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 6.62 (dt, J = 8.8 Hz, 2H), 6.48 (t, J = 5.8 Hz, 1H), 6.25 (t, J = 5.6 Hz, 1H), 4.98 — 4.88 (m, 1H), 3.50 (q, J = 5.8 Hz, 2H), 3.33 (q, J = 5.6 Hz, 2H), 2.91 — 2.68 (m, 3H), 2.16 — 2.09 (m, 1H), 1.80 — 1.72 (m, J = 2.8 Hz, 4H), *C NMR (101 MHz, CDCls) ò 171.8, 169.6, 169.1, 167.7, 166.6, 158.3, 146.8, 145.6, 138.3, 137.7, 136.2, 132.4, 132.3, 131.4, 130.1, 130.1, 129.5, 129.1, 128.6, 126.7, 126.5, 123.9, 123.2, 120.5, 120.2, 117.1, 116.8, 111.6, 109.8, 48.8, 42.1, 39.8, 31.3, 29.7, 27.0, 26.5, 22.7; LC-MS (ESI) m/z [M + H]" calculated for
C37H30Cl2F3NsOs8S: 830.12; found: 830.10. 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
On 7
C+ © © % © F
[00302] lodomethane (0.181 mL, 2.896 mmol) was added dropwise to 2-(2,6- dioxopiperidin-3-yl)-4-fluorcisoindoline-1,3-dione (200 mg, 0.724 mmol) and potassium carbonate (200 mg, 1.448 mmol) in DMF (7 mL). The reaction mixture was stirred at room temperature for 2h. Upon reaction completion, water (50 mL) was added, and the reaction mixture was extracted with EtOAc (2x 100 mL). The organic phase was dried over magnesium sulfate and the organic layers were evaporated under reduced pressure. The crude mixture was purified by flash column chromatography using a gradient of 1-7%
MeOH/DCM to obtain to obtain 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)iscindoline-1,3- dione (125 mg, 0.431 mmol, 59.5 % yield) as a white solid.
[00303] 'H NMR (400 MHz, CDCls) 8 7.79 (ddd, J = 8.3, 7.4, 4.3 Hz, 1H), 7.74 — 7.68 (m, 1H), 7.44 (td, J = 8.5, 0.9 Hz, 1H), 5.11 -4.92 (m, 1H), 3.20 (s, 3H), 3.05 — 2.93 (m, 2H), 2.83-2.72 (m, 1H), 2.22 — 2.09 (m, 1H). LC-MS (ESI) m/z [M + H]* calculated for
C14H41FN2O4: 291.07; found: 291.05. tert-butyl (6-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yhamino)hexyhcarbamate (KE179) un 20°C
O. / © © % © NH
[00304] In a 10 mL flask, 4-fluoro-2-{1-methyl-2,6-dioxopiperidin-3-yhisoindoline-1,3- dione (60.0 mg, 0.207 mmol) and tert-butyl (6-aminohexyl)carbamate (0.051 mL, 0.227 mmol) were were dissolved in DMF (2 mL) followed by addition of DIPEA (0.036 mL, 0.207 mmol). The reaction mixture was stirred at 90 °C overnight. Upon reaction completion, water (20 mL) was added, and the reaction mixture was extracted with EtOAc (2x 30 mL). The organic phase was dried over magnesium sulfate and the organic layers were evaporated under reduced pressure. The crude product was used further in the next step without purification.
tert-butyl (4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoiscindolin-4- yhamino)butyl)carbamate un BC
Oo
Oo 4]
Oo NH 5 [00305] In a 10 mL flask, 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (60.0 mg, 0.207 mmol) and tert-butyl (4-aminobutyl)carbamate (0.047 mL, 0.248 mmol) were dissolved in DMF (2 mL) followed by addition of DIPEA (0.036 mL, 0.207 mmol). The reaction mixture was stirred at 90 °C overnight. Upon reaction completion, water (20 mL) was added, and the reaction mixture was extracted with EtOAc (2x 30 mL). The organic phase was dried over magnesium sulfate and the organic layers were evaporated under reduced pressure. The crude product was used further in the next step without purification. 4-{(6-aminohexyl}amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
NH,
A 7
Oo © ke
Oo NH
[00306] Ina 10 mL flask, tert-butyl (6-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino}hexyl)carbamate (18.00 mg, 0.037 mmol) was dissolved in TFA (2 mL, 26.0 mmol) and the mixture was stirred at RT for 1h. Upon reaction completion, DCM (5
ML) was added, and the mixture was concentrated under reduced pressure to obtain 4-((6- aminohexyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-ylisoindoline-1,3-dione as a TFA salt.
The crude product was used further in the next step without further purification. 4-((4-aminobutyl)amino)-2-(1-methyl-2 6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Ts NH,
Oo
Oo a
Oo NH
[00307] In a 10 mL flask, tert-butyl (4-({(2-(1-methyl-2,6-dioxopiperidin-3-yl})-1,3- dioxoisoindolin-4-yl}amino)butyl)carbamate (35.0 mg, 0.076 mmol) was dissolved in TFA (3 mL, 38.9 mmol) and the mixture was stirred at RT for 1h. Upon reaction completion, DCM (5
ML) was added, and the mixture was concentrated under reduced pressure to obtain 4-((4- aminobutyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yljisoindoline-1,3-dione as a TFA salt.
The crude product was used further in the next step without further purification. 4-(4-chloro-2-({4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-(6-((2-(1-methyl- 2,6-dioxopiperidin-3-yl}-1,3-dioxoisoindolin-4-yhamino)hexyl}benzamide
FF o
Cl
OD
HN Oo N 9
Oo Oo
Cl N
Ö H
[00308] In a 25 mL flask, 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyljsulfonamido)}phenoxy)benzoic acid (39.2 mg, 0.077 mmol) was dissolved in DMF (5.00 mL) followed by addition of HATU (33.9 mg, 0.089 mmol) and DIPEA (0.031 mL, 0.179 mmol). 4-{(6-aminohexyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3- yhisoindoline-1,3-dione (23.00 mg, 0.060 mmol) dissolved in DMF (5.00 mL) was added to the benzoic acid mixture and stirred at RT for 2h. Upon reaction completion, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3x120 mL). The combined organic layers were washed with brine (100 mL). The organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The crude mixture was purified by reverse phase automated flash column chromatography using a gradient of 30- 90% ACN/H2O to obtain 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl)sulfonamido) phenoxy)-N-(6-((2-(1-methyl-2,6-dioxopiperidin-3-yl}-1,3- dioxoisoindolin-4-yl)}amino}hexyl)benzamide (16 mg, 0.018 mmol, 9 % yield over three steps) as a yellow solid.
[00309] 'H NMR (400 MHz, CDCls) ò 8.07 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.72 (d, J =
2.5 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.56 — 7.45 (m, 2H), 7.35 (s, 1H), 7.20 — 7.05 (m, 2H), 6.88 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 8.3 Hz, 2H), 6.31 (d, J =6.2
Hz, 1H), 4.90 (q, J = 5.6 Hz, 1H), 3.47 (q, J = 6.8 Hz, 2H), 3.28 (t, J = 6.8 Hz, 2H), 3.18 (s, 3H), 3.00-2.92 (m, 1H), 2.79-2.69 (m, 2H), 2.08 (s, 1H), 1.79 - 1.61 (m, 4H), 1.59 — 1.32 (m, 4H). 13C NMR (101 MHz, CDCl5) ò 171.5, 169.9, 169.2, 167.9, 166.6, 158.3, 147.1, 145.4, 138.2, 138.0, 136.3, 132.6, 132.6, 131.5, 130.7, 130.4, 129.8, 129.5, 128.5, 126.9, 126.7, 123.6, 123.3, 120.5, 120.2, 117.3, 116.7, 111.6, 110.1, 49.7, 42.6, 40.1, 32.0, 29.1, 27 4, 26.7, 22.3. LC-MS (ESI) m/z [M + HJ* calculated for C49Ha3sCl2F3N5OsS: 874.16; found: 874.05. 4-(4-chloro-2-({4-chloro-3-(trifluoromethylyphenyl)sulfonamido) phenoxy)-N-(4-((2-(1-methyl- 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yhamino)butyl)benzamide 0 ©
AL on On je { B 0=8=0 Ô N . Oo i
CI F F
[00310] In a 25 mL flask, 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyljsulfonamido)}phenoxy)benzoic acid (37.3 mg, 0.074 mmol) was dissolved in DMF (5 mL) followed by addition of HATU (38.2 mg, 0.100 mmol) and DIPEA (0.035 mL, 0.201 mmol). 4-{(4-aminobutyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3- ylhisoindoline-1,3-dione (24.00 mg, 0.067 mmol) dissolved in DMF (5 mL) was added to the benzoic acid mixture and stirred at RT for 2h. Upon reaction completion, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3x120 mL). The combined organic layers were washed with brine (100 mL). The organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The crude mixture was purified by reverse phase automated flash column chromatography using a gradient of 30-90%
ACN/H20 to obtain 4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-
N-(4-{(2-(1-methyl-2,6-dioxopiperidin-3-yl}-1,3-dioxoisocindolin-4-yl)amino}butyl)benzamide (7 mg, 0.008 mmol, 4 % yield over three steps) as a yellow solid.
[00311] 'H NMR (400 MHz, CDCls) 8 8.07 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.4, 2.3 Hz, 1H), 7.73 (d, J= 2.5 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.57 — 7.43 (m, 2H), 7.21 (s, 1H), 7.14 — 7.07 (m, 2H), 6.90 (dd, J = 8.6, 0.7 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 6.21 (t, J = 5.9 Hz, 1H), 4.96 — 4.86 (m, 1H), 3.53 (d, J = 4.9 Hz, 2H), 3.34 (d, J = 6.1
Hz, 2H), 3.20 (s, 3H), 3.04 -2.91 (m, 1H), 2.83 -2.74 (m, 2H), 2.15-2.05 (m, 1H), 1.82 —
1.73 (m, 4H). %3C NMR (151 MHz, CDCl3) ò 171.4, 169.9, 169.2, 167.9, 166.9, 158.4, 146.9, 145.4, 138.2, 138.0, 136.3, 132.6, 132.6, 131.5, 130.5, 130.4, 129.8, 129.6, 129.3, 128.5, 126.9, 126.7, 123.5, 122.8, 121.0, 120.2, 117.4, 116.8, 111.8, 110.3, 49.8, 42.3, 39.8, 32.0, 27.4, 27.3, 26.7, 22.3. LC-MS (ESI) m/z [M + H]" calculated for CasH32Cl2F3NsOsS: 845.13; found: 845.90. 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate
Tp
POI
[00312] 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethan-1-ol) (97 g, 500 mmol) was dissolved in DCM (60 mL) under nitrogen atmosphere. The solution was cooled to 0°C with an ice bath and triethylamine (10.45 mL, 75 mmol) was added. Subsequently, 4- methylbenzenesulfonyl chloride (9.53 g, 50 mmol) was added in portions to the cooled reaction mixture. After complete addition, the solution was allowed to warm to room temperature and was stirred for 18 hours. The mixture was washed with water (3x100 mL), the aqueous fractions were re-extracted with DCM (3x300 mL) and the combined organic layers were washed with 5% citric acid (2x500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using a gradient of 2.5-10% MeOH in ethyl acetate to obtain 2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (14.81 g, 42.5 mmol, 85 % yield) as a clear oil.
[00313] 'H NMR (400 MHz, CDCl3) ò 7.79 (d, J = 8.4 Hz, 2H), 7.37 — 7.29 (d, J = 8.1 Hz, 2H), 4.19 - 4.12 (m, 2H), 3.75 — 3.56 (m, 14H), 2.44 (s, 3H). LC-MS (ESI) m/z [M + H]* calculated for C15H2407S: 349.12; found: 349.00. 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (KE02)}
Oe
POI
[00314] 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-ol) {15.02 g, 100 mmol) was dissolved in
DCM (15 mL)under a nitrogen atmosphere. The solution was cooled to 0°C with an ice bath and triethylamine (2.091 mL, 15.00 mmol) was added. Subsequently, 4- methylbenzenesulfonyl chloride (1.906 g, 10 mmol) was added in portions to the cooled reaction mixture. After complete addition, the solution was allowed to warm to room temperature and was stirred for 18 hours. The mixture was washed with water (3x25 mL), the aqueous fractions were re-extracted with DCM and the combined organic layers were washed with 5% citric acid (3x15 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography using a gradient of 0-20% Acetone in DCM to obtain 2-(2-(2- hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.53 g, 8.30 mmol, 83 % yield) as a clear oil.
[00315] 'H NMR (400 MHz, CDCls) 8 7.82 (d, J = 8.4 Hz, 2H), 7.36 (d, J= 8.1 Hz, 2H), 422-415(, J=6 Hz 2H), 3.72 (q, J = 4.6 Hz, 4H), 3.61 (m, 6H), 2.46 (s, 3H). LC-MS (ESI) m/z [M + H]* calculated for C13H2006S: 305.10; found: 305.00. 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate
Ty $ Oo dor
[00316] 2,2'-oxybis(ethan-1-ol) (53.1 g, 500 mmol) was dissolved in DCM (60 mL) under nitrogen atmosphere. The solution was cooled to 0°C with an ice bath and triethylamine (10.45 mL, 75 mmol) was added. Subsequently 4-methylbenzenesulfonyl chloride (9.53 g, 50 mmol) was added in portions to the cooled reaction mixture. After complete addition, the solution was allowed to warm to room temperature and was stirred for 18 hours. The mixture was washed with water (3x100 mL), the aqueous fractions were re-extracted with DCM {3x300 mL) and the combined organic layers were washed with 5% citric acid (2x500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using a gradient of 2.5-10% MeOH in EtOAc to obtain 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (9.50 g, 36.5 mmol, 73 % yield) as a clear oil.
[00317] 'H NMR (400 MHz, CDCls) ò 7.86 — 7.79 (m, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.25 — 4.18 (m, 2H), 3.75 — 3.66 (m, 4H), 3.59 — 3.52 (m, 2H), 2.47 (s, 3H). LC-MS (ESI) m/z [M +
H]* calculated for C11H160sS: 261.07; found: 261.00. 1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyhtriaza-1,2-dien-2-ium
Neng AO SON
N o OH
[00318] Sodium azide (0.949 g, 14.59 mmol) was added to a solution of 2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (3.18 g, 9,12 mmol) in
Acetonitrile (20 mL) and the mixture was heated to reflux and stirred for 8 hours. Upon reaction completion, the solution was allowed to cool down to room temperature and HO (20 mL) was added to the solution. The aqueous phase was extracted with DCM (3 x 20 mL) and the combined organic portions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography using an eluent gradient of 60-100% EtOAC/PE to obtain 1-(2-(2-(2-(2- hydroxyethoxy}ethoxy)}ethoxy)ethyljtriaza-1,2-dien-2-ium (1.667 g, 7.57 mmol, 83 % yield) as a clear oil.
[00319] 'H NMR (400 MHz, CDCl) 8 3.79 — 3.60 (m, 14H), 3.42 (t, J = 5.0 Hz, 2H). LC-
MS (ESI) m/z [M + HJ] calculated for CsH1sNsO4": 221.13; found: 220.05. 1-(2-(2-(2-hydroxyethoxy)ethoxy)ethyhtriaza-1,2-dien-2-ium
Mang, AO OH
[00320] Sodium azide (2.210 g, 34 mmol) was added to a solution of 2-(2-(2- hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (5.17 g, 17,00 mmol) in Acetonitrile (50 mL) and the mixture was refluxed overnight. Upon reaction completion, the solution was allowed to cool down to room temperature and HO (50 mL) was added to the solution. The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic portions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography using a gradient of 40-100% EtOAc in PE to obtain 1-(2-(2-(2-hydroxyethoxy)ethoxy)ethyhtriaza-1,2-dien-2-ium (2.097 g, 11.90 mmol, 70 % yield) as a clear oil.
[00321] LC-MS [(ESI)] m/z calculated [M+H] +: 175; found [M+H] +: 176. *H NMR (400
MHz, CDCls) ò 3.80 — 3.67 (m, 8H), 3.67-3.61 (m, 2H), 3.43 (dd, J= 5.5, 4.4 Hz, 2H). LC-MS (ESI) m/z [M + HJ" calculated for CsH14N3sOs*: 176.10; found: 176.85. 1-(2-(2-hydroxyethoxy)ethyl}triaza-1,2-dien-2-ium i Oo
[90322] Sodium azide (2,013 g, 31,0 mmol) was added to a solution of 2-(2- hydroxyethoxy)ethyl 4-methylbenzenesulfonate (3,12 g, 12,00 mmol} in Acetonitrile (50 mL) and the mixture was refluxed for 8 hours. Upon reaction completion, the solution was allowed to cool down to room temperature and H2O (50 mL) was added to the solution. The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic portions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography using a gradient of 40-100% EtOAc in PE to yield 1-(2-(2- hydroxyethoxy)ethyl)triaza-1,2-dien-2-ium (1,316 g, 9,96 mmol, 83 % yield) as a clear oil.
[00323] 'H NMR (400 MHz, CDCl) ò 3.80 — 3.74 (m, 2H), 3.71 (dd, J = 5.5, 4.4 Hz, 2H), 3.66 — 3.59 (m, 2H), 3.42 (t, 2H). 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetic acid
NL Oo
NE AO OA
[00324] A solution of chromium trioxide Jones reagent (1.510 g, 15.10 mmol} in 1.5 M
H2SOs (31 mL) was added dropwise to a solution of the compound 1-(2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethyl)triaza-1,2-dien-2-ium (1.040 g, 4,72 mmol) in Acetone (55 mL) at 0 °C by an additional funnel. The reaction was allowed to stir at room temperature overnight. Reaction progress was monitored by TLC (DCM:MeOH, 9:1). The reaction was quenched by addition of isopropanol (30 mL). The reaction mixture was then concentrated under vacuum and the residue was extracted by DCM (50 mL x 4). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica flash chromatography using a gradient of 2.5-10% MeOH in
DCM to obtain 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetic acid (0.760 g, 3.26 mmol, 69 % yield) as a clear oil.
[00325] 'H NMR (400 MHz, CDCls) ò 4.21 (s, 2H), 3.83 — 3.67 (m, 10H), 3.43 (t, J = 5.5, 4.5 Hz, 2H). LC-MS (ESI) m/z [M - HJ calculated for CsH:sN3Os*: 232.10; found: 231.95. 2-(2-(2-azidoethoxy)ethoxy)acetic acid
Oo
ANT oO Aon
[00326] A solution of chromium trioxide Jones reagent (1792 mg, 17.92 mmol) in 1.5 M
H2SOa (31 mL) was added dropwise to a solution of the compound 1-(2-(2-(2- hydroxyethoxy)ethoxy)ethyljtriaza-1,2-dien-2-ium (987 mg, 5,6 mmol) in Acetone (55 mL) at 0 °C by an additional funnel. The reaction was allowed to stir at room temperature overnight.
Reaction progress was monitored by TLC (DCM:MeOH, 9:1). The reaction was quenched by addition of isopropanol (30 mL). The reaction mixture was then concentrated under vacuum and the residue was extracted by DCM (50 mL x 4). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica flash chromatography using a gradient of 2-5% MeOH in DCM to obtain 2-(2-(2- azidoethoxy)ethoxy)acetic acid (540 mg, 2.85 mmol, 51 % yield) as a clear oil.
[00327] 'H NMR (400 MHz, CDCl) ò 4.20 (s, 2H), 3.82 — 3.74 (m, 2H), 3.78 — 3.65 (m, 4H), 3.43 (t, J = 5.6, 4.5 Hz, 2H). LC-MS (ESI) m/z [M - HT calculated for CsH+1N3O4": 188.08; found: 188.05. 2-(2-azidoethoxy)acetic acid
NL OH
NE AOA
[00328] A solution of chromium trioxide Jones reagent (1792 mg, 17.92 mmol) in 1.5 M
H2SOa in water (31 mL) was added dropwise to a solution of 1-(2-(2- hydroxyethoxy)ethyl)triaza-1,2-dien-2-ium (740 mg, 5,6 mmol) in Acetone (55 mL) at 0 °C by an additional funnel. The reaction was allowed to stir at room temperature overnight.
Reaction progress was monitored by TLC (DCM:MeOH, 9:1). The reaction was quenched by addition of isopropanol (30 mL). The reaction mixture was then concentrated under vacuum and the residue was extracted by DCM (50 mL x 4). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica flash chromatography using a gradient of 1-5% MeOH in DCM to obtain 2-(2- azidoethoxy)acetic acid (332 mg, 2.288 mmol, 41 % yield) as a clear oil.
[00329] 'H NMR (400 MHz, CDCl) ò 7.26 (s, 2H), 6.81 (dd, J = 5.5, 4.5 Hz, 2H), 6.53 (t,
J= 5.5, 4.4 Hz, 2H). LC-MS (ESI) m/z [M - HJ calculated for C4H7:N30O3*: 144.05; found: 144.05. 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yhacetamide
NL Oo
INE AO OA 00
Obd
N Oo
Oo
[00330] 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetic acid (0.247 g, 1,06 mmol) was dissolved in thionyl chloride (10 mL, 137 mmol) and heated at 85 °C for 1h. After reaction completion, a third of the acid chloride (1.06 mmol) was transferred to a separate flask, evaporated, and dissolved in dry THF (15 mL) To this solution was added Pomalidomide (0.290 g, 1.060 mmol). The resulting mixture was refluxed for 8 h. After cooling to room temperature, the reaction mixture was filtered through celite. The reaction mixture was diluted with water (10 mL) and extracted twice with EtOAc (2x50 mL). The combined organic layers were washed with water (30mL) and brine (30mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using a gradient of 5-10% MeOH in DCM to obtain 2-(2-(2-(2-azidoethoxy)ethaxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl}acetamide (0.264 g, 0.541 mmol, 51 % yield) as a yellow solid.
[00331] 'H NMR (400 MHz, MeOD) 5 8.81 (dd, J = 8.5, 0.9 Hz, 1H), 7.82 (dd, J = 8.5, 7.4
Hz, 1H), 7.62 (dd, J = 7.4, 0.8 Hz, 1H), 5.17 (dd, J = 12.6, 5.4 Hz, 1H), 4.25 (s, 2H), 3.85 (m, 4H), 3.73 — 3.70 (m, 2H), 3.68 — 3.62 (m, 4H), 3.34 (t, J = 3.3, 1.6 Hz, 2H), 2.97 — 2.86 (m, 1H), 2.84 — 2.70 (m, 2H), 2.24 — 2.16 (m, 1H). LC-MS (ESI) m/z [M + H]" calculated for
C21H24NsOs"*: 489.16; found: 489. 18. 1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxoethoxy)ethoxy)ethyltriaza-1,2-dien-2-ium (KE18 OR 22)
Oo eto oy oo
LL
N Oo
Oo
[00332] 1-(2-(2-(carboxymethoxy)ethoxy)ethyljtriaza-1,2-dien-2-ium (228 mg, 1.200 mmol) was dissolved in thionyl chloride (7 mL, 96 mmol) and heated at 65°C 1h. After reaction completion, thionyl chloride was evaporated under reduced pressure. The crude mixture was then dissolved in dry THF (10 mL). To this solution was added Pomalidomide (219 mg, 0.8 mmol). The resulting mixture was refluxed for 18h. Upon reaction completion, the reaction was diluted with water (10 mL) and extracted twice with EtOAc (2x50 mL). The combined organic layers were washed with water (30mL) and brine (30mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude mixture was purified using an isocratic elution of 3% MeOH in DCM to obtain 1-(2-(2- (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylyamino)-2- oxoethoxy)ethoxy)ethyl)triaza-1,2-dien-2-ium (307 mg, 0.689 mmol, 86 % yield) as a slightly yellow solid.
[00333] 'H NMR (400 MHz, CDCls) ò 10.47 (s, 1H), 8.88 (dd, J = 8.5, 0.8 Hz, 1H), 8.02 (s, 1H), 7.74 (dd, J = 8.5, 7.3, 0.5 Hz, 1H), 7.59 (dd, J = 7.4, 0.8 Hz, 1H), 5.01 — 4.92 (m, 1H), 4.22 (s, 2H), 3.88 — 3.79 (m, 4H), 3.73 (dd, J = 5.6, 4.7 Hz, 2H), 3.43 — 3.36 (m, 2H), 2.98 -2.70 (m, 3H), 2.23 — 2.13 (m, 1H). LC-MS (ESI) m/z [M + Na]* calculated for
C1gH21NsO7": 467.98; found: 467.00. 2-(2-azidoethoxy)-N-(2-(2 8-dioxopiperidin-3-yI)-1,3-dioxoisoindolin-4-yl)acetamide
N. Oo
NE AOA 0 0
IL
N Oo
O
[00334] 2-(2-azidoethoxy)acetic acid (154 mg, 1.06 mmol) was dissolved in thionyl chloride (7 mL, 96 mmol) and heated at 65°C 1h. After reaction completion, thionyl chloride was evaporated under reduced pressure. The crude mixture was then dissolved in dry THF (11 mL). To this solution was added Pomalidomide (290 mg, 1.06 mmol). The resulting mixture was refluxed for 18h. Upon reaction completion, the reaction was diluted with water (10 mL) and extracted twice with EtOAc (2x50 mL). The combined organic layers were washed with water (30mL) and brine (30mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude mixture was purified by flash column chromatography using an isocratic elution of 2% MeOH in DCM to obtain 2-(2- azidoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (264 mg, 0.659 mmol, 62 % yield) as an off-white solid.
[00335] 'H NMR (400 MHz, DLC-MSO) ò 11.16 (s, 1H), 10.35 (s, 1H), 8.71 (d, J = 8.4
Hz, 1H), 7.87 (dd, J=8.5, 7.3 Hz, 1H), 7.84 (d, J= 7.3 Hz, 1H), 5.17 (dd, J = 13.0, 5.4 Hz, 1H), 4.25 (s, 2H), 3.81 (t, J = 4.9 Hz, 2H), 3.58 (t, / = 4.9 Hz, 2H), 2.97 — 2.83 (m, 1H), 2.65 — 2.54 (m, 2H), 2.14 — 2.01 (m, 1H). LC-MS (ESI) m/z [M + H]* calculated for C47H1NeOs": 401.11; found: 401.00. 4-{4-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl)sulfonamido) phenoxy)-N-(prop-2-yn-1- ylibenzamide
E F CI
0 0=5=0 0
SCOOTS
©
[00336] To a mixture of 4-(4-chloro-2-{{4-chloro-3- (trifluoromethyl)phenylysulfonamido)phenoxy)benzoic acid (304 mg, 0,6 mmol), HOBt (101 mg, 0.658 mmol), EDC (126 mg, 0.658 mmol) in anhydrous DMF (15 mL) was added dropwise propargylamine (0.046 mL, 0,718 mmol), and the mixture was stirred at RT for 0.5h, then DIPEA (0.314 mL, 1.795 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 0.5h. The mixture was allowed to warm to RT, and the stirring was continued for additional 18h. Water (36 mL) was added, and the resulting mixture was extracted with EtOAc (3x60 mL). The combined organic layers were washed with water (150mL) and brine (150 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The organic layer was evaporated under reduced pressure to give 4-(4-chloro-2-((4-chloro-3-(trifluoromethylyphenyl)sulfonamido) phenoxy)-N- (prop-2-yn-1-yljbenzamide (300 mg, 0.552 mmol, 92% yield) as a brown oil without purification.
[00337] 'H NMR (400 MHz, MeOD) 5 8.01 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.4, 2.2 Hz, 1H), 7.76 — 7.66 (m, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.7, 2.6 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.64 — 6.55 (m, 2H), 4.15 (d, J = 2.5 Hz, 2H), 2.60 (t, J
= 2.5 Hz, 1H). LC-MS (ESI) m/z [M + H]* calculated for C23H1sCl2F3N2O4S: 543.00; found: 542.95. 4-(4-chloro-2-({4-chloro-3- (trifluoromethyl phenyl)sulfonamido) phenoxy)-N-{{(1-(2-(2-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylJamino)-2-oxoethoxy)ethoxy)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yhmethyl)benzamide
Cl EF le ‘ 0 ee 17) © ©
LN U JN
NH No ON 0 0 ©
[00338] 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)acetamide (40.0 mg, 0.082 mmol), 4-(4-chloro-2-({(4-chloro-3- (trifluoromethyl) phenyl)sulfonamido)phenoxy)-N-(prop-2-yn-1-yl)benzamide (66.7 mg, 0.123 mmol), (+)-Sodium L-ascorbate (97 mg, 0.491 mmol) and copper(ll) sulfate pentahydrate (61.2 mg, 0.246 mmol) were dissolved in Water (1,640 mL) and tert-Butanol (6,4 mL) at RT for 20 hr. Upon reaction completion, water (10mL) was added to the mixture and extracted with DCM (3x20mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (60 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude mixture was purified on a biotage automatic column using a gradient elution of 1-5% MeOH in DCM to obtain 4-(4-chloro-2-((4- chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-((1-(2-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisocindolin-4-ylyamino)-2-oxoethoxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-ylymethyl}benzamide (45 mg, 0.044 mmol, 53 % yield) as a slightly green solid.
[00339] 'H NMR (400 MHz, CDCls) d 10.33 (s, 1H), 9.79 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 8.3, 2.2 Hz, 1H), 7.76 — 7.61 (m, 4H), 7.53 (dd, J =14.7, 7.8 Hz, 2H), 7.03 (dd, J = 8.8, 2.5 Hz, 1H), 6.66 (d, J = 8.7 Hz, 1H), 6.48 (d,J=7.7 Hz, 2H), 4.97 (dd, J = 12.2, 5.5 Hz, 1H), 4.64 (s, 2H), 4.48 (s, 2H), 4.22 — 3.97 (m, 2H), 3.85 (s, 2H), 3.71 — 3.52 (m, 8H), 2.80 (ddt, 3H), 2.15 (d, J = 4.9 Hz, 1H). LC-MS (ESI) m/z [M + H]" calculated for C44Ha3sCl2F3NsO12S: 1031.17; found: 1031.15. 4-(4-chloro-2-({4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-((1-(2-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylyamino)-2-oxoethoxy)ethoxy)ethyl)-1H-1,2, 3- triazol-4-yl)methyl\benzamide
©
HN
E Cl ] ON
EE cl Od, 7 o
U
ANA,
[00340] 1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-y1}-1,3-dioxoisoindolin-4-yl)amino)-2- oxoethoxy)ethoxy)ethyl)triaza-1,2-dien-2-ium (39.0 mg, 0.088 mmol), 4-(4-chloro-2-((4- chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-(prop-2-yn-1-yl)benzamide (52.3 mg, 0.096 mmol), (+)-Sodium L-ascorbate (52.0 mg, 0.263 mmol) and copper(ll) sulfate pentahydrate (21.80 mg, 0.088 mmol) were dissolved in Water (0.600 mL), tert-Butanol (3 mL) and DCM (2.2 mL) at RT for 1 hr. Upon reaction completion, water (10mL}) was added to the mixture and extracted with DCM (3x20mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (60 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude mixture was purified on a biotage automatic column using a gradient elution of 1%-10% MeOH in DCM to obtain 4-(4-chloro-2-((4-chloro-3-(trifluoromethylyphenyl)sulfonamido)phenoxy)-N-((1-(2-(2- (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl}amino)-2-oxoethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-ylymethyl)benzamide (40 mg, 0.040 mmol, 46 % yield} as an off white solid.
[00341] 'H NMR (400 MHz, CDCls) 8 10.33 (s, 1H), 9.74 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.43 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.84 (d, J= 7.9 Hz, 1H), 7.73 — 7.66 (m, 2H), 7.64 (d, J = 2.5 Hz, 2H), 7.52 (dd, J= 13.9, 7.8 Hz, 2H), 7.06 (dd, J= 8.8, 2.5 Hz, 1H), 6.70 (d, J=8.7
Hz, 1H), 6.47 (d, J=7.4 Hz, 2H), 4.99 (d, J = 14.2 Hz, 1H), 4.53 (d, J = 40.7 Hz, 4H), 4.11 — 3.96 (m, 2H), 3.92 (s, 2H), 3.70 (s, 4H), 2.93 — 2.85 (m, 3H), 2.15 (s, 1H). LC-MS (ESI) m/z [M + H]* calculated for C42Hs3sCl2F3NsO+1S: 987.15; found: 987.10. 4-{4-chloro-2-({4-chloro-3- (trifluoromethyl) phenyl)sulfonamido) phenoxy)-N-((1-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylyamino)-2-oxoethoxy)ethyl)-1H-1,2,3-triazol-4- ylimethyl)benzamide
Cl EF
F 0
Co ? A 2 o HN-S o © ©
Q ~~ lp 4 No oy 0 0 Oo
[00342] 2-(2-azidoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yhacetamide (0.032 g, 0.080 mmol), 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl)sulfonamido)phenoxy)-N-(prop-2-yn-1-yl)benzamide (0.043 g, 0.080 mmol), {+)-Sodium L-ascorbate (3.17 mg, 0.016 mmol) and copper(I} sulfate pentahydrate {3.98 mg, 0.016 mmol) were dissolved in THF (0.799 mL) and two drops of water at RT for 20 hr. Upon reaction completion, water (10mL) was added to the mixture and extracted with
DCM (3x20mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (60 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude mixture was purified on a biotage automatic column using a gradient elution of 1-5% MeOH in DCM to obtain 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl)sulfonamido)}phenoxy)-N-({1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)-2-oxoethoxy)ethyl}-1H-1,2,3-triazol-4-ylymethyl)benzamide (37 mg, 0.039 mmol, 49 % yield) as an off white solid.
[00343] 'H NMR (400 MHz, MeOD) 8 8.72 (d, J= 8.4 Hz, 1H), 8.22 (s, 1H), 7.96 (d, J = 2.2Hz 1H), 7.81 -7.71 (m, 2H), 7.63 (d, J= 2.6 Hz, 1H), 7.60 — 7.52 (m, 3H), 7.48 (d, J = 8.3 Hz, 1H), 7.22 (dd, J= 8.8, 2.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.45 (d, J= 8.5 Hz, 2H), 5.23 (dd, J=12.7,5.4 Hz, 1H), 4.76 (t, J= 4.8 Hz, 2H), 4.67 — 4.53 (m, 2H), 4.15 (s, 2H), 4.05 (t, J=4.9 Hz, 2H), 2.97 — 2.83 (m, 1H), 2.81 — 2.66 (m, 2H), 2.23 - 2.13 (m, 1H). LC-
MS (ESI) m/z [M + H]* calculated for C49H3:1Cl2F3Ns8O:S: 943.12; found: 943.10. tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate
HNT Oo Oy
Boc
[00344] To a solution of 2,2'-((oxybis(ethane-2,1-diyl}}bis(oxy)})bis(ethan-1-amine) (0.584 mL, 3.12 mmol) in DCM (20 mL), Boc-anhydride (0.109 mL, 0.468 mmol) in DCM (20 mL) was added dropwise at 0°C using a syringe pump over 2h. The reaction was stirred at 0°C for 4h and then 18h at RT. The organic phase was then washed with water (5x20mL). The organic layers were combined, dried over magnesium sulfate and concentrated under vacuum to afford tert-butyl (2-{2-{2-(2-aminoethoxy}ethoxy)ethoxy}ethyl)carbamate (87 mg, 0.298 mmol, 64 % yield) as a clear oil without purification.
[00345] 'H NMR (400 MHz, CDCls) ò 5.42 (s, 1H), 3.70-3.59 (m, 8H), 3.54 (q, J = 5.4
Hz, 4H), 3.31 (q, J = 5.4 Hz, 2H), 2.91 (s, 1H), 1.77 (s, 2H), 1.44 (s, 2H). LC-MS (ESI) m/z [M + H]* calculated for C:13H28N2Os: 293.20; found: 293.10. tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate
MNS Oy
Boc
[00346] To a solution of 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine) (8.76 mL, 60 mmol) in DCM (70 mL), Boc-anhydride (2.090 mL, 9.00 mmol) in DCM (70 mL) was added dropwise at 0°C using a syringe pump over 2h. The reaction was stirred at 0°C for 4h and then 18h at RT. The organic phase was then washed with water (5x60mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum to afford tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (1.1 g, 4.43 mmol, 49 % yield) as a slightly yellow oil.
[00347] 'H NMR (400 MHz, CDCls) ò 5.15 (s, 2H), 3.62 (d, J = 1.5 Hz, 4H), 3.53 (dtd, J = 10.3, 5.6, 1.5 Hz, 4H), 3.32 (q, J = 5.5 Hz, 2H), 2.92 — 2.85 (m, 2H), 1.44 (d, J = 1.6 Hz, 11H). LC-MS (ESI) m/z [M + H]* calculated for C11H24N204: 249.17; found: 249.05. tert-butyl(1-(4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)phenoxy)phenyl)- 1-0x0-5,8,11-trioxa-2-azatridecan-13-ylcarbamate
E F CI
0 0=8=0 Oo
Cl NH NS Ong On Be
COC
O
[00348] Ina 10 mL flask, tert-butyl (2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyl)ycarbamate (54.7 mg, 0.187 mmol}, 4-(4-chloro-2-((4- chloro-3-(trifluoromethyl)phenyl)sulfonamido}phenoxy)benzoic acid (86 mg, 0.17 mmol),
DIPEA (0.030 mL, 0.170 mmol), HATU (84 mg, 0.221 mmol) were dissolved in DMF (1.5 mL) and stirred at room temperature for 2h. Upon reaction completion, 10 mL of water was added and the reaction mixture was washed with EtOAc (4x10 mL). The combined organic layers were washed with brine (40 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The. The crude product was purified by silica column chromatography using 3% MeOH in DCM to obtain tert-butyl (1-(4-(4-chloro-2-((4- chloro-3-(trifluoromethyljphenyl)sulfonamido)phenoxy)phenyl)-1-0x0-5,8,11-trioxa-2-
azatridecan-13-yl)carbamate (69 mg, 0.088 mmol, 52 % yield) as a clear oil.
[00349] 'H NMR (400 MHz, CDCl) 8 8.11 (s, 1H), 7.84 (dd, J = 8.4, 2.3 Hz, 1H), 7.70 (s, 1H), 7.89 (d, J = 2.6 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.7, 2.6 Hz, 1H), 6.95 (s, 1H), 6.73 (d, J = 8.7 Hz, 1H), 6.66 — 6.58 (m, 2H), 5.08 (t, J = 5.8 Hz, 1H), 3.67 (s, 8H), 3.65 — 3.58 (m, 4H), 3.50 (t, J = 5.2 Hz, 2H), 3.29 — 3.21 (m, 2H), 1.44 (s, 1H), 1.42 (s, 9H). LC-
MS (ESI) m/z [M + H]* calculated for C33H3sCl2F3N23OsS: 780.16; found: 780.10. tert-butyl(2-(2-(2-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)benzamido) ethoxy)ethoxy)ethyl)carbamate
E F CI
0 0=$=0 Oo Boc
COC o
[90350] In a 10 mL flask, tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (74.5 mg, 0.300 mmol), 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)benzoic acid (101 mg, 0.2 mmol}, DIPEA (0.035 mL, 0.200 mmol), HATU (99 mg, 0.260 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 2h. Upon reaction completion, 20 mL of water was added, and the reaction mixture was washed with ethyl acetate (4x20 mL). The combined organic layers were washed with brine (80 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica column chromatography using 5% MeOH in DCM to obtain tert-butyl (2-(2-(2-(4-(4- chloro-2-({4-chloro-3- (trifluoromethyl)phenylysulfonamido)phenoxy)benzamido)ethoxy)ethoxy)ethyl)carbamate (66 mg, 0.090 mmol, 45 % yield) as a clear oil.
[00351] 'H NMR (400 MHz, CDCls) 8 8.10 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.4, 2.3 Hz, 1H), 7.79 (s, 1H), 7.72 — 7.64 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 6.78 (s, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H), 5.02 (s, 1H), 3.72 — 3.62 (m, 8H), 3.54 (t, J = 5.2 Hz, 2H), 3.28 (q, J = 5.4 Hz, 2H), 2.24 - 2.13 (m, 1H), 1.43 (s, 9H). LC-
MS (ESI) m/z [M + H]* calculated for C3:H34Cl2F3N30OsS: 736.14; found: 736.05. (2R,35,4R,5S)-N-(4-((1-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)phenyl)-1-oxo-5,8,11-trioxa-2-azatridecan-13- ylycarbamoyl)-2-methoxyphenyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamide
Cl ~
Nx, | > …L ‚NH cl Fe
FO” NH co 5 0=$-0
HN Cl
AON ON IJ o N o
[00352] tert-butyl (1-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)phenyl)-1-ox0-5,8,11-trioxa-2-azatridecan-13- yl)carbamate (0.069 g, 0.088 mmol) was dissolved in MeOH (5 mL) under Nitrogen and then 4N HCI solution in dioxane (1.5 mL) was added. The reaction mixture was stirred at room temperature for 3h. The reaction mixture was then evaporated under reduced pressure to obtain N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(4-chloro-2-({4-chloro-3- (trifluoromethyl)phenyl}sulfonamido}phenoxy)benzamide (0.060 g, 0.088 mmol, quant.) as a yellow foam. The crude product was used without further purification. N-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyl)-4-(4-chloro-2-{{4-chloro-3- (trifluoromethyl)phenylysulfonamido)phenoxy)benzamide (59.9 mg, 0.088 mmol) and 4- ((2R,3S5,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentyl pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (54.3 mg, 0.088 mmol) were added to a 10 mL round-bottom flask. HATU (40.2 mg, 0.106 mmol), DMF (1 mL) and DIPEA (0.031 mL, 0.176 mmol) were then added, and the reaction was stirred at room temperature for 1h.
Upon reaction completion, 10 mL of water was added, and the reaction mixture was washed with ethyl acetate (3x20 mL). The combined organic layers were washed with water (2x20mL) and brine (1x30 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The The crude mixture was purified on a biotage column chromatography apparatus using a gradient of 2-5%MeOH in DCM to obtain (2R,3S5,4R,5S)-N-(4-((1-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)phenyl)-1-oxo0-5,8,11-trioxa-2-azatridecan-13- ylycarbamoyl)-2-methoxyphenyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamide (53 mg, 0.041 mmol, 47 % yield) as a white solid.
[00353] 'H NMR (400 MHz, CDCls) d 10.43 (s, 1H), 8.52 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.08 (d,J=2.2Hz 1H), 7.77 (dd, J = 8.4, 2.3 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.64 — 7.60 (m, 2H), 7.58 — 7.51 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 — 7.20 (m, 2H), 7.19 - 7.08 (m,
4H), 7.06 (dd, J = 8.7, 2.5 Hz, 1H), 8.98 (t, J = 5.3 Hz, 1H), 6.90 (t, J = 5.3 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 6.58 — 6.44 (m, 2H), 4.76 (dd, J = 8.7, 1.3 Hz, 1H), 4.59 (t, J = 9.0 Hz, 1H), 4.15 -4.05 (m, 1H), 3.93 (s, 3H), 3.65 (d, J = 7.0 Hz, 10H), 3.63 — 3.59 (m, 4H), 3.59 — 3.49 (m, 2H), 2.87 — 2.80 (m, 1H), 1.60 (dd, J = 14.5, 9.7 Hz, 1H), 1.40 (dd, J = 14.4, 1.4 Hz, 1H), 1.02 (s, 9H). 13C NMR (101 MHz, CDCls) 8 170.8, 166.9, 166.5, 161.0, 158.5, 157.8, 155.3, 148.4, 145.7, 138.6, 137.4, 136.3, 136.2, 132.2, 131.4, 131.3, 131.3, 130.3, 130.1, 129.9, 129.8, 129.8, 129.0, 128.8, 127.5, 126.6, 126.5, 125.3, 125.3, 124.7, 124.6, 124.2, 123.2, 121.4, 121.2, 120.4, 118.8, 118.1, 117.9, 117.0, 109.9, 70.5, 70.4, 70.2, 70.1, 69.8, 69.7, 65.0, 64.9, 64.3, 63.1, 83.1, 55.7, 50.1, 44.9, 39.9, 39.8, 30.4, 29.8. LC-MS (ESI) m/z [M +
H]* calculated for CssHs7Cl4FsNsO+0S: 1277.25; found: 1277.25. (2R,3S,4R,5S)-N-{(4-((2-{2-{2-{4-{4-chloro-2-((4-chloro-3- {triflucromethyl)phenyl)sulfonamido)phenoxy) benzamido)ethoxy)ethoxy)}ethyl}carbamoyl)-2- methoxyphenyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamide
Cl N
DD. | cl cl FL
F N ol og on,
H 0 0=5=0 ohn on o H
Oo
[00354] tert-butyl(2-(2-(2-(4-(4-chloro-2-{{4-chloro-3- (trifluoromethyl) phenyl) sulfonamido) phenoxy) benzamido) ethoxy)ethoxy)ethyl)carbamate (0.066 g, 0.090 mmol) was dissolved in MeOH (5 mL) under Nitrogen and then 4N HCI solution in dioxane (1.5 mL) was added.
The reaction mixture was stirred at room temperature for 3h. The reaction mixture was then evaporated under reduced pressure to obtain N-(2-(2-(2-aminoethoxy)ethoxy)ethyl}-4-(4- chloro-2-((4-chloro-3-(triflucromethyl) phenyl) sulfonamido) phenoxy) benzamide (3.82 g, 6.00 mmol, quant.) as a yellow foam. The crude product was used without further purification. N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(4-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl) sulfonamido}phenoxy)benzamide (0.066 g, 0.104 mmol) and 4-((2R,3S,4R,5S)-3-(3- chloro-2-flucrophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)-3-methoxybenzoic acid (0.081 g, 0.099 mmol) were added to a round-bottom flask. HATU (0.045 g, 0.119 mmol), DMF (1 mL) and DIPEA (0.034 mL, 0.198 mmol) were then added, and the reaction was stirred at room temperature for 1h. Upon reaction completion, 10 mL of water was added, and the reaction mixture was washed with ethyl acetate (3x20 mL). The combined organic layers were washed with water (2x20mL) and brine (1x30 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under vacuum. The crude mixture was purified on a biotage column chromatography apparatus using a gradient of 2-5%MeOH in DCM to obtain (2R,3S,4R,5S5)-
N-(4-{(2-(2-(2-(4-(4-chloro-2-((4-chloro-3-(trifluoromethylyphenyl) sulfonamido) phenoxy)- benzamido) ethoxy) ethoxy)ethyl)carbamoyl)-2-methoxyphenyl)-3-(3-chloro-2-flucrophenyl)- 4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamide (55 mg, 0.045 mmol, 45 % yield} as white solid.
[00355] 'H NMR (400 MHz, CDClz) d 10.46 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.01(d,J=2.2Hz, 1H), 7.72 (dd, J =8.4, 2.3 Hz, 1H), 7.63 (d, J = 2.5 Hz, 2H), 7.62 (d, J = 2.1 Hz, 1H), 7.60 — 7.55 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.26 — 7.08 (m, 6H), 7.06 (dd, J = 8.7, 2.5 Hz, 1H), 6.96 (t, J = 5.4 Hz, 1H), 6.77 (t, J = 5.3 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.56 — 6.48 (m, 2H), 4.75 (dd, J = 8.7, 1.4 Hz, 1H), 4.63 (t, J = 9.0 Hz, 1H), 4.14 — 4.04 (m, 1H), 3.93 (s, 3H), 3.69 — 3.62 (m, 10H), 3.56 (t, J = 7.0, 5.3, 2.3 Hz, 2H), 2.92 — 2.82 (m, 1H), 1.60 (dd, J = 14.5, 9.8 Hz, 1H), 1.39 (dd, J = 14.5, 1.5 Hz, 1H), 1.02 (s, 9H). 13C NMR (101
MHz, CDCls) ò 171.0, 166.9, 166.7, 161.0, 158.8, 158.5, 157.8, 155.3, 148.4, 145.4, 138.6, 137.3, 136.3, 136.2, 132.2, 131.3, 130.2, 130.1, 129.8, 129.3, 129.0, 128.9, 127.6, 126.6, 126.3, 125.3, 124.6, 124.4, 124.1, 123.2, 121.3, 121.1, 120.8, 120.4, 118.7, 118.0, 117.8, 117.7, 117.7, 116.8, 109.9, 70.4, 70.2, 69.9, 69.6, 65.1, 65.0, 84.3, 63.1, 63.0, 55.7, 50.0, 44.9, 40.0, 39.7, 30.4, 29.8. LC-MS (ESI) m/z [M + H]" calculated for Cs7Hs3Cl4FsNsOeS: 1233.23; found: 1233.15. 4-{4-chloro-2-nitrophenoxy)phenol
NO, "CL
JA cl
[00356] In a 500 mL flask hydroquinone (6.27 g, 57.0 mmol), 4-chloro-1-fluoro-2- nitrobenzene (1.342 mL, 11.39 mmol) and potassium carbonate (3.15 g, 22.79 mmol) were dissolved in DMF (150 mL) and stirred at 110 °C for 2h. Upon completion, the reaction mixture was diluted in 100 mL water and washed with diethyl ether (3x250 mL} and brine {500 mL). The organic layer was dried over Magnesium sulfate then concentrated under reduced pressure. The crude mixture was purified by flash column chromatography using a gradient elution of 20-50% EtOAc/petroleum ether to obtain 4-(4-chloro-2- nitrophenoxy)phenol (2.597 g, 9.78 mmol, 86 % yield) as a yellow solid.
[00357] 'H NMR (400 MHz, CDClz) ò 7.92 (d, J = 2.6 Hz, 1H), 7.41 (dd, J = 9.0, 2.6 Hz, 1H), 7.01 — 6.92 (m, 2H), 6.91 — 6.82 (m, 3H), 4.89 (s, 1H). LC-MS (ESI) m/z [M - HJ calculated for C12HsCINO: 264.01; found: 263.90.
2-(2-(2-(2-(4-(4-chloro-2-nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol
DX Dg
Oo
DO
Cl
[00358] In a 50 mL flask, 4-{4-chloro-2-nitrophenoxy)phenol (755 mg, 2.84 mmol), potassium iodide (42.9 mg, 0.258 mmol) and potassium carbonate (1071 mg, 7.75 mmol) were dissolved in DMF (20 mL). The reaction mixture was heated for 1h at 60 °C followed by dropwise addition of 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (900 mg, 2.58 mmol) (dissolved in 5 mL DMF). The reaction mixture was stirred at 60 °C for 24h. Upon reaction completion, water (200 mL) was added, and the mixture was extracted with Diethyl ether (5x100 mL) and the combined organic layers were washed with brine (1x 500 mL). The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography using an gradient elution of 1-10% MeOH/DCM ether to obtain 2-(2-(2-(2-(4- (4-chloro-2-nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (500 mg, 1.132 mmol, 44 % yield) as a yellow oil.
[00359] 'H NMR (400 MHz, CDCl3) 8 7.92 (d, J = 2.6 Hz, 1H), 7.41 (dd, J = 9.0, 2.6 Hz, 1H), 7.04 — 6.90 (m, 4H), 6.86 (d, J = 9.0 Hz, 1H), 4.19 - 4.10 (m, 2H), 3.89 — 3.82 (m, 2H), 3.78 — 3.66 (m, 11H), 3.65 — 3.58 (m, 3H). LC-MS (ESI) m/z [M + H]" calculated for
C29H24CINOs: 442.12; found: 442.05. 2-(2-(2-(4-(4-chloro-2-nitrophenoxy)phenoxy)ethoxy)ethoxy)ethan-1-ol
Io oO
Td
Cl
[00360] In a 50 mL flask, 4-(4-chloro-2-nitrophenoxy)phenol (768 mg, 2.88 mmol), potassium iodide (43.6 mg, 0.263 mmol) and potassium carbonate (1090 mg, 7.89 mmol) were dissolved in DMF (20 mL). The reaction mixture was heated for 1h at 80 °C followed by dropwise addition of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (800 mg, 2.63 mmol) (dissolved in 5 mL DMF). The reaction mixture was stirred at 60 °C for 24h. Upon reaction completion, water (200 mL) was added, and the mixture was extracted with Diethyl ether (3x100 mL) and the combined organic layers were washed with brine (2x 300 mL). The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography using a gradient elution of 20-100% EtOAc/petroleum ether to obtain 2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethan-1-ol (776 mg, 1.951 mmol, 74 % yield) as a yellow oil.
[00361] 'H NMR (400 MHz, CDCls) 7.92 (d, J = 2.6 Hz, 1H), 7.41 (dd, J = 9.0, 2.6 Hz, 1H), 7.07 — 6.90 (m, 4H), 6.87 (d, J = 9.0 Hz, 1H), 4.17 — 4.10 (m, 2H), 3.91 — 3.85 (m, 2H), 3.79 — 3.68 (m, 7H), 3.68 — 3.60 (m, 2H), 2.38 (d, J = 6.8 Hz, 1H). LC-MS (ESI) m/z [M + H]* calculated for C18H29CINO7: 398.09; found: 398.00. 2-(2-(2-(2-(4-(4-chloro-2-nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethyl 4- methylbenzenesulfonate
COO
Oo ; TL
DQ
CI
[00362] In a 50 mL flask, 2-(2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol {308 mg, 0.697 mmol), triethylamine (0.194 mL, 1.394 mmol), DMAP (8.52 mg, 0.070 mmol) were dissolved in DCM (6.5 mL). tosyl-Cl (199 mg, 1.046 mmol) was then added to the reaction mixture and the reaction was stirred at RT for 2h. Upon reaction completion, the mixture was diluted with water (30 mL) and washed with DCM (3x50 mL). The combined organic layers were washed with 5% citric acid (1x70 mL), dried over Magnesium sulfate then concentrated under reduced pressure.
The crude mixture was purified by flash column chromatography using a gradient elution of 60-100%EtOAc in petroleum ether to obtain 2-(2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (228 mg, 0.383 mmol, 55 % yield) as a yellow oil.
[00363] 'H NMR (400 MHz, CDCls) 87.92 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 9.0, 2.6 Hz, 1H), 7.38 — 7.31 (m, 2H), 7.02 — 6.97 (m, 2H), 6.96 — 6.92 (m, 2H), 6.86 (d, J = 8.9 Hz, 1H), 4.21 — 4.09 (m, 4H), 3.92 — 3.83 (m, 2H}, 3.76 — 3.63 (m, 6H), 3.60 (d, J =1.1 Hz, 4H), 2.44 (s, 3H). LC-MS (ESI) m/z [M + H]" calculated for C27H39CINO6S: 596.13; found: 596.05. 2-{2-(2-{4-(4-chloro-2-nitrophenoxy)phenoxy)}ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (KE93)
Q 0
OU
"0
Cl
[00364] In a 50 mL flask, 2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethan-1-ol (415 mg, 1.043 mmol), TEA (0.291 mL, 2.086 mmol), DMAP (12.75 mg, 0.104 mmol) were dissolved in DCM (10 mL). tosyl-CI (298 mg, 1.565 mmol) was then added to the reaction mixture and the reaction was stirred at RT for 2h. Upon reaction completion, the mixture was diluted with water (60 mL) and washed with DCM (3x100 mL). The combined organic layers were washed with 5% citric acid (1x150 mL), dried over Magnesium sulfate then concentrated under reduced pressure. The crude mixture was purified by flash column chromatography using a gradient elution of 40- 100%EtOAC in petroleum ether to obtain 2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (495 mg, 0.897 mmol, 86 % yield) as a yellow oil.
[00365] 'H NMR (400 MHz, CDCls) 8 7.92 (d, J = 2.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 9.0, 2.6 Hz, 1H), 7.36 — 7.32 (m, 2H), 7.00 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 9.2
Hz, 2H), 6.87 (d, J = 9.0 Hz, 1H), 4.20 — 4.14 (m, 2H), 4.14 — 4.09 (m, 2H), 3.87 — 3.82 (m, 2H), 3.74 — 3.66 (m, 4H), 3.65 — 3.61 (m, 2H), 2.44 (s, 3H). LC-MS (ESI) m/z [M + H]* calculated for C25H2sCINOsS: 552.10; found: 552.00. 4-(2-(2-(2-(2-(4-(4-chloro-2-nitrophenoxy)phenoxy)}ethoxy)ethoxy)ethoxy)}ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione 0
Oo
Oo
N
Or
Oo
DQ
CI
[00366] In a 10 mL flask,2-(2,6-dioxopiperidin-3-yl}-4-hydroxyisoindoline-1,3-dione (100 mg, 0.364 mmol) and potassium carbonate (76 mg, 0.546 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was heated for 30m at 40 °C followed by dropwise addition of 2-(2-
(2-(2-(4-(4-chloro-2-nitrophenoxy)phenoxy)ethoxy)ethoxyjethoxy)ethyl 4- methylbenzenesulfonate (228 mg, 0.383 mmol) (dissolved in 1 mL DMF). The reaction mixture was stirred at 60 °C for 18h. Upon reaction completion, water (20 mL) was added and the mixture was extracted with Diethyl ether (3x15 mL) and the combined organic layers were washed with brine (1x 30 mL). The organic layer was then dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by reverse phase flash column chromatography using a gradient elution of 10-100%
MeCN/HzO to obtain 4-(2-(2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (111 mg, 0.159 mmol, 44 % yield) as a yellow oil.
[00367] 'H NMR (400 MHz, CDCls) ò 8.10 (s, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 8.5, 7.3 Hz, 1H), 7.47 (dd, J = 7.3, 0.7 Hz, 1H), 7.43 — 7.38 (m, 1H), 7.26 (d, J = 4.1 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.95 — 6.91 (m, 2H), 6.86 (d, J = 9.0 Hz, 1H), 4.95 (dd, J = 12.3, 5.3 Hz, 1H), 4.37 — 4.31 (m, 2H), 4.12 (dd, J = 5.7, 3.8 Hz, 2H), 3.98 — 3.89 (m, 2H), 3.91 — 3.82 (m, 2H), 3.83 — 3.77 (m, 2H), 3.76 — 3.72 (m, 2H), 3.71 — 3.66 (m, 4H), 2.98 — 2.66 (m, 3H), 2.17 — 2.09 (m, 1H). LC-MS (ESI) m/z [M + H]* calculated for C33H32CIN30:2: 898. 17; found: 698.15. 4-(2-(2-(2-(4-(4-chloro-2-nitrophenoxy)phenoxy)ethoxy) ethoxy)ethoxy)-2-(2,8-dioxopiperidin- 3-yl)isoindoline-1,3-dione
OU oo
NH on. Oe © :
Cl
[00368] In a 10 mL flask,2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (49.7 mg, 0.181 mmol) and potassium carbonate (37.6 mg, 0.272 mmol) were dissolved in DMF (1 mL). The reaction mixture was heated for 30m at 40 °C followed by dropwise addition of 2-(2- {2-(4-(4-chloro-2-nitrophenoxy) phenoxy) ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (100 mg, 0.181 mmol) (dissolved in 0.8 mL DMF). The reaction mixture was stirred at 60 °C for 18h. Upon reaction completion, water (20 mL) was added and the mixture was extracted with
Diethyl ether (3x15 mL} and the combined organic layers were washed with brine (1x 30 mL).
The organic layer was then dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by reverse phase flash column chromatography using a gradient elution of 10-100% MeCN/H:0 to obtain 4-(2-(2-(2-(4-(4- chloro-2-nitrophenoxy) phenoxy)ethoxy)ethoxy)ethoxy)-2-(2,8-dioxopiperidin-3-yl)isoindoline-
1,3-dione (37 mg, 0.057 mmol, 31 % yield) as a brown solid.
[00369] 'H NMR (400 MHz, CDCl) ò 8.37 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.67 (dd, J = 8.5, 7.3 Hz, 1H), 7.51 = 7.37 (m, 2H), 7.30 - 7.16 (m, 1H), 7.05 - 6.89 (m, 4H), 6.86 (d, J = 9.0 Hz, 1H), 4.94 (dd, J = 12.0, 5.3 Hz, 1H), 4.41 — 4.30 (m, 2H), 4.11 (dd, J = 5.6, 3.9 Hz, 2H), 4.02 — 3.94 (m, 2H), 3.91 = 3.79 (m, 4H), 3.80 — 3.74 (m, 2H), 2.94 — 2.68 (m, 3H), 2.16 — 2.08 (m, 1H). LC-MS (ESI) m/z [M + H]* calculated for C3:H28CIN30::: 854. 14; found: 654.10. 4-(2-(2-(2-(2-(4-(2-amino-4-chlorophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy}-2-(2,6- dioxepiperidin-3-yl)isoindoline-1,3-dione
Oo 27
Oo
Oo
N
Or
Oo "0
Cl
[00370] In a 10 mL flask 4-(2-(2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yljisoindoline- 1,3-dione {111 mg, 0.159 mmol) and tin(ll) chloride dihydrate (179 mg, 0.795 mmol) were dissolved in Ethyl acetate (3 mL). The reaction mixture was stirred at 40 °C for 18h. Upon reaction completion, 15 mL of 3M NaOH solution was added and the mixture was stirred at
RT for 10m. The reaction mixture was then diluted with water (15 mL) and extracted with
EtOAc (3x75 mL). The combined organic layers were washed with brine (1x 150 mL). The organic layer was then dried over magnesium sulfate and the solvent was evaporated under reduced pressure to obtain crude 4-(2-(2-(2-(2-(4-(2-amino-4- chlorophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-(2,8-dioxopiperidin-3-yl)iscindoline- 1,3-dione as a yellow oil. The crude was used in the next step without further purification.
[00371] LC-MS (ESI) m/z [M + H]* calculated for C33H34CIN3O+0: 668.19; found: 668.20. 4-(2-(2-(2-(4-(2-amino-4-chlorophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-ylisoindoline-1,3-dione
OU oo
NH ran] TI 0
CI
[00372] In a 10 mL flask4-(2-(2-(2-(4-(4-chloro-2- nitrophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (37.0 mg, 0.057 mmol} and tin(ll) chloride dihydrate (63.8 mg, 0.283 mmol) were dissolved in
Ethyl acetate (1 mL). The reaction mixture was stirred at 40 °C for 18h. Upon reaction completion, 5 mL of 3M NaOH solution was added and the mixture was stirred at RT for 10m. The reaction mixture was then diluted with water (5 mL) and extracted with EtOAc {3x25 mL). The combined organic layers were washed with brine (1x 60 mL}. The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure to obtain crude 4-(2-(2-(2-(4-(2-amino-4- chlorophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-ylisoindoline-1,3- dione as a yellow oil. The crude was used in the next step without further purification.
[00373] LC-MS (ESI) m/z [M + H]* calculated for C3:H359CIN3Oe: 624.18; found: 624.10. 4-chloro-N-(5-chloro-2-(4-(2-(2-(2-(2-({2-(2,6-dioxopiperidin-3-yI)-1,3-dioxoisoindolin-4- yhoxy)ethoxy)ethoxy)ethoxy)ethoxy)phenoxy)phenyl)-3-(trifluoromethyl)benzenesulfonamide
Oo 25
Oo
Oo
N
Cr o HT
F3C St eC
Cl Cl
[00374] A 10 mL flask was charged with4-(2-(2-(2-(2-(4-(2-amino-4- chlorophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-ylisoindoline- 1,3-dione (81 mg, 0.121 mmol) and DMAP (1.481 mg, 0.012 mmol) dissolved in pyridine (0.8 mL). 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (33.8 mg, 0.121 mmol) dissolved in pyridine (0.4 mL) was added dropwise at RT. The reaction mixture was stirred at RT for 2 hr.
Upon reaction completion, pyridine was evaporated under reduced pressure and the residue was taken up in EtOAc (40 mL) and washed with 1M HCI (3x 40 mL). The organic layer was dried over Magnesium sulfate then concentrated under reduced pressure. The crude mixture was purified by reverse phase flash column chromatography using a gradient elution of 10- 100% MeCN/H:O to obtain 4-chloro-N-(5-chloro-2-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenoxy)phenyl)-3- {triflucromethyl)benzenesulfonamide (44 mg, 0.048 mmol, 30 % yield over two steps) as a white solid.
[00375] 'H NMR (400 MHz, CDCl) ò 8.41 (s, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 8.4, 2.3 Hz, 1H), 7.67 (dd, J = 8.5, 7.3 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.48 — 7.39 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.8, 2.5 Hz, 1H), 6.82 - 6.75 (m, 2H), 6.55 -6.47 (m, 3H), 4.95 (dd, J = 12.2, 5.3 Hz, 1H), 4.35 (t, J = 4.7 Hz, 2H), 4.08 (dd, J=5.7, 3.7 Hz, 2H), 3.96 (dd, J = 5.6, 3.7 Hz, 2H), 3.86 (dd, J = 5.7, 3.7 Hz, 2H), 3.83 — 3.79 (m, 2H), 3.77 — 3.68 (m, 6H), 3.01 — 2.64 (m, 3H), 2.27 — 2.01 (m, 1H). "*C NMR (101
MHz, CDCls) ò 171.4, 168.4, 167.0, 165.8, 156.4, 155.7, 148.4, 147.7, 138.1, 137.8, 136.7, 133.7, 132.4, 131.6, 128.3, 127.1, 126.7, 126.7, 126.6, 126.5, 123.2, 120.5, 119.9, 119.5, 117.5, 117.2, 116.3, 115.9, 71.1, 70.8, 70.6, 70.5, 69.7, 69.4, 69.2, 67.8, 49.1, 31.4, 22.6, 22.5. LC-MS (ESI) m/z [M + H]* calculated for C49H3sCl2F3N3012S: 910.13; found: 910.10. 4-chloro-N-(5-chloro-2-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl}-1,3-dioxoiscindolin-4- yhoxy)ethoxyjethoxyjethoxy)phenoxy)phenyl)-3-(trifluoromethyl)benzenesulfonamide
OO TTL
XI os 9 °S CF; : SZ
Cl ©
[00376] A 10 mL flask was charged with4-(2-(2-(2-(4-(2-amino-4- chlorophenoxy)phenoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yliscindoline-1,3- dione (37.0 mg, 0.059 mmol), 4-chloro-3-{trifluoromethyhbenzenesulfonyl chloride (16.55 mg, 0.059 mmol}, DMAP (0.724 mg, 5.93 pmol) and Pyridine (0.6 mL). The reaction mixture was stirred at RT for 2 hr. Upon reaction completion, pyridine was evaporated under reduced pressure and the residue was taken up in EtOAc (20 mL) and washed with 1M HCI (3x 20 mL). The organic layer was dried over Magnesium sulfate then concentrated under reduced pressure. The crude mixture was purified by reverse phase flash column chromatography using a gradient elution of 10-100% MeCN/H20 to obtain 4-chloro-N-(5-chloro-2-(4-(2-(2-(2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yljoxy)ethoxy) ethoxy)ethoxy)phenoxy)phenyl)-3-(trifluoromethyl)benzenesulfonamide (19 mg, 0.022 mmol, 37.0 % yield over two steps) as a pink solid.
[00377] 'H NMR (400 MHz, CDCl) 8 8.29 (s, 1H), 8.12 (d, J =2.2 Hz, 1H), 7.86 (dd, J = 8.4,2.3Hz, 1H), 7.73 -7.62 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 7.3 Hz, 2H), 7.27 (d, J = 6.3 Hz, 1H), 6.99 (dd, J = 8.8, 2.5 Hz, 1H), 6.89 — 6.73 (m, 2H), 6.63 — 6.43 (m, 3H), 4.91 (dd, J = 12.3, 5.3 Hz, 1H), 4.36 (t, J = 4.7 Hz, 2H), 4.08 (dd, J = 5.7, 3.8 Hz, 2H), 4.04 — 3.94 (m, 2H), 3.89 — 3.85 (m, 2H), 3.85 — 3.82 (m, 2H), 3.80 — 3.75 (m, 2H), 3.04 — 2.61 (m, 3H), 2.21 — 2.05 (m, 1H). LC-MS (ESI) m/z [M + H]* calculated for CasHs2C12F3N30+:S: 866.11; found: 866.05. tert-butyl (1-{4-(4-chloro-2-{{4-chloro-3-(trifluoromethyl)phenyl)sulfonamido}phenoxy)phenyl)- 1-0x0-5,8,11-trioxa-2-azatridecan-13-ylcarbamate
CI F E
J
0=8=0 O 1 Le
SCO 0
Oo
[00378] To a solution of 4-(5-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)benzoic acid (208 mg, 0,410 mmol) in DMF {(2mL) was added dropwise tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (100 mg, 0,342 mmol) (diluted in 0.25mL DMF) followed by addition of 1- ((dimethylamino){dimethyliminio)methyl}-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide (121 mg, 0,513 mmol) and N-ethyl-N-isopropylpropan-2-amine (0,209 mL, 1,197 mmol}. The reaction was left to stir at room temperature for 4h. Upon reaction completion the mixture was diluted with HzO (around 10 mL and extracted with EtOAc (3x10mL). The organic layer was dried over Magnesium sulfate then concentrated under reduced pressure. The residue was purified by silica column chromatography using a gradient eluent system of ethyl acetate - petroleum ether ( starting with 60/40 to 100 ethyl acetate) to yield tert-butyl (1-(4-(5-chloro-2- {(4-chloro-3-(trifluoromethyl)phenyl}sulfonamido)phenoxy)phenyl)-1-oxo-5,8,11-trioxa-2- azatridecan-13-yljcarbamate (200 mg, 0,256 mmol, 75 % yield).
[00379] LC-MS (ESI) m/z calculated [M+H] +: 780; found [M+H] +: 680 (-Boc). '"H NMR (400 MHz, MeOD) ò 8.02 (d, J =2.2 Hz, 1H), 7.83 (dd, J = 8.5, 2.3 Hz, 1H), 7.72 (d, J = 8.8
Hz, 2H), 7.64 (d, J = 2.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 8.8, 2.6 Hz, 1H), 6.85 (d, J =8.8 Hz, 1H), 6.59 (d, J = 8.9 Hz, 2H), 3.69 — 3.54 (m, 12H), 3.51 — 3.44 (m, 2H), 3.22 — 3.16 (m, 2H), 1.42 (s, 9H). tert-butyl(2-(2-(2-(4-(4-chloro-2-{(4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)benzamido) ethoxy)ethoxyjethylycarbamate
CI F E
0=8=0 0 H
COOK o Oo
[00380] To a solution of 4-(5-chloro-2-{{4-chloro-3- (trifluoromethyl) phenyl}sulfonamido)phenoxy)benzoic acid (245 mg, 0,483 mmol) in DMF (2 mL) was added dropwise tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (100 mg, 0,403 mmol) (diluted in 0.25mL DMF) followed by addition of 1- {(dimethylamino)(dimethyliminio)ymethyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide (142 mg, 0,604 mmol} and N-ethyl-N-isopropylpropan-2-amine (0,246 mL, 1,409 mmol). The reaction was left to stir at room temperature for 4h. Upon reaction completion the mixture was diluted with HzO (10 mL) and extracted with EtOAc(3x10mL). The organic layer was dried over
Magnesium sulfate then concentrated under reduced pressure. The residue was purified by silica column chromatography using a gradient eluent system of ethyl acetate -petroleum ether ( starting with 60/40 to 100 ethyl acetate) to yield tert-butyl (2-(2-(2-(4-(5-chloro-2-((4- chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)benzamidojethoxy)ethoxy)ethyl)carbamate (100 mg, 0,136 mmol, 34 % yield).
[00381] LC-MS (ESI) m/z calculated [M+H] +: 736; found [M+H] +: 636 (-Boc). '"H NMR (400 MHz, MeOD) ò 8.02 (d, J = 2.2 Hz, 1H), 7.81 (dd, 1H), 7.72 (d, 2H), 7.64 (d, J = 2.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.8, 2.6 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.60 (d, 2H), 3.68 — 3.61 (m, 6H), 3.58 (t, 2H), 3.51 (t, 2H), 3.23 — 3.18 (m, 2H), 1.42 (s, 9H).
N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(4-chloro-2-((4-chloro-3- (trifluoromethylphenyl) sulfonamido) phenoxy}benzamide (rv51)
CI F E
J
0=8$=0 Oo
SCOT
©
[00382] To tert-butyl (1-(4-(5-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)phenyl)-1-oxo0-5,8,11-trioxa-2-azatridecan-13- yl)carbamate (200 mg, 0,256 mmol) dissolved in DCM (6 mL) was added TFA(0,020 mL,
0,256 mmol) and the reaction was left to stir at room temperature for 30 min. Upon reaction completion the solvents were evaporated under reduced pressure to yield N-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyl}-4-(5-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido) phenoxy)benzamide (170 mg, 0,250 mmol, 98 % yield).
[00383] 'H NMR (400 MHz, MeOD) 8 8.02 (d, 1H), 7.84 (dd, J = 8.4, 2.3 Hz, 1H), 7.72 (dd, J = 8.9 Hz, 2H), 7.65 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.23 (dd, J =8.8, 2.6
Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 8.9 Hz, 2H), 3.75-3.61 (m, 12H), 3.60 — 3.56 (m, 2H), 3.14 — 3.10 (m, 2H). LC-MS (ESI) m/z [M + H]" calculated for C28H3oCl2F3N30;S: 680.11; found: 680.10.
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido) phenoxy)benzamide (rv54)
Cl F E
J
0=5=0 Oo
SCOT
0 H
[00384] To tert-butyl (2-(2-(2-(4-(5-chloro-2-((4-chloro-3-(trifluoromethyl) phenyl) sulfonamido) phenoxy) benzamido) ethoxy)ethoxy)ethyl)carbamate (100 mg, 0,136 mmol) dissolved in DCM (3 mL) was added TFA 2,2,2-trifluoroacetic acid (1,25 mL, 0,136 mmol) and the reaction was left to stir at room temperature for 30 min. Upon reaction completion the solvents were evaporated under reduced pressure to yield N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)-4-(4-chloro-2-({4-chloro-3- (trifluoromethyl) phenyl)sulfonamido)phenoxy) benzamideN-(2-(2-(2- aminoethoxy)ethoxy)ethyl}-4-(5-chloro-2-((4-chloro-3- (trifluoromethyl) phenyl) sulfonamido)phenoxy)benzamide (85 mg, 0,134 mmol, 98 % yield).
[00385] LC-MS [(ESI)] m/z calculated [M+H] +: 636; found [M+H] +: 636. *H NMR (400
MHz, MeOD) ò 8.03 (d, J=2.2 Hz, 1H), 7.84 (dd, J = 8.4, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.65 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.6 Hz, 1H), 6.85 (d,
J =8.8 Hz, 1H), 6.60 (d, J = 8.9 Hz, 2H), 3.72 — 3.65 (m, 8H), 3.58 (t, J = 5.6 Hz, 2H), 3.11 (t,
J =5.0 Hz, 2H). LC-MS (ESI) m/z [M + H]" calculated for CzsH26Cl2F3N3OsS: 636.09; found: 636.10. 4-(5-chloro-2-({4-chloro-3- (trifluoromethyl) phenyl)sulfonamido) phenoxy)-N-(2-(2-(2-(2-({2- (2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- vljamino)ethoxy)ethoxy)ethoxyjethylhbenzamide
Oo 0)
Oo 0=S=0 0 HN c Ee
RO
Oo
[00386] To a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(5-chloro-2- ((4-chloro-3-{trifluoromethyl}phenyl)sulfonamido)phenoxy)benzamide (170 mg, 0,250 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (57,5 mg, 0,208 mmol) in DLC-
MSO (5mL) was added N-ethyl-N-isopropylpropan-2-amine (0,109 mL, 0,625 mmol). The reaction was stirred at 90°C for 3h. Upon reaction completion the mixture was diluted with
H2O (10 mL), extracted with EtOAc (3x10 mL), and then washed with water (2x10mL} and brine (1x10mL). The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The crude mixture was purified by reverse phase flash column chromatography using a gradient elution of 10-80% MeCN/H20 to yield 4-(5-chloro-2-((4- chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxeisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyljbenzamide (3mg, 3,20 umol, 2 % yield).
[00387] 'H NMR (600 MHz, MeOD) 8 8.01 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.4, 2.2 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 2.6 Hz, 1H), 7.57 — 7.51 (m, 2H), 7.19 (dd, J = 8.8, 2.6 Hz, 1H), 7.07 —= 7.02 (m, 2H), 6.82 (d, J = 8.7 Hz, 1H), 6.57 (d, J = 8.8 Hz, 2H), 5.05 — 5.02 (m, 1H), 3.69 (t, J = 5.3 Hz, 2H), 3.68 — 3.65 (m, 4H), 3.65-3.62 (m, 6H), 3.55 (t, J = 5.5 Hz, 2H), 3.47 (t, J = 5.3 Hz, 2H), 2.88 — 2.82 (m, 1H), 2.76 — 2.66 (m, 2H), 2.12 — 2.07 (m, 1H). LC-MS (ESI) m/z [M + H]* calculated for C41H3sCl2F3NsO1:S: 936.16; found: 936.10. 4-(4-chloro-2-({4-chloro-3-(trifluoromethyl)phenyl)sulfonamido) phenoxy)-N-(2-(2-(2-((2-(2 &- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylyamino)ethoxy)ethoxy)ethyl)benzamide (RV56)
Cl F E 0 og 23 © © 0=8=0 Oo H N
A
0 H
[00388] To a solution of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(5-chloro-2-((4-chloro-3- {triflucromethyl)phenyl) sulfonamido)phenaxy)benzamide (40 mg, 0,063 mmol) and2-(2,6-
dioxopiperidin-3-yl}-4-fluoroisoindoline-1,3-dione (14,47 mg, 0,052 mmol) in DLC-MSO (2 ml) was added N-ethyl-N-isopropylpropan-2-amine (20,31 mg, 0,157 mmol). The reaction was stirred at 120°C overnight. Upon reaction completion the mixture was diluted with water (10 mL) and extracted with EtOAc (3x10mL). The organic layers were then combined, washed with H2O (2x10mL) and brine (1x10mL) then dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by reverse phase flash column chromatography using a gradient elution of 10-80% MeCN/H:20 to yield -(5-chloro-2-((4- chloro-3-(trifluoromethyl}phenyl)sulfonamido) phenoxy)-N-{2-(2-(2-{(2-(2,6-dioxopiperidin-3- yh-1,3-dioxoisoindolin-4-ylyamino)ethoxy)ethoxy)ethyljbenzamide (3mg, 3,36 umol, 6 % yield).
[00389] 'H NMR (400 MHz, MeOD) 5 8.00 (d, J=2.2 Hz, 1H), 7.81 (dd, J = 8.3, 2.2, 0.5
Hz, 1H), 7.69 — 7.65 (m, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.55 — 7.50 (m, 1H}, 7.20 (dd, J = 8.8, 2.6 Hz, 1H), 7.07 —= 7.01 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 9.0 Hz, 2H), 5.05 — 4.99 (m, 1H), 3.74 (t, J = 5.7, 4.8 Hz, 2H), 3.71 — 3.63 (m, 6H), 3.57 (t, J = 5.4 Hz, 2H), 3.47 (dd, J = 5.7, 4.9 Hz, 2H), 2.88 —- 2.78 (m, 1H), 2.75 -2.61 (m, 2H), 2.10 — 2.03 (m, 1H). LC-
MS (ESI) m/z [M + H]* calculated for C39H34Cl2F3N5019S: 892.13.16; found: 892.00. 4-(4-Methylthiazol-5-yl)benzonitrile
EN
S
N
[00390] 4-bromobenzonitrile (5.1 g, 28.0 mmol) and 4-methylthiazole (5.6 g, 56.0 mmol) were dissolved in dimethylacetamide (60 mL), followed by the addition of potassium acetate (5.5 g, 56.0 mmol) and palladium (lI) acetate (83.0 mg, 0.28 mmol, 1 mol %). The reaction was stirred at 150 °C under inert conditions for 20h. Upon reaction completion, the mixture was diluted with EtOAc (500 mL), and washed with water (4x 300 mL). The first wash was then back extracted with EtOAc (300 mL), and then washed with water (4x 100 mL). The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 4-(4-Methylthiazol-5-yl)benzonitrile (5.6 g, 28 mmol). The crude product was directly used without further purification. The characterization data matched the reported data.?’ (4-(4-Methylthiazol-5-yl)phenyl)methanamine
A
S
CJ
N
[00391] A solution of 4-(4-Methylthiazol-5-yl)benzonitrile (5.6 g, 28.0 mmol) in methanol (30 mL) was cooled to 0 °C. CoCl: (282 mg, 42.0 mmol) was added, followed by portionwise addition of NaBHa (5.3 g, 140.0 mmol). The resulting mixture was stirred for 90 min and then quenched with water and ammonium hydroxide. The mixture was extracted with DCM (6x 100 mL). The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure to obtain (4-(4-Methylthiazol-5-yl)phenyl)methanamine.?®
The crude product was used without further purification. (9H-fluoren-9-yl)methyl(2S ,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbam- oyhpyrrolidine-1-carboxylate 0
N FmocN ©
[00392] (4-(4-Methylthiazol-5-yl)phenyl)methanamine (5.7g, 28 mmol) and Fmoc-
Hyp(tBu)-OH (9.2 g, 22.4 mmol) were dissolved in DCM (120 mL), followed by addition of
HCTU (496.5 mg, 22.4 mmol) and DIPEA (11.7 mL, 67.2 mmol). The reaction mixture was stirred for 18h at RT. Upon reaction completion, the reaction mixture was concentrated in vacuum and re-dissolved in EtOAc, washed with 1M HCI (2x 100 mL), sat. aq. NaHCO: (3x100 Ml) and brine (100 MI). The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography using a gradient of 0-8% EtOAc/n-Heptane to obtain (SH- fluoren-9-ylymethyl(2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbam- oyl)pyrrolidine-1-carboxylate (2.0 g, 3.4 mmol, 12% over two steps).
[00393] 'H NMR (300 MHz, Chloroform-d) 8 8.60 (s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.51 (t,
J=9.8Hz 2H), 7.35 (t, J= 7.7 Hz, 3H), 7.28 — 7.22 (m, 5H), 4.50 - 4.15 (m, 7H), 3.66 (dd, J = 10.6, 6.5 Hz, 1H), 3.30 (dd, J= 10.5, 6.1 Hz, 1H), 2.48 — 2.37 (m, 4H), 1.99 (s, 1H), 1.20 (d, J=6.5 Hz, 9H). *C NMR (75 MHz, Chloroform-d) ò 171.54, 156.14, 148.37, 143.71, 141.28, 138.14, 130.82, 129.43, 127.81, 127.71, 127.09, 125.05, 120.05, 74.12, 69.65, 67.89, 59.19, 53.25, 47.09, 43.01, 36.31, 28.31, 16.04. (9H-fluoren-9-ylimethyl((S)-1-((2S ,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5-yl)benzyl) carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate
Oo ee rd =o
S Oo < =. nC
Fmoc
[00394] (9H-fluoren-9-yl)methyl(2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5- yhbenzyl)carbam-oyl) pyrrolidine-1-carboxylate (2.0 g, 3.4 mmol) was dissolved in 50% diethylamine/DCM (30 mL) stirred at RT for 3h. Upon reaction completion, the reaction mixture was concentrated in vacuum and coevaporated with toluene (3x 20 mL). The deprotected intermediate and Fmoc-Tle-OH (1.5 g, 4.1 mmol) were dissolved in DCM (40 mL), followed by addition of HCTU (1.7 g, 4.1 mmol) and DIPEA (2.1 mL, 11.9 mmol). The reaction mixture was stirred at RT for 18h. Upon reaction completion, the reaction mixture was concentrated in vacuo and re-dissolved in EtOAc (40 mL), washed with 1M HCI (2x 20 mL), sat. ag. NaHCO; (3x 20 mL) and brine (30 mL). The organic layer was then dried over
Magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography using a gradient of 0-8%
MeOH/DCM to obtain (9H-fluoren-9-ylymethyl((S)-1-((2S,4R)-4-(tert-butoxy)-2-((4-(4- methylthiazol-5-yl)benzyl) carbamoyl) pyrrolidin-1-yl)-3, 3-dimethyl-1-oxobutan-2-yl)carbamate (1.99, 2.7 mmol, 79%).
[00395] 'H NMR (300 MHz, Chloroform-d) ò 8.88 (s, 1H), 7.79 — 7.73 (m, 2H), 7.58 (d, J =7.4 Hz, 2H), 7.43 -7.28 (m, 8H), 5.43 (d, /=9.7 Hz, 1H), 4.72 (dd, J= 8.3, 3.1 Hz, 1H), 4.60 — 4.07 (m, 8H), 3.75 (dd, J= 10.0, 6.6 Hz, 1H), 3.64 — 3.50 (m, 1H), 2.57 (s, 5H), 1.20 (s, 9H), 0.92 (s, 9H). "*C NMR (75 MHz, Chloroform-d) ò 172.15, 170.87, 156.28, 144.01, 141.48, 138.84, 129.73, 128.54, 127.90, 127.24, 125.28, 125.23, 120.18, 74.38, 70.09, 67.24, 58.96, 58.81, 54.71, 47.38, 43.36, 35.87, 35.10, 28.44, 26.42, 15.52. (9H-fluoren-9-ylYmethyl(2-(2-(2-(((S)-1-((2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5- yhbenzyhn carbamoyl)pyrrolidin-1-y1-3,3-dimethyl-1-oxobutan-2-yl}amino)-2-oxoethoxy)-
N
S o NH o
Orr 0 : 36 ethoxy)ethyl)carbamate
[00396] (SH-fluoren-9-yl)methyl((S)-1-((2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5- yhibenzyl) carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (567 mg, 0.8 mmol) was dissolved in 50% diethylamine/DCM (10 mL) and stirred at RT for 3h. Upon reaction completion, the reaction mixture was concentrated in vacuum and coevaporated with toluene (3x 10 mL). The deprotected intermediate and Fmoc-PEG2-CH2COOH (385 mg, 1.0 mmol) were dissolved in DCM (10 mL), followed by addition of HCTU (431 mg, 1.0 mmol) and DIPEA (0.5 mL, 2.8 mmol). The reaction mixture was stirred at RT for 18h. Upon reaction completion, the reaction mixture was concentrated in vacuo and re-dissolved in
EtOAc (20 mL), washed with 1M HCI (2x 10 mL), sat. aq. NaHCO; (3x 10 mL) and brine (15 mL). The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography using a gradient of 0-8% MeOH/DCM to obtain (9H-fluoren-S-yl)methyl (2- (2-(2-(((S)-1-((2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidin- 1-y)-3,3-dimethyl-1-oxobutan-2-yl)amino)}-2-oxoethoxy}- ethoxy)ethyl)carbamate (572 mg, 0.67 mmol, 84%).
[00397] 'H NMR (300 MHz, Chloroform-d) ò 8.67 (d, J= 1.7 Hz, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.56 (ddt, J= 25.5, 15.2, 7.8 Hz, 3H), 7.44 — 7.35 (m, 2H), 7.34 — 7.16 (m, 5H), 4.83 — 4.57 (m, 3H), 4.46 — 4.00 (m, 6H), 3.97 — 3.76 (m, 2H), 3.76 — 3.19 (m, 8H), 3.18 — 2.82 (m, 1H), 2.47 (d, J = 18.5 Hz, 2H), 2.40 — 1.90 (m, 2H), 1.21 (d, J= 3.6 Hz, 9H), 0.96 (d, J= 17.1
Hz, 8H). HRMS calculated for C47HseNsOsS 854.4163 [M+H]*; found 854.4133. (9H-fluoren-9-ylymethyl((S)-14-((2S ,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5-yl)benzyl) carbamoylhpyrrolidine-1-carbonyl}-15,15-dimethyl-12-0x0-3,6,9-trioxa-13- azahexadecyl)carbamate
I \
S oM, ]
N Oo Oo .Fmoc ory Tx 3 ~N 6
[00398] (9H-fluoren-S-yl)methyl((S)-1-((2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5- yhbenzyl) carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (567 mg, 0.8 mmol) was dissolved in 50% diethylamine/DCM (10 mL) and stirred at RT for 3h. Upon reaction completion, the reaction mixture was concentrated in vacuum and coevaporated with toluene (3x 10 mL). The deprotected intermediate and Fmoc-PEG:-COOH (443 mg, 1.0 mmol) were dissolved in DCM (10 mL), followed by addition of HCTU (443 mg, 1.0 mmol) and DIPEA {0.5 mL, 2.8 mmol). The reaction mixture was stirred at RT for 18h. Upon reaction completion, the reaction mixture was concentrated in vacuo and re-dissolved in
EtOAc (20 mL), washed with 1M HCI (2x 10 mL}, sat. ag. NaHCO: (3x 10 mL) and brine (15 mL). The organic layer was then dried over Magnesium sulfate and the solvent was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography using a gradient of 0-8% MeOH/DCM to obtain (9H-fluoren-9-yl)methyl ((S)- 14-((2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- carbonyl)-15,15-dimethyl-12-0x0-3,6,9-trioxa-13-azahexadecyl} carbamate (624 mg, 0.69 mmol, 86%).
[00399] 'H NMR (300 MHz, Chloroform-d) ò 8.59 (s, 1H), 7.67 (dt, J=7.5, 1.0 Hz, 2H), 7.51(d, J=7.5Hz, 2H), 7.35-7.17 (m, 9H), 6.79 (d, J = 9.2 Hz, 1H), 5.53 (t, J= 5.9 Hz, 1H), 4.84 — 4.51 (m, 2H), 4.51 — 4.37 (m, 2H), 4.37 — 4.02 (m, 4H), 3.74 — 3.38 (m, 14H), 3.29 (q, J=5.3 Hz, 3H), 2.42 (s, 5H), 1.78 (dt, J= 12.4, 8.1 Hz, 1H), 1.11 (s, 9H), 0.83 (s, 9H). 13C NMR (75 MHz, Chloroform-d) 8 171.66, 170.95, 156.64, 144.01, 141.33, 138.14, 129.53, 128.15, 127.72, 127.08, 125.12, 120.02, 74.18, 70.47, 70.27, 70.14, 69.98, 67.38, 66.61, 58.68, 56.65, 54.59, 47.29, 43.15, 40.96, 36.98, 35.65, 35.25, 28.31, 26.38, 16.06.
HRMS calculated for CsoHesNsOeS 912.4581 [M+H]*; found 912.4591. (2S.4R)-1-((S)-12-(tert-butyl)-1-(4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl) sulfonamido)phenoxy)phenyl)-1,10-dioxo-5,8-dioxa-2,11-diazatridecan-13-oyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
N
LJ
— ©
J HN. HF 0 NH, ; o oC
N ©
Sr
HO
[00400] (9H-fluoren-S-ylymethyl(2-(2-(2-(((S)-1-((2S,4R)-4-(tert-butoxy)-2-((4-(4- methylthiazol-5-yl)benzyl) carbamoyl) pyrrolidin-1-yl)-3, 3-dimethyl-1-oxobutan-2-ylJamino)-2- oxoethoxy)-ethoxy)ethyl) carbamate (20 mg, 25 pmol) was dissolved in 50% diethylamine/ACN (3 mL) and stirred at RT for 3h. Upon reaction completion, the reaction mixture was concentrated in vacuum. The deprotected intermediate and 4-(4-chloro-2-((4- chloro-3-(trifluoromethyljphenyl)sulfonamido)phenoxy)benzoic acid (12 mg, 0.023 mmol) were dissolved in DMF (1 mL), followed by addition of PyBOP (16 mg, 1.2) and DIPEA (0.5 m) and the reaction mixture was stirred at RT for 18h. The reaction mixture was concentrated in vacuo and co-evaporated with toluene (3x 5 mL). After treatment with TFA, HPLC purification was followed to yield (2S,4R)-1-((S)-12-(tert-butyl)-1-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl}phenyl) sulfonamido)phenoxy)phenyl)-1,10-dioxo-5,8-dioxa-2,11- diazatridecan-13-oyl}-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (10.21 mg, 10.8 pmol, 43%).
[00401] 'H NMR (300 MHz, DMSO-d) ò 9.07 (s, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.80 (dd,
J=8.5,2.1 Hz, 1H), 7.73 -7.64 (m, 2H), 7.60 (dd, J = 2.5, 1.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.48 — 7.32 (m, 4H), 7.17 (dd, J = 8.7, 2.5 Hz, 1H), 6.79 (dd, J = 8.8, 1.5 Hz, 1H), 6.56 (d, J = 9.1 Hz, 2H), 4.70 (s, 1H), 4.62 — 4.39 (m, 3H), 4.29 (d, J = 15.7 Hz, 1H), 4.09 — 3.93 (m, 2H), 3.87 — 3.48 (m, 10H), 2.47 (s, 3H), 2.28 — 1.99 (m, 2H), 1.00 (s, 9H). *C NMR (75
MHz, DMSO-d) ò 174.23, 172.15, 171.77, 168.90, 160.27, 148.93, 140.99, 140.63, 133.82, 132.90, 130.49, 130.39, 129.04, 128.51, 128.20, 122.05, 118.09, 72.38, 71.18, 71.00, 70.95, 70.84, 80.86, 58.22, 58.15, 43.70, 41.00, 38.99, 37.31, 27.02, 15.24. LC-MS: Rt = 8.77 min,
MS ES+ (amu): 1065.04 [M+H]+. HRMS calculated for C48Hs1CI2F3NsO1082 1063.2516 [M+H]+; found 1063.2585. (2S,4R)-1-((S)-16-(tert-butyl)-1-(4-(4-chloro-2-({(4-chloro-3- {triflucromethyl)phenyl)sulfonamido) phenoxy)phenyl)-1,14-dioxo-5,8,11-trioxa-2,15- diazaheptadecan-17-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl\benzyl)pyrrolidine-2- carboxamide
N
0 iej
Oo
J HN. HF 0 NH ; 0 oC
N Oo Oo
Sry TT Dg ON o
HO
[00402] (9H-fluoren-9-yl)methyl{(S)-14-((2S,4R)-4-(tert-butoxy)-2-((4-(4-methylthiazol-5- yl)benzyljcarbamoyl) pyrrolidine-1-carbonyl)-15,15-dimethyl-12-ox0-3,6,9-trioxa-13- azahexadecyl) carbamate (22.8 mg, 25 pmol) was dissolved in 50% diethylamine/ACN (3 mL) and stirred at RT for 3h. Upon reaction completion, the reaction mixture was concentrated in vacuum. The deprotected intermediate and 4-(4-chloro-2-({4-chloro-3-
(trifluoromethyl)phenyl)sulfonamido}phenoxy)benzoic acid {12 mg, 0.023 mmol) were dissolved in DMF (1 mL), followed by addition of PyBOP (16 mg,) and DIPEA (0.5 m) and the reaction mixture was stirred at RT for 18h. The reaction mixture was concentrated in vacuo and co-evaporated with toluene (3x 5 mL). After treatment with TFA, HPLC purification was followed to yield (2S,4R)-1-((S)-16-(tert-butyl)-1-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamido)phenoxy)phenyl)-1,14-dioxo-5,8,11-trioxa-2,15- diazaheptadecan-17-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (8.38 mg, 9.4 umol, 38%).
[00403] 'H NMR (300 MHz, Methanol-d4) ò 9.09 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.87 — 7.32 (m, 9H), 7.16 (t, J = 8.9 Hz, 1H), 6.81 (d, J = 9.4 Hz, 1H), 6.56 (d, J = 8.9
Hz, 2H), 4.68 — 4.23 (m, 5H), 3.93 — 3.43 (m, 16H), 2.59 — 2.39 (m, 5H), 2.26 — 1.92 (m, 2H), 0.98 (d, J = 8.9 Hz, 9H). 13C NMR (75 MHz, Methanol-d4) ò 174.49, 173.68, 172.11, 168.88, 160.29, 148.90, 141.00, 140.81, 133.82, 132.90, 130.62, 130.43, 130.36, 129.07, 128.54, 128.32, 127.35, 127.28, 122.10, 117.99, 71.60, 71.60, 71.51, 71.37, 71.29, 71.07, 70.61, 68.26, 60.81, 58.92, 58.01, 43.67, 40.97, 38.94, 37.32, 36.79, 27.03, 15.18. LC-MS: Rt = 8.71 min, MS ES+ (amu): 1121.05 [M+H]+. HRMS calculated for Cs1Hs7Cl2F3sNsO14S2 1121.2935 [M+H]+; found 1121.2938.
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Claims (25)

ConclusiesConclusions 1. Verbinding of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, in het bezit van de structurele formule (I) zoals die hieronder is weergegeven: O=5=0 NH ATL Es Nt 9 Forme) waarbij X is geselecteerd uit -C(O)NRX- of -O-, en waarbij Rx is geselecteerd uit waterstof of (1-4C)alkyl; L een linker is; Ej; een E3 ubiquitine ligase-bindende groep is; ring A fenyl of een 5- of 6-ledig heteroaryl is; geheel getal a gelijk is aan 0, 1 of 2; elke Y onafhankelijk geselecteerd is uit halo of (1-4C)haloalkyl; ring B een fenyl of een 6-ledig heteroaryl is; geheel getal b gelijk is aan 0, 1, 2 of 3; en elke Z onafhankelijk is geselecteerd uit (1-4C)alkyl, halo, (1- 4C)haloalkyl, cyaan en SO:(1-4C}alkyl.1. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, having the structural formula (I) shown below: O=5=O NH ATL Es Nt 9 Forme) wherein X is selected from -C(O)NRX- or -O-, and wherein Rx is selected from hydrogen or (1-4C)alkyl; L is a linker; Ej; is an E3 ubiquitin ligase binding group; ring A is phenyl or a 5- or 6-membered heteroaryl; integer a is 0, 1, or 2; each Y is independently selected from halo or (1-4C)haloalkyl; ring B is a phenyl or a 6-membered heteroaryl; integer b is 0, 1, 2, or 3; and each Z is independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, cyano, and SO:(1-4C)alkyl. 2. Verbinding volgens conclusie 1, waarbij de verbinding een verbinding is met de formule I-I of I-II zoals die hieronder terug te vinden zijn, dan wel een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan:2. A compound according to claim 1, wherein the compound is a compound of formula I-I or I-II as found below, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: ls 0=8=0 0 NH oa A LE, ONT © pit 8 i R on Mx (th > {= S= O NH n O.L Zr B OD (1-11) waarbij Rx, L, E3, ring A, geheel getal a, ring B, geheel getal b, en Z telkens zijn zoals gedefinieerd in conclusie 1.ls 0=8=0 0 NH oa A LE, ONT © pit 8 i R on Mx (th > {= S= O NH n O.L Zr B OD (1-11) where Rx, L, E3, ring A, integer a, ring B, integer b, and Z are each as defined in claim 1. 55 3. Verbinding volgens conclusie 1 of 2, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij ring A fenyl, thiofeen, of pyridine is.3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein ring A is phenyl, thiophene, or pyridine. 4. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij het geheel getal a gelijk is aan 1 of 2, en waarbij elke Y onafhankelijk geselecteerd is uit fluor, chloor, CF3, CF:H, en CFH:.A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the integer a is 1 or 2, and wherein each Y is independently selected from fluoro, chloro, CF3, CF:H, and CFH:. 5. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij ring B fenyl of pyridine is.A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein ring B is phenyl or pyridine. 6. Verbinding volgens een der voorgaande conclusies, of een farmaceutische aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij het geheel getal b gelijk 15 aan 1, 2, of 3, en waarbij elke Z onafhankelijk geselecteerd is uit methyl, ethyl, fluor, chloor, CF3, CF:H, en CFHy, cyaan, en SO:2Me.A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the integer b is 1, 2, or 3, and wherein each Z is independently selected from methyl, ethyl, fluoro, chloro, CF3, CF:H, and CFHy, cyano, and SO:2Me. 7. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij:7. A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: i. Es een kleine molecule of peptide Es ubiquitine ligase-bindende groep 1s; of u. E35 een E3 ubiquitine ligase-bindende groep is die in staat 1s om te binden met een E3 ubiquitine ligase die geselecteerd is uit de groep die bestaat wit: von Hippel-Lindau (VHL), cereblon, XIAP, E34; MDM2: Anaphase-bevorderend complex; EIBRS (RDI): SOQCS/BO- box/ eleBC/ CULS/ RING; LNXp8D; CBX4; CBLLI; HACEL HECTDI; HECTDZ, HECTDS; HECW I; HECW2; HERCT HERCZ: HERCS; HERC4; HUWE]L; VPCH; NEDD4: NEDD4L; PPIL2; PRPF19; PIAS: PIAS2; PIAS3; PIAS4 RANBPZ; RNF4; RBX1; SMURF 1; SMURFZ2; STUB1; TOPORS; TRIP 12; UBE3A; UBESE; UBE2C, UBB4A; URE4B; UBOXS; UBR5, WWP1, WWPZ, Parkin; A20/TNFAIP3; AMFR/gp78; ARAS4; beta TrUPUBTRC, BRCAL CBL; CHIP/STUB 1; Eg: EGSAP/UBBSA: F-box proteine INFBX015; FRXWT/Cded; GR AIL/BNE 128; HOIP/RNE31; cl AP-VHIAP-2: cl AP-Z/HIAP-l clAP (pan); ITCH/AIP4 KAP]; MARCHS; Mind Bomb VMIB1: Mind Bomb 2/MIB2; MuRF 1 /PRIM63 NDFIP1, NEDD4, Nlel: Parkin; RNFZ; RNF4; RNF8; RNFI68; RNF43; SARTI: Skp2; SMURFZ; TRAFA: TRAF-2; TRAF-3; TRAF-4; TRAF-5; TRAF-6; TRIMS; TRIMZ21; TRIM32; UBRS; and ZNRF2.i. Es a small molecule or peptide Es ubiquitin ligase-binding group 1s; or you. E35 is an E3 ubiquitin ligase-binding moiety capable of binding 1s with an E3 ubiquitin ligase selected from the group consisting of white: von Hippel-Lindau (VHL), cereblon, XIAP, E34; MDM2: Anaphase-promoting complex; EIBRS (RDI): SOQCS/BO- box/ eleBC/ CULS/ RING; LNXp8D; CBX4; CBLLI; HACEL HECTDI; HECTDZ, HECTDS; HECW I; HECW2; HERCT HERCZ: HERCS; HERC4; HUWE]L; VPCH; NEDD4: NEDD4L; PPIL2; PRPF19; PIAS: PIAS2; PIAS3; PIAS4 RANBPZ; RNF4; RBX1; SMURF 1; SMURFZ2; STUB1; TOPORS; TRIP 12; UBE3A; UBESE; UBE2C, UBB4A; URE4B; UBOXS; UBR5, WWP1, WWPZ, Parkin; A20/TNFAIP3; AMFR/gp78; ARAS4; beta TrUPUBTRC, BRCAL CBL; CHIP/STUB 1; Eg: EGSAP/UBBSA: F-box protein INFBX015; FRXWT/Cded; GR AIL/BNE 128; HOIP/RNE31; cl AP-VHIAP-2: cl AP-Z/HIAP-l clAP (pan); ITCH/AIP4 KAP]; MARCHS; Mind Bomb VMIB1: Mind Bomb 2/MIB2; MuRF 1 /PRIM63 NDFIP1, NEDD4, Nlel: Parkin; RNFZ; RNF4; RNF8; RNFI68; RNF43; SARTI: Skp2; SMURFZ; TRAFA: TRAF-2; TRAF-3; TRAF-4; TRAF-5; TRAF-6; TRIMS; TRIMZ21; TRIM32; UBRS; and ZNRF2. 8. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij E: een E3 ubiquitine ligase-bindende groep is die in staat is om te binden met een E3 ubiquitine ligase die geselecteerd is uit de groep die bestaat uit von Hippel-Lindau (VHL) of cereblon.8. A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein E is an E3 ubiquitin ligase binding moiety capable of binding an E3 ubiquitin ligase selected from the group consisting of von Hippel-Lindau (VHL) or cereblon. 9. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij Ei is geselecteerd uit thalidomide, pomalidomide, lenalidomide, VHL ligand, methyl-bestatine, nutline of een nutline- derivaat (bijvoorbeeld idasanutline).9. A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Ei is selected from thalidomide, pomalidomide, lenalidomide, VHL ligand, methylbestatin, nutline or a nutline derivative (e.g., idasanutline). 10. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij E; 1s geselecteerd uit thalidomide, pomalidomide, lenalidomide, VHL ligand, nutline, of idasanutline.A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein E; I is selected from thalidomide, pomalidomide, lenalidomide, VHL ligand, nutline, or idasanutline. 11. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij Es is geselecteerd uit:A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Es is selected from: 1. de 3 (TG N- : O \1. the 3 (TG N- : O \ il. Co \ \ N 0 Rg | .il. Co \ \ N 0 Rg | . il.il. Q N 4 2 Ry NF - \ ö iv. A Xx NH NA mmm Ray >Q N 4 2 Ry NF - \ ö iv. A Xx NH NA mmm Ray > V. = (7 N 3 _— © rE FN “ion H u Na ~~ 0 vi.V. = (7 N 3 _— © rE FN “ion H u Na ~~ 0 vi. J iS YORJ iS YOR H . i! NL e= ~~ a Q : 0” a lo Ly OX EON cl A oO N= =H HN—" = 2 of pu i / Nc A FK) AN ID cs waarbij 3 het verbindingspunt met L aanduidt; R4 waterstof of fluor is; en X is geselecteerd uit -CH2- of -C(O)-.H . i! NL e= ~~ a Q : 0” a lo Ly OX EON cl A oO N= =H HN—" = 2 or pu i / Nc A FK) AN ID cs where 3 indicates the connection point to L; R4 is hydrogen or fluorine; and X is selected from -CH2- or -C(O)-. 12. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij E3 is geselecteerd uit: {1} 2 Ann 3 WN Poe : NM Pa An As / Nl Ny De / 7 Pr u ed - # Rg h\ a12. A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein E3 is selected from: {1} 2 Ann 3 WN Poe : NM Pa An As / Nl Ny De / 7 Pr u ed - # Rg h\ a {#)} \ po ed T = Js NT ; \ — £ i 4 én == Ne # JL A NE 0 {ih A B N " Pe N \ ZN > )aiOH i Sa” i Q : {iW Co 4, <3 Loe EN ii TR ns JA NN \ ZF ~~ AN ol oa J j ì EN Ao ë ! Sa Ï {v3{#)}\po ed T = Js NT ; \ — £ i 4 en == Ne # JL A NE 0 {ih A B N " Pe N \ ZN > )aiOH i Sa” i Q : {iW Co 4, <3 Loe EN ii TR ns JA NN \ ZF ~~ AN ol oa J j ì EN Ao ë ! Sa Ï {v3 \ # A H HN = 2, [7 NN Cl\ # A H HN = 2, [7 NN Cl & A. / We . ow DN / STN J / N - i Oo | ON FAN [ Cr vi) Y JF FEN H HIN Nm& A. / We . ow DN / STN Y / N - i Oo | ON FAN [ Cr vi) Y JF FEN H HIN Nm 2. Nr NL / (ll -È NL i {i > te A hi a CI NF waarbij 3 het verbindingspunt met L aanduidt; R4 waterstof is; en Xs -C(O)-1s.2. No. NL / (ll -È NL i {i > te A hi a CI NF where 3 denotes the point of attachment with L; R4 is hydrogen; and Xs is -C(O)-1s. 13. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij Ej is geselecteerd uit:A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Ej is selected from: {Hh Q no 3 WN A Ne iN / \ MN 3 A / A ed A | J Rg \ Q >of 0, “a § nn Xa Ne a . Ek N FEY / ae oo TS $ £ Ie Pa Ry” \{Hh Q no 3 WN A Ne iN / \ MN 3 A / A ed A | J Rg \ Q >of 0, “a § nn Xa Ne a . Ek N FEY / ae oo TS $ £ Ie Pa Ry” \ 3 . waarbij 2 het verbindingspunt met L aanduidt; R4 waterstof is; en Xa -C(O)- 1s.3 . where 2 denotes the point of attachment to L; R4 is hydrogen; and Xa is -C(O)- 1s. 14. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij L een linker is met:A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is a linker with: 1. 3 tot en met 40 kettingatomen;1. 3 to 40 chain atoms; 1. 3 tot en met 30 kettingatomen;1. 3 to 30 chain atoms; ui. 3 tot en met 20 kettingatomen;onion. 3 to 20 chain atoms; iv. 3 tot en met 15 kettingatomen;iv. 3 to 15 chain atoms; Vv. 3 tot en met 10 kettingatomen; of vi. 3 tot en met 8 kettingatomen.Vv. 3 to 10 chain atoms inclusive; or vi. 3 to 8 chain atoms inclusive. 15. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij L een linker is met:A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is a linker with: 1. 3 tot en met 40 kettingatomen;1. 3 to 40 chain atoms; u. 3 tot en met 30 kettingatomen;u. 3 to 30 chain atoms; 111. 3 tot en met 20 kettingatomen;111. 3 to 20 chain atoms; IV. 3 tot en met 15 kettingatomen;IV. 3 to 15 chain atoms; Vv. 3 tot en met 10 kettingatomen; of vi. 3 tot en met 8 kettingatomen; en waarbij:Vv. 3 to 10 chain atoms inclusive; or vi. 3 to 8 chain atoms inclusive; and where: a. de linker een alkyleenketen omvat waarin één of meerdere koolstofatomen optioneel vervangen zijn door een groep die geselecteerd is uit: -O-, -NH-, - N(CH3)-, -CO-, -CONH-, --0-, -NH-, -N(CH3)-, -CO-, - CONH-, - NHCO-, -C(O)O-, -OC(O)-, triazol, / \ [ON rj Nn ef \ / No / CX ef} ? | Nee NV — —— ‘of b. de linker een alkyleenketen omvat waarin één of meerdere koolstofatomen optioneel vervangen zijn door een groep die geselecteerd is uit: -O-, -NH-, -N(CH3)-, - CONH-, -NHCO-, -C(0)0-, -OC(O)-, of triazol;a. the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, - N(CH3)-, -CO-, -CONH-, --O-, -NH-, -N(CH3)-, -CO-, - CONH-, - NHCO-, -C(O)O-, -OC(O)-, triazole, / \ [ON rj Nn ef \ / No / CX ef} ? | Nee NV — —— ‘or b. the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -N(CH3)-, - CONH-, -NHCO-, -C(O)O-, -OC(O)-, or triazole; c. de linker een alkyleenketen omvat waarin één of meerdere koolstofatomen optioneel vervangen zijn door een groep die geselecteerd is uit: -O-, -NH-, -CONH-, - NHCO-, -C(O)O-, - OC(O)-, of triazol;c. the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -CONH-, - NHCO-, -C(O)O-, - OC(O)-, or triazole; d. de linker een alkyleenketen omvat waarin één of meerdere koolstofatomen optioneel vervangen zijn door een groep die geselecteerd is uit: -O-, -NH-, -CONH-, - NHCO- of triazol.d. the linker comprises an alkylene chain in which one or more carbon atoms are optionally replaced by a group selected from: -O-, -NH-, -CONH-, -NHCO-, or triazole. 16. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij L een linker is met formule: “Ar Xr Are Xs Arg Ke waarbij: * het verbindingspunt aanduidt met X; ** het verbindingspunt aanduidt met Es; Ar: 1s (1-15C)alkyleen, (2-8C)alkenyleen, (2-8C)alkynyleen, - (CHy),1-[0-CH3CHglaz of -[O- CHsCHs}42-(CH)a1; Xx» ofwel afwezig is of is geselecteerd uit -O-, NR 3, -C(O)-, - C(O)NR412, -NRx12C(0)-, -C(O)O-, - OC(O)- of triazol; waarbij Rx12 waterstof of methyl is; Ais afwezig is of (1-15C)alkyleen, -[CHsCHs0]44-(CH:),3- of - (CH>)a3-[OCH;CH:la4 is; Xs afwezig is of -O-, NRx1,3, -C{O)-, -C{O)NR4,3-, -NRx13C(0)- of triazol is; waarbij Ry; 3; waterstof of methyl is; A13 afwezig is of (1-15C)alkyleen, -[CHsCH:O]a48-(CHs)45- of - (CH>)45-[OCH:CHslas is; Xs afwezig is of -O-, -C(O)-, -C(O)NRx14-, -NRx14C(O)- of triazol is; waarbij Rx14 waterstof of methyl is; de gehele getallen al, a3, en a5 elk telkens onafhankelijk een waarde hebben die gelegen is tussen 1 en 4; en de gehele getallen a2, a4, en a6 elk telkens onafhankelijk een waarde hebben die gelegen is tussen 1 en 7.A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is a linker of the formula: “Ar Xr Are Xs Arg Ke where: * denotes the point of attachment by X; ** denotes the point of attachment by Es; Ar: 1s (1-15C)alkylene, (2-8C)alkenylene, (2-8C)alkynylene, -(CHy),1-[O-CH3CHglaz, or -[O-CH5CH5}42-(CH)a1; Xx» is either absent or selected from -O-, NR3, -C(O)-, -C(O)NR412, -NRx12C(O)-, -C(O)O-, -OC(O)-, or triazole; wherein Rx12 is hydrogen or methyl; A1s is absent or (1-15C)alkylene, -[CHsCHsO]44-(CH:),3- or -(CH>)a3-[OCH;CH:la4; Xs is absent or is -O-, NRx1,3, -C{O)-, -C{O)NR4,3-, -NRx13C(O)-, or triazole; where Ry; 3; is hydrogen or methyl; A13 is absent or is (1-15C)alkylene, -[CHsCH:O]a48-(CHs)45-, or -(CH>)45-[OCH:CHsla4; Xs is absent or is -O-, -C(O)-, -C(O)NRx14-, -NRx14C(O)-, or triazole; where Rx14 is hydrogen or methyl; the integers a1, a3, and a5 each independently have a value between 1 and 4; and the integers a2, a4, and a6 each independently have a value between 1 and 7. 17. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij L een linker is met formule:A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is a linker of the formula: “Ar Xi Aro Xi3 waarbij: * het verbindingspunt met X aanduidt; ** het verbindingspunt met E3 aanduidt; of Ap, is (1-6C)alkyleen of -(CHy),;-[0-CH,CHy) 0+; Xto ofwel afwezig is of geselecteerd is uit -O-, NRx12, -C(O)-, - C(O)NRx;12, -NR2C(0O)-, -C(O)O-, - OC(O)- of triazol; waarbij Rx» waterstof of methyl is; Ar» ofwel afwezig is of (1-6C)alkyleen of -[CHsCH;0l,4-(CH;)3- 1s; X, 3 ofwel afwezig is of -O-, NRx13, -C(O)-, -C(O)NRx; 5- of -NRx13C(0)- of (2-4C)alkynyl is; waarbij Rx13 waterstof of methyl is; de gehele getallen al en a3 elk onafhankelijk een waarde hebben die gelegen is tussen 1 en 3; en de gehele getallen a2 en a4 elk onafhankelijk een waarde hebben die gelegen is tussen 1 en 4.“Ar Xi Aro Xi3 where: * denotes the point of attachment with X; ** denotes the point of attachment with E3; or Ap, is (1-6C)alkylene or -(CHy),;-[O-CH,CHy) O+; Xto is either absent or selected from -O-, NRx12, -C(O)-, -C(O)NRx;12, -NR2C(OO)-, -C(O)O-, -OC(O)- or triazole; where Rx» is hydrogen or methyl; Ar» is either absent or (1-6C)alkylene or -[CHsCH;01,4-(CH;)3- 1s; X, 3 is either absent or -O-, NRx13, -C(O)-, -C(O)NRx; 5- or -NRx13C(O)- or (2-4C)alkynyl; where Rx13 is hydrogen or methyl; the integers a1 and a3 each independently have a value between 1 and 3; and the integers a2 and a4 each independently have a value between 1 and 4. 18. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij L een linker is met formule: *-CH;-CH:-0-CH;-CH;-0-CH;-CHs-X,9-**; *-CHs-CHs-0-CH;-CH;-0-CH;-CH-0-CHs-CHo-X2-**%; *-CHs-CHs-CHs-CHs-X2-**; *-CH,-CH,-CH,-CH,-CH,-CHo-X | o-*%;A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is a linker of the formula: *-CH;-CH;-O-CH;-CH;-O-CH;-CHs-X,9-**; *-CHs-CHs-O-CH;-CH;-O-CH;-CH-O-CHs-CHo-X2-**%; *-CHs-CHs-CHs-CHs-X2-**; *-CH,-CH,-CH,-CH,-CH,-CHo-X | o-*%; *.CH;-[triazol]-CHs-CH5-0-CH;-X13-**; *-CHs-[trazol]-CHs-CH5-0-CH>-CH:-0-CH;-X13-**; *-CHo-[triazol]-CH,-CH;-0-CH;-CH--0-CH:-CH;-0-CH;-X13-**; waarbij: * het verbindingspunt met X aanduidt; ** het verbindingspunt met Es aanduidt; Xt» geselecteerd is uit -O-, NRx12, -C(O)-, -C(O)NRy; 2, of -NRx12C{(O)-, waarbij Rx» waterstof of methyl is; en*.CH;-[triazole]-CHs-CH5-O-CH;-X13-**; *-CHs-[trazol]-CHs-CH5-O-CH>-CH:-O-CH;-X13-**; *-CHo-[triazole]-CH,-CH;-O-CH;-CH--O-CH:-CH;-O-CH;-X13-**; wherein: * denotes the point of attachment with X; ** denotes the point of attachment with Es; Xt» is selected from -O-, NRx12, -C(O)-, -C(O)NRy; 2, or -NRx12C{(O)-, where Rx» is hydrogen or methyl; and Xia 18 geselecteerd uit -0O-, NRs13, -C{O)-, -C{(O)NRx1s- of -NRx3C{0)-; waarbij Ry» waterstof of methyl is.Xia 18 selected from -O-, NRs13, -C{O)-, -C{(O)NRx1s- or -NRx3C{O)-; where Ry» is hydrogen or methyl. 19. Verbinding volgens conclusie 18, of een farmaceutisch aanvaardbaar zout daarvan, waarbij: Xr 1s geselecteerd uit -O-, NRx1s, -C(O)-, -C(O)NRxy9, of -NRy; sC(O)-, waarbij Rx» waterstof is; en X13 -C(O)NRx; 3- 1s, waarbij Rx13 waterstof is.A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein: Xr 1s is selected from -O-, NRx 1s , -C(O)-, -C(O)NRxy 9 , or -NRy; sC(O)-, where Rx → is hydrogen; and X 13 -C(O)NRx; s- 1s, where Rx 13 is hydrogen. 20. Verbinding volgens conclusie 18, of een farmaceutisch aanvaardbaar zout daarvan, waarbij E; gedefinieerd is zoals hierboven in conclusie 11, 12, of 13.A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein E; is as defined above in claim 11, 12, or 13. 21. Verbinding volgens een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, waarbij de verbinding is geselecteerd uit: 2 Os J 0 So YA PN EA +) Ms N oe PY NHN SN og H Gedo A ba A he F YOR i UF 4-(4-chloor-2-((4-chloor-3- (trifluormethyl)fenyl)sulfonamide)fenoxy)-N-(6-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)hexyl)benzamideA compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is selected from: 2 Os J 0 So YA PN EA +) Ms N oe PY NHN SN og H Gedo A ba A he F YOR i UF 4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamide)phenoxy)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)benzamide © HNK Ox, /© HNK Ox, / © . Fa SN he Ag SEA LE Pea ns oy 7 a pi ~ SEA eel JN SR ~~ NE A, ar 3 a at Y a HN a 4 4 ï 1 O Q=B=Q sa Sg F a Fo 4-(4-chloor-2-((4-chloor-3- (trifluormethyl)fenyl)sulfonamide)fenoxy)-N-(4-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yhamino)butyl)benzamide a FF CQ OJ - HN gi nik YJ 3 an N ie] = N \_/ [0 En 2 N I = oa £3 4-(4-chloor-2-((4-chloor-3-(trifluormethyl)fenyl)sulfonamide)fenoxy)- N-((1-(2-(2-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)-2-oxo-ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- vyDmethyDbenzamide HN FF … © £3] 2 F N 4 KN > £9 INS NENT “ad NON oY Kal is = in od, 7 NH NH NX © £2© . Fa SN he Ag SEA LE Pea ns oy 7 a pi ~ SEA eel JN SR ~~ NE A, ar 3 a at Y a HN a 4 4 ï 1 O Q=B=Q sa Sg F a Fo 4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamide)phenoxy)-N-(4-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yhamino)butyl)benzamide a FF CQ OJ - HN gi nik YJ 3 an N ie] = N \_/ [0 En 2 N I = oa £3 4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamide)phenoxy)- N-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-vyDmethylbenzamide HN FF … © £3] 2 F N 4 KN > £9 INS NENT “ad NON oY Kal is = in od, 7 NH NH NX © £2 4-(4-chloor-2-((4-chloor-3-(trifluormethyl)fenyl)sulfonamide)fenoxy)- N-((1-(2-(2-2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)-2-oxo-ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamide)phenoxy)- N-((1-(2-(2-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- vDmethyl)benzamide 5] EE _ F i. ie: On o ini} 7 © EN |] N NN vn N 3 ii NOT 4-(4-chloor-2-((4-chloor-3-(trifluormethyl)fenyl)sulfonamide)fenoxy)-N- ((1-(2-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxo-ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide Cl A \ SN F / Nx, | > \ . NH wm Foe F 7 Spa” TNH OH Ox = 6e ee oo | pi HN $d BN Ag Tr a” N ox H (2R,3S,4R,55)-N-(4-((1-(4-(4-chloox-2-((4-chloor-3- (trifluormethyl)fenyl)sulfonamide)fenoxy)fenyl)-1-0xo0-5,8,11-trioxa-2- azatridecan-13-ylcarbamoyl)-2-methoxyfenyl)-3-(3-chloor-2-fluorfenyl)-4- (4-chloor-2-fluorfenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamidevDmethyl)benzamide 5] EE _ F i. ie: On o ini} 7 © EN |] N NN vn N 3 ii NOT 4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamide)phenoxy)-N- ((1-(2-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxo-ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide Cl A \ SN F / Nx, | > \ . NH wm Foe F 7 Spa” TNH OH Ox = 6e ee oo | pi HN $d BN Ag Tr a” N ox H (2R,3S,4R,55)-N-(4-((1-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamide)phenoxy)phenyl)-1-0xo0-5,8,11-trioxa-2-azatridecan-13-ylcarbamoyl)-2-methoxyphenyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide RelRel DD. a oF F F E i, nd NT HN = CQ 7 H 3 Q=S=C TAM on, HN OY o H -DD. a oF F F E i, nd NT HN = CQ 7 H 3 Q=S=C TAM on, HN OY o H - (2R.3S8,4R,55)-N-(4-((2-(2-(2-(4-(4-chloor-2-((4-chloor-3- (trifluormethyl)fenyl)sulfonamide)fenoxy) benzamide)ethoxy)ethoxy)ethyl)carbamoyl)-2- methoxyfenyl1)-3-(3-chloor- 2-fluorfenyl)-4-(4-chloor-2-fluorfenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamide HN or or N ~ H 7 Fat S N or 3 o 4-chloor-N-(5-chloor-2-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-cdioxo- isoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)fenoxy)fenyl)-3- (trifluormethyl)benzeensulfonamide ooo OEL HN enen H o vs Fa ol = 4-chloor-N-(5-chloor-2-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxo-1soindolin-4-(2R.3S8,4R,55)-N-(4-((2-(2-(2-(4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamide)phenoxy)benzamide)ethoxy)ethoxy)ethyl)carbamoyl)-2-methoxyphenyl1)-3-(3-chloro- 2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide isoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenoxy)phenyl)-3-(trifluoromethyl)benzenesulfonamide ooo OEL HN enes H o vs Fa ol = 4-chloro-N-(5-chloro-2-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-) yl)-1,3-dioxo-1soindolin-4- yhoxy)ethoxy)ethoxy)ethoxy)fenoxy)fenyl)-3- (trifluormethyl)benzeensulfonamide oO HN oF ® 5 F oO . G=8=0 Di HN Gl CD N ge H Q 4-(5-chloor-2-((4-chloor-3-(trifluormethyDfenyl)sulfonamide)fenoxy)- N-(2-2-(2-2-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-isoindolin-4- yDamino)ethoxy)ethoxy)ethoxy)ethyl)benzamide 2 F E 0 © =S zij 3 H N OD U H 3 4-(4-chloor-2-((4-chloor-3- (trifluormethyl)fenyDsulfonamide)fenoxy)-N-(2-2-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-isoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)benzamideyhoxy)ethoxy)ethoxy)ethoxy)phenoxy)phenyl)-3-(trifluoromethyl)benzenesulfonamide oO HN oF ® 5 F oO . G=8=0 Di HN Gl CD N ge H Q 4-(5-chloro-2-((4-chloro-3-(trifluoromethylphenyl)sulfonamide)phenoxy)- N-(2-2-(2-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylDamino)ethoxy)ethoxy)ethoxy)ethyl)benzamide 2 F E 0 © =S ze 3 H N OD U H 3 4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenylsulfonamide)phenoxy)-N-(2-2-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)benzamide N . iN i oF \ Zé + mn F / NN HN. F oe D F a NH A & ‚N eN = - 7 N Te Ne HG (2S,4R)-1-((S)-12-(texrt-butyl)-1-(4-(4-chloox-2-((4-chloor-3- (trifluormethyl)fenyl) sulfonamide)fenoxy)fenyl)-1,10-dioxo-5,8-dioxo- 2,11-diazatridecan-13-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yDbenzyl)pyrrolidine-2-carboxamide N op ee > LA © ~~ HN. TF BE NH Oo ” TH “el N © OR \ i] HG (2S,4R)-1-((S)-16-(tert-butyl)-1-(4-(4-chloor-2-((4-chloor-3- (trifluormethyl)fenyl)sulfonamide)fenoxy)fenyl)-1,14-dioxo-5,8,11- trioxa-2,15-diazaheptadecan-17-oyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideN . iN i oF \ Zé + mn F / NN HN. F oe D F a NH A & .N eN = - 7 N Te Ne HG (2S,4R)-1-((S)-12-(texrt-butyl)-1-(4-(4-chloro-2-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamide)phenoxy)phenyl)-1,10-dioxo-5,8-dioxo- 2,11-diazatridecan-13-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yDbenzyl)pyrrolidine-2-carboxamide N op ee > LA © ~~ HN. TF BE NH Oo ” TH “el N © OR \ i] HG (2S,4R)-1-((S)-16-(tert-butyl)-1-(4-(4-chloro-2-((4-chloro-3- (trifluoromethyl)phenyl)sulfonamide)phenoxy)phenyl)-1,14-dioxo-5,8,11-trioxa-2,15-diazaheptadecan-17-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 22. Farmaceutische samenstelling, omvattende een verbinding zoals die gedefinieerd is in een der voorgaande conclusies, of een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, in de vorm van een mengsel waaraan een farmaceutisch aanvaardbaar drager of verdunningsmiddel is toegevoegd.22. A pharmaceutical composition comprising a compound as defined in any preceding claim, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the form of a mixture to which has been added a pharmaceutically acceptable carrier or diluent. 23. Verbinding, of farmaceutische aanvaardbaar zout, hydraat, of solvaat daarvan, zoals gedefinieerd in een der conclusies 1 tot en met 21, of een farmaceutisch aanvaardbare samenstelling zoals gedefinieerd in conclusie 22, voor gebruik in:23. A compound, or pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined in any one of claims 1 to 21, or a pharmaceutically acceptable composition as defined in claim 22, for use in: 1. therapie,1. therapy, u. de behandeling van een ziekte of aandoening waarbij CCR2-activiteit een bepalende rol speelt;u. the treatment of a disease or condition in which CCR2 activity plays a determining role; m1. de behandeling van immuno-infectieuze pathologieën;m1. the treatment of immuno-infectious pathologies; IV. de behandeling van kanker, atherosclerose, neuropathische pijn, neurodegeneratieve ziektes (bijvoorbeeld de ziekte van Alzheimer, ataxia, de ziekte van Huntington, de ziekte van Parkinson, motorneuronziekte, meervoudige systeematrofie, progressieve supranucleaire verlamming, multiple sclerose, amyotrofe laterale sclerose, Lewy body dementie, spieratrofie van Aran-Duchenne), hepatische fibrose, en/of reumatoïde artritis; ofIV. the treatment of cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g., Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body dementia, Aran-Duchenne muscular atrophy), hepatic fibrosis, and/or rheumatoid arthritis; or Vv. de behandeling van kanker, meer bepaald tumorigenese en metastasen.For the treatment of cancer, more specifically tumorigenesis and metastases. 24. Gebruik van een verbinding, of van een farmaceutisch aanvaardbare zout, hydraat, of solvaat daarvan, zoals gedefinieerd in een der conclusies 1 tot en met 21, of van een farmaceutische samenstelling zoals gedefinieerd in conclusie 22, bij de productie van een geneesmiddel voor gebruik in:24. Use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1 to 21, or a pharmaceutical composition as defined in claim 22, in the manufacture of a medicament for use in: 1. therapie,1. therapy, u. de behandeling van een ziekte of aandoening waarbij CCR2-activiteit een bepalende rol speelt;u. the treatment of a disease or condition in which CCR2 activity plays a determining role; ui. de behandeling van immuno-infectieuze pathologieën;onion. the treatment of immuno-infectious pathologies; IV. de behandeling van kanker, atherosclerose, neuropathische pijn, neurodegeneratieve ziektes (bijvoorbeeld de ziekte van Alzheimer, ataxia, de ziekte van Huntington, de ziekte van Parkinson, motorneuronziekte, meervoudige systeematrofie, progressieve supranucleaire verlamming, multiple sclerose, amyotrofe laterale sclerose, Lewy body dementie, spieratrofie van Aran-Duchenne), hepatische fibrose, en/of reumatoide artritis; ofIV. the treatment of cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g. Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body dementia, Aran-Duchenne muscular atrophy), hepatic fibrosis, and/or rheumatoid arthritis; or Vv. de behandeling van kanker, meer bepaald tumorigenese en metastasenV. the treatment of cancer, more specifically tumorigenesis and metastases 25. Werkwijze voor het behandelen van:25. Method for treating: i. een een ziekte of aandoening waarbij CCR2-activiteit een bepalende rol speelt;i. a disease or condition in which CCR2 activity plays a determining role; ii. de behandeling van immuno-infectieuze pathologieën;ii. the treatment of immuno-infectious pathologies; 1m. de behandeling van kanker, atherosclerose, neuropathische pijn, neurodegeneratieve ziektes (bijvoorbeeld de ziekte van Alzheimer, ataxia, de ziekte van Huntington, de ziekte van Parkinson, motorneuronziekte, meervoudige systeematrofie, progressieve supranucleaire verlamming, multiple sclerose, amyotrofe laterale sclerose, Lewy body dementie, spieratrofie van Aran-Duchenne), hepatische fibrose, en/of reumatoïde artritis; of iv. de behandeling van kanker, meer bepaald tumorigenese en metastasen; waarbij de werkwijze het toedienen omvat aan een subject dat behoefte heeft aan een dergelijke behandeling, van een therapeutisch werkzame hoeveelheid van een verbinding, of van een farmaceutisch aanvaardbaar zout, hydraat, of solvaat daarvan, zoals gedefinieerd in een der conclusies 1 tot en met 21, of van een farmaceutische samenstelling zoals gedefinieerd in conclusie 22.1m. the treatment of cancer, atherosclerosis, neuropathic pain, neurodegenerative diseases (e.g. Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body dementia, Aran-Duchenne muscular atrophy), hepatic fibrosis, and/or rheumatoid arthritis; or iv. the treatment of cancer, in particular tumorigenesis and metastases; wherein the method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined in any one of claims 1 to 21, or a pharmaceutical composition as defined in claim 22.
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