EA044376B1 - COMPOUNDS OF SUBSTITUTED 3-((3-AMINOPHENYL)AMINO)PIPERIDINE-2,6-DIONE, THEIR COMPOSITIONS AND METHODS OF TREATMENT USING THEIR HELP - Google Patents

Description

Related applications

The invention claims the benefit of US Provisional Application Nos. 62/782298, filed December 2018, and 62/879900, filed July 29, 2019, the disclosures of each of which are incorporated herein by reference in their entirety.

Field of technology

The invention provides certain 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions containing an effective amount of such compounds, and methods for treating or preventing androgen receptor-mediated diseases comprising administering an effective amount of such 3-( (3-aminophenyl)amino)piperidine-2,6-dione compounds to a subject in need thereof. Also provided herein are compounds and compositions for use in these methods.

State of the art

Androgen receptor signaling is known to play a critical role in the pathogenesis of prostate cancer and is involved in the development of other androgen receptor-positive cancers (Chen Y et al., Lancet Oncol, 2009, 10:981-91; Mills I G, Nat Rev Cancer , 2014, 14:187-98; Taplin M E, Nat Clin Pract Oncol, 2007, 4:236-44; Wirth M P et al., Eur Urol, 2007, 51(2):306-13). Inhibition of androgen receptor signaling by antiandrogens, which antagonize the androgen receptor, has been used or proposed for the treatment of prostate cancer.

The androgen receptor is usually found in the cytoplasm and is associated with chaperones such as HSP90. (Brinkmann A O et al., J Steroid Biochem Mol Biol, 1999, 69:307-13). Upon binding of dihydrotestosterone (DHT), the androgen receptor changes its conformation and translocates to the nucleus, where it binds androgen-responsive elements (AREs), driving the transcription of canonical targets such as KLK3 (also known as prostate-specific antigen PSA), TMPRSS2, and KLK2. (Tran C et al., Science, 2009, 324:787-90; Murtha P et al., Biochemistry (Mosc), 1993, 32:6459-64).

Prostate cancer (PCa) is one of the most commonly diagnosed non-skin cancers among men in the United States and the second leading cause of cancer death, with more than 200,000 new cases and more than 30,000 deaths annually in the United States.

Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer. Patients with advanced PCa undergo ADT with either luteinizing hormone releasing hormone (LHRH) agonists, LHRH antagonists, or bilateral orchiectomy. Despite the initial response to ADT, disease progression is inevitable and the cancer progresses to castration-resistant prostate cancer (CRPC). Up to 30% of prostate cancer patients treated initially with radiation or surgery develop metastatic disease within 10 years of initial treatment. Approximately 50,000 patients per year will develop metastatic disease, called metastatic CRPC (mCRPC).

There continues to be a significant need for safe and effective treatments, prevention, and control of AR-mediated diseases, especially AR-mediated diseases that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy, and hormonal therapy, while reducing or preventing toxicities and/or side effects associated with traditional treatments.

The citation or identification of any reference in this section of this application should not be construed as an admission that such reference is prior art with respect to this application.

The essence of the invention

Provided herein are compounds having the following formula (I):

(I) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein ^Rn , ^R1 , ^R2 , ^R3 , ^R4 , X, L, V, m and n are as defined herein. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof (each referred to herein as a piperidinedione compound) is useful for the treatment or prevention of androgen receptor-mediated diseases in a subject.

In one aspect, this document provides piperidinedione compounds as described in this disclosure, such as, for example, in the table.

In one aspect, provided herein are pharmaceutical compositions comprising an effective amount of a compound as described herein and a pharmaceutically acceptable carrier, excipient, or base. In one aspect, this document provides pharmaceutical

- 1044376 compositions containing an effective amount of a piperidinedione compound as described herein, and a pharmaceutically acceptable carrier, excipient or carrier medium. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration.

In one aspect, provided herein are methods of treating or preventing androgen receptor-mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein; and a pharmaceutically acceptable carrier, excipient or base. In one aspect, provided herein are methods of treating or preventing androgen receptor-mediated diseases in a subject, comprising administering to the subject in need thereof an effective amount of a compound as described herein and a pharmaceutically acceptable carrier, excipient or base. In another aspect, provided herein are compounds for use in methods of treating androgen receptor-mediated diseases. In another aspect, this document provides piperidinedione compounds for use in methods of treating androgen receptor-mediated diseases.

In another aspect, this document provides methods for preparing compounds as described herein. In another aspect, this document provides methods for preparing piperidinedione compounds as described herein.

The present embodiments may be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

Detailed description

Definitions.

In the context of this document, the terms containing and including may be used interchangeably. The terms containing and including should be interpreted as indicating the presence of the specified features or components as set forth, but do not exclude the presence or addition of one or more features or components, or groups thereof. Additionally, the terms containing and including are intended to include examples covered by the term consisting of. Therefore, the term consisting of may be used in place of the terms containing and including to provide more specific embodiments of the invention.

The term consisting of means that an item has at least 90, 95, 97, 98 or 99% of the stated features or components of which it is composed. In another embodiment, the term consisting of excludes from the scope of any subsequent discussion any other features or components other than those that are not essential to achieving the technical effect.

As used herein, the term or should be interpreted to include or to mean any one or any combination. Therefore, A, B or C means any of the following: A; IN; WITH; A and B; A and C; B and C; A, B, and C. An exception to this definition will only occur if the combination of elements, functions, steps, or activities is in some way mutually exclusive.

An alkyl group is a saturated, partially saturated or unsaturated, straight or branched, acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or, in some embodiments, 1 to 6, 1 up to 4 or 2 to 6 carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Typical saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2methylpentyl, -3-methylpentyl, -4-methylpentyl, -2, 3-dimethylbutyl and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also called an alkenyl or alkynyl group. An alkenyl group is an alkyl group that contains one or more carbon-carbon double bonds. An alkenyl group is an alkyl group that contains one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3) , -C(CH2CH3)=CH2, -C CH, -C SAN;), -C C(CH2CH;). -SNA O!.. -SSCHOSAIL and -SSCHOSAN2SN;). among others. The alkyl group may be substituted or unsubstituted. When alkyl groups described herein are referred to as substituted, they may be substituted with any substituent or substituents such as those found in the illustrative compounds and embodiments described herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy; cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy, oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylamino, aralkylyamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrosourea; oxime; hydroxylamine; alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio (-SH), alkylthio;=S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formed; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2. In certain embodiments, when alkyl groups described herein are referred to as substituted, they may be substituted with any substituent or substituents, such as those identified in the illustrative compounds and embodiments described herein as well as halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioester; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine, N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

A cycloalkyl group is a saturated or partially saturated cyclic alkyl group containing from 3 to 10 carbon atoms, having one cyclic ring or more fused or bridged rings, which may be optionally substituted. In some embodiments, the cycloalkyl group has from 3 to 8 ring members, while in other embodiments, the number of carbon atoms in the ring is from 3 to 5, from 3 to 6, or from 3 to 7. in some embodiments, the cycloalkyl groups are saturated cycloalkyl groups. Such saturated cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl and the like, or multiple or bridged ring structures, such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like. In other embodiments, the cycloalkyl groups are unsaturated cycloalkyl groups. Examples of unsaturated cycloalkyl groups include, but are not limited to, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. The cycloalkyl group may be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol and the like.

An aryl group is an aromatic carbocyclic group of 6-14 carbon atoms having a single ring (eg, phenyl) or multiple fused rings (eg, naphthyl or anthryl). In some embodiments, aryl groups contain 6 to 14 carbon atoms, and in others, 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Specific aryls include phenyl, biphenyl, naphthyl and the like. The aryl group may be substituted or unsubstituted. The phrase aryl groups also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (eg, indanyl, tetrahydronaphthyl and the like).

A heteroaryl group is an aromatic ring system containing one to four heteroatoms as ring atoms in a heteroaromatic ring system where the remaining atoms are carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 carbon atoms, and in others, 6 to 9 or even 6 to 10 carbon atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g. benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g. indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g. 1Hbenzo[d] imidazolyl), imidazopyridyl (e.g. azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g. 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g. benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g. 3,4dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl and quinazolinyl groups. The heteroaryl group may be substituted or unsubstituted.

A heterocyclyl is an aromatic (also called heteroaryl) or non-aromatic cycloalkyl in which one to four ring carbon atoms are independently replaced by a heteroatom from the group consisting of O, S, and N. In some embodiments, heterocyclyl groups include from 3 to 10 members per ring, while other such groups have from 3 to 5, from 3 to 6 or from 3 to 8 members in the ring. Heterocyclyls can also be linked to other groups at any ring atom (that is, at any carbon atom or heteroatom of the heterocyclic ring). The heterocycloalkyl group may be substituted or unsubstituted. Heterocyclyl groups

- 3 044376 ps include unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (eg imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring forms, including those containing fused aromatic and non-aromatic groups, such as, for example, 1-2-aminotetralin, benzotriazolyl (for example, 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (eg 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom, such as, but not limited to, quinuclidyl. Typical examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furniture perazinil (eg , piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g. tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithienyl, dihydrodithionyl, 1 ,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl, (for example, indolyl-2onyl or isoindolin-1-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl ), indazolyl, indolizinyl, benzotriazolyl (for example, 1Hbenzo[d][1,2,3]triazolyl), benzimidazolyl (for example, 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithinyl, benzoxatinyl, benzothiazinyl, benzoxatinyl, benzoxazolyl (e.g. benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (e.g. 1H-pyrazolo[3 ,4b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g. azabenzimidazolyl or 1Himidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g. 3,4-dihydroisoquinolin-1(2H)-onyl), quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl , tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one and tetrahydroquinolinyl groups. Typical non-aromatic heterocyclyl groups do not include fused ring compounds that contain a fused aromatic group. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g. imidazolidin-4-onyl or imidazolidin2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g. piperazin-2-onyl) . Exemplary substituted heterocyclyl groups may be monosubstituted or substituted more than once, for example, without limitation, pyridyl or morpholinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with various substituents such as those listed below.

As used herein, unless otherwise indicated, a cycloalkylalkyl group is a radical of the formula -alkylcycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted on the alkyl, cycloalkyl, or both alkyl and cycloalkyl portions of the group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl and the like.

As used herein, unless otherwise indicated, an aralkyl group is a radical of the formula: -alkylaryl, where alkyl and aryl are as defined above. Substituted aralkyl groups may be substituted on the alkyl, aryl, or both alkyl and aryl moieties of the group. Typical aralkyl groups include, but are not limited to, benzyl and phenethyl groups and aralkyl groups in which the aryl group is fused to a cycloalkyl group such as indan-4-yl-ethyl.

As used herein, unless otherwise indicated, a heterocyclylalkyl group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined above. The heteroarylalkyl group is a radical of the formula: -alkyl-heteroaryl, where alkyl and heteroaryl are as defined above. The heterocycloalkylalkyl group is a radical of the formula: -alkylheterocycloalkyl, where alkyl and heterocycloalkyl are as defined above. Substituted heterocyclylalkyl groups may be substituted on the alkyl, heterocyclyl, or both alkyl and heterocyclyl moieties of the group. Typical heterocyclyl alkyl groups include, but are not limited to, morpholin-4-yl-ethyl, morpholin-4-yl-propyl, furan-2-yl-methyl, furan-3-yl-methyl, pyridin-3-yl-4 044376 methyl, tetrahydrofuran-2-yl-ethyl and indol-2-yl-propyl.

Halogen is fluorine, chlorine, bromine or iodine.

A hydroxyalkyl group is an alkyl group as described above, substituted with one or more hydroxy groups.

An alkoxy group is -O-(alkyl), where alkyl is as defined above.

An alkoxyalkyl group is -(alkyl)-O-(alkyl), where alkyl is as defined above.

An amino group is a radical of the formula: -NH2, -NH(R#) or -N(R#) ₂ , where each R# is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (for example, heteroaryl or heterocycloalkyl) or heterocyclylalkyl (eg, heteroarylalkyl or heterocycloalkylalkyl) group as defined above, each of which is independently substituted or unsubstituted.

In one embodiment, the amino group is an alkylamino group, which is a radical of the formula: -NH-alkyl or -N(alkyl) ₂ , wherein each alkyl is independently defined above. The term cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, or the like reflects the above description for alkylamino, where the term alkyl is replaced by cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, and the like, respectively.

The carboxyl group is a radical with the formula -C(O)OH.

As used herein, unless otherwise indicated, an acyl group is a radical of the formula: -C(O)(R#) or -C(O)H, wherein R# is as defined above. The formyl group is a radical with the formula -C(O)H.

As used herein, unless otherwise indicated, an amido group is a radical of the formula: -C(O)-NH2, -C(O)-NH(R#), -C(O)-N(R#)2, -NH-C(O)H, -NH-C(O)-(R#), -N(R#)-C(O)H or -N(R#)C(O)-(R#) , where each R# is independently defined above.

In one embodiment, the amido group is an aminocarbonyl group, which is a radical of the formula: -C(O)-NH2, -C(O)-NH(R#), -C(O)-N(R#) ₂ . where each R# is independently defined above.

In one embodiment, the amido group is an acylamino group, which is a radical of the formula: -NH-C(O)H, -NH-C(O)-(R#), -N(R#)-C(O) H or -N(R#)-C(O)-(R#), where each R# is independently defined above.

The sulfonylamino group is a radical of the formula: -NHSO2(R#) or

-N(alkyl)SO ₂ (R#), where each alkyl and R# are defined above.

The urea group is a radical of the formula: N(alkyl)C(O)N(R#) ₂ , -N(alkyl)C(O)NH(R#), -N(alkyl)C(O)NH2, -NHC (O)N(R#)2, -NHC(O)NH(R#) or -NH(CO)NH2, where each alkyl and R# are independently defined above.

When groups described herein, other than the alkyl group, are referred to as substituted, they may be substituted with any suitable substituent or substituents. Illustrative examples of substituents include those compounds exemplified herein and in the embodiments, as well as halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioester; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamine; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxylamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH) ₂ , O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or unfused polycyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or heterocyclyl, which may be monocyclic or fused or unfused polycyclic (eg, pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (for example, phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

As used herein, the term piperidinedione compound refers to compounds of formula (I), as well as additional embodiments presented herein. In one embodiment, the piperidinedione compound is a compound listed in the table. The term piperidinedione compound includes pharmaceutically acceptable salts, tautomers, isotopologues and stereoisomers of the compounds provided herein.

As used herein, the term pharmaceutically acceptable salt(s) refers to a salt derived from a pharmaceutically acceptable non-toxic acid or base, including inorganic acid and base and organic acid and base. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to

- 5 044376 them, metal salts obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts obtained from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N -methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furonic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic , hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric and p-toluenesulfonic acids. Representative non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric and methanesulfonic acids. Examples of representative salts thus include formic acid hydrochloride and mesylate salts. Others are well known in the field, see, for example, Remington's Pharmaceutical Sciences, ^18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, ^19th eds., Mack Publishing, Easton PA ( 1995).

As used herein and unless otherwise indicated, the term stereoisomer or stereoisomerically pure means one stereoisomer of a piperidinedione compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, more about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. Piperidinedione compounds may have chiral centers and may occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

The use of stereoisomerically pure forms of such piperidinedione compounds, as well as the use of mixtures of these forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular piperidinedione compound may be used in the methods and compositions disclosed herein. These isomers can be synthesized asymmetrically or separated using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

It should also be noted that piperidinedione compounds may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In some embodiments, the piperidinedione compounds are isolated as either the E- or Z-isomer. In other embodiments, the piperidinedione compounds are a mixture of E and Z isomers.

Tautomers refer to isomeric forms of a compound that are in equilibrium with each other. Concentrations of isomeric forms will depend on the environment in which the compound is found and may differ depending, for example, on whether the compound is a solid or in organic or aqueous solution. For example, in aqueous solution, pyrazoles can have the following isomeric forms, which are called tautomers of each other:

As will be readily appreciated by one skilled in the art, a wide range of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are included within the scope of the present invention.

It should also be noted that piperidinedione compounds may contain unusual proportions of atomic isotopes at one or more atoms. For example, compounds may be labeled with radioactive isotopes, such as tritium ( ^3H ), iodine-125 ( ^125I ), cepa-35 ( ^35S ), or carbon-14 ( ^14C ), or may be enriched with isotopes , such as deuterium ( ^2H ), carbon-13 ( ^13C ) or nitrogen-15 ( ^15N ). In the context of this document, isotopologue means an isotopically enriched

- 6 044376 unity. The term isotopically enriched refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. Isotopically enriched may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. The term isotopic composition refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, for example, anti-cancer therapeutic agents, research reagents, for example, binding assay reagents, and diagnostic agents, for example, in vivo imaging agents. All isotopic variants of the piperidinedione compounds as described herein, whether radioactive or not, are intended to be within the scope of the embodiments presented herein. In some embodiments, isotopologues of piperidinedione compounds are provided, for example, the isotopologues are deuterium-, carbon-13-, and/or nitrogen-15-rich piperidinedione compounds. As used herein, the term deuterated means a compound in which at least one hydrogen (H) is replaced by deuterium (denoted D or H), that is, the compound is enriched in deuterium at at least one position.

It is understood that, regardless of stereoisomeric or isotopic composition, each piperidinedione compound mentioned herein may be provided in the form of any of the pharmaceutically acceptable salts discussed herein. It is equally understood that the isotopic composition may vary independently of the stereoisomeric composition of each piperidinedione compound mentioned herein. In addition, the isotopic composition, while limited to those elements present in the corresponding piperidinedione compound or salt thereof, may otherwise vary regardless of the choice of pharmaceutically acceptable salt of the corresponding piperidinedione compound.

It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure is given greater weight.

Treatment, as used herein, means alleviating, in whole or in part, a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition, or slowing or stopping further progression or worsening of those symptoms, or alleviating or eliminating the cause(s) ) disorder, disease or condition itself. In one embodiment, the disorder is an androgen receptor-mediated disease, as described herein, or a symptom thereof.

Prevention, as used herein, means a method of delaying and/or preventing the occurrence, recurrence or spread, in whole or in part, of a disorder, disease or condition; preventing the subject from acquiring a disorder, disease or condition; or reducing the risk of a subject acquiring a disorder, disease or condition. In one embodiment, the disorder is an androgen receptor mediated disease, as described herein, or symptoms thereof.

The term effective amount in connection with a piperidinedione compound means an amount capable of treating or preventing the disorder, disease or condition or symptoms thereof described herein.

The terms subject and patient as used herein include an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig , in one embodiment a mammal, in another embodiment a human. In one embodiment, the subject is a person who has or is at risk of an androgen receptor-mediated disease or a symptom thereof.

The term androgen receptor, or AR, or NR3C4 as used herein refers to a nuclear hormone receptor activated by the binding of androgen hormones, including testosterone or dihydrotestosterone. The term androgen receptor may refer to the nucleotide or protein sequence of a human androgen receptor (eg, Entrez 367, Uniprot P10275, RefSeq NM_000044, or RefSeq NP_000035).

The term AR-full length (AR-FL) as used herein refers to an AR protein that contains all four functional domains, including the N-terminal transactivation domain (NTD, exon 1), DNA binding domain (DBD, exons 2-3) , hinge domain (exon 4) and C-terminal ligand binding domain (LBD, exons 4–8).

The term castration-resistant prostate cancer (CRPC) refers to advanced prostate cancer that worsens or progresses while the patient continues to take androgen deprivation therapy or other treatments aimed at lowering testosterone levels, or prostate cancer that is considered hormone-refractory, hormone-naïve, androgen-independent or resistant to chemical or surgical castration. Castration-resistant prostate cancer (CRPC) is advanced prostate cancer that has developed despite ongoing ADT and/or surgical castration. Castration-resistant prostate cancer is defined as

- 7 044376 is defined as prostate cancer that continues to progress, worsen, or negatively impact the patient's health despite prior surgical castration, ongoing treatment with gonadotropin-releasing hormone agonists (eg, leuprolide) or antagonists (eg, degarelix or abarelix), antiandrogens ( eg, bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutetamide), chemotherapeutic agents (eg, docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabozantinib ( Cometriq®, also known as XL184)) or other treatments for prostate cancer (eg, vaccines (sipuleucel-T (Provenge®), GVAX, etc.), herbal (PCSPES) inhibitors and lyase inhibitor (abiraterone)), such as evidenced by increased or increased serum levels of prostate specific antigen (PSA), metastases, bone metastases, pain, lymph node involvement, increased tumor size or serum markers of tumor growth, worsening diagnostic markers of prognosis, or patient condition.

Piperidinedione compounds.

Provided herein are compounds having the following formula (I):

or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein:

R ^N represents H;

each R ¹ is independently selected from halogen, CN, and C ₁ - ₃ alkyl;

R ² and R ³ are each independently selected from H, and C1_3alkyl, or R ² and ^R3 and the carbon atom to which they are attached form a substituted or unsubstituted C3-6cycloalkyl;

each R ⁴ independently represents a substituted or unsubstituted C1_3alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl, or two R ⁴ groups together with non-adjacent the carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;

X represents N;

L represents -O(C ₁ _ ₆ alkyl)- or -(C ₁ _ ₉ alkyl)-;

n is 0-4;

m is 0-8;

V represents where A represents N, CH, or CRA;

B represents N, CH, or CR ^B ;

each RA is independently selected from halogen, substituted or unsubstituted C _{1_6} alkyl, and _substituted or unsubstituted C _3-6 cycloalkyl;

each RA is independently selected from halogen and substituted or _{unsubstituted C 1_6 alkylα} ;

R ^C represents halogen or CF ₃ ;

R ⁵ and R ⁶ represent C1_3 alkyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted _C3-6 cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3; and b is 0-2.

Provided herein are compounds having the following formula (I):

or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein:

RN is H;

Each R ¹ is independently selected from halogen, CN and C _1-3 alkyl;

R ² and R ³ are each independently selected from H and C1-3 alkyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl;

each R ⁴ independently represents a substituted or unsubstituted C _1-3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they

- 8 044376 are attached to form a substituted or unsubstituted C _3-6 cycloalkyl, or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

X represents N;

L represents -O(CH ₂ ) _p - or -(CH ₂ ) _p ;

n is 0-4;

m is 0-8;

p equals 1-3;

V represents where A represents N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C3-6 alkyl, and substituted or unsubstituted _C3-6 cycloalkyl;

each R ^a is independently selected from halogen and substituted or _{unsubstituted} C _{1_6} αlkyl;

RC is halogen or CF3;

R ⁵ and R ⁶ represent C1_3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3_ ₅ cycloalkyl or 3-5 membered heterocyclyl;

and equals 0-3; and b is 0-2.

In one embodiment of a compound of formula (I), the compound is

In another embodiment of a compound of formula (I), the compound is

(Пь).

In some embodiments of the compounds of formula (I), (IIa) and (IIb), each R ¹ is independently selected from halogen and C _1-3 alkyl. In some embodiments of the compounds of formula (I), (IIa) and (IIb), each R ¹ is independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl. In other embodiments, each R ¹ is independently selected from Cl, F, CN, and -CH3. In some other embodiments, each R ¹ is independently selected from Cl, F, and CN.

In some embodiments of the compounds of formula (I), n is 0. In other embodiments, n is 1 or 2.

In some embodiments of compounds of formula (I), the compound is

In other embodiments of compounds of formula (I), the compound is

In yet other embodiments of compounds of formula (I), the compound is

- 9 044376

In some embodiments, the compound is a compound of formula (III), (IV) or (V), wherein each R ¹ is independently selected from Cl, F, CN and CH3. In some such embodiments, the compound is a compound of formula (III), (IV) or (V) wherein R ¹ represents F or Cl. In some embodiments of compounds of formula (III), R ¹ is F, Cl, or CN. In some embodiments of compounds of formula (IV), R ¹ is F.

In some embodiments of the compounds of formula (I), R2 and ^R3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R2 and ^R3 and the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl. In some such embodiments, R2 and ^R3 are each independently selected from H and methyl or R2 and ^R3 and the carbon atom to which they are attached form unsubstituted cyclopropyl. In some similar embodiments, R2 and ^R3 are both H or methyl, or R2 and ^R3 and the carbon atom to which they are attached form unsubstituted cyclopropyl. In some embodiments, R2 and ^R3 are H.

In some embodiments of the compounds of formula (I), each R ⁴ is independently selected from substituted or unsubstituted methyl and ethyl, or two R ⁴ groups together with the same carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl or cyclobutyl. In some embodiments, each R ⁴ is independently substituted or unsubstituted methyl, or two R ⁴ groups together with the same carbon atom to which they are attached form unsubstituted cyclopropyl. In other embodiments, each R ⁴ is independently selected from methyl, CF ₃ and CH2OH, or two R ⁴ groups together with the same carbon atom to which they are attached form unsubstituted cyclopropyl. In yet other embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is ethyl.

In some embodiments of the compounds of formula (I), m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, or 2.

In some embodiments of compounds of formula (I), two R ⁴ groups, together with the non-adjacent carbon atoms to which they are attached, form an unsubstituted 4-7 membered heterocyclyl. In some embodiments, the connection is

In some such embodiments, the connection is

In some such embodiments, the connection is

In some embodiments of compounds of formula (I), (IIa), (IIb), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X), typical L-groups include, but are not limited to, -O(CH2)(CH2)-, -O(CH2)(CH(CH3))-, -O(CH2)(C(CH3)2)-, -O (CH(CH3))(CH2)-, -O(C(CH3)2)(CH2)-, -O(CH(CH3))(CH(CH3))-,

- 10 044376

-O(CH(CH3))(C(CH3)2)-, -O(C(CH3) ₂ )(CH(CH3))-, -(CH2)-, -(CH2ХСН2)-, -( _CH2 )(CH ₂ )(CH ₂ )-,

-(C(CH3)2)(C(CH3)2)-, -(CH(CH3))-, -(C(CH3)2)-, -(CH(CH3))(CH(CH3))- , -(CH(CH3))(C(CH3)2)-,

-(C(CH3)2)(CH(CH3))-, -(C(CH3)2)(C(CH3)2)-, -( _CH3 )( _CH3 )(CH( _CH3 ))- , -(CH2)(CH( _CH3 ))(CH2)(CH(CH3))(CH2)(CH2)-, -(CH2)(CH2)(C(CH2)2)-, -(CH2)( C(CH2)2)(CH2)-, (C(CH2)2)(CH2)(CH2)-,

- (CH2)(CH(CH3))(CH(CH3))-, -(CH(CH3))(CH(CH3))(CH(CH3))-, -(CH(CH3))(CH(CH3 ))(CH2)-,

- (СН(СНз))(СН2)(СН(СНз))-, -(СН2)(СН(СНз))(С(СНз)2)-, -(СШЧСНзМСНХССНХ)-,

- (C(CH3)2)(CH2)(C(CH3)2)-, -(CH2)(C(CH3)2)(C(CH3)2)-, -(CH2)(C(CH3)2 )(CH(CHz))-,

-(CH(CH3)(C(CH3)2)(CH2)-, -(C(CH3)2)(CH2)(CH(CH3))-, -(C(CH3)2)(CH(CH3) )(CH2)-,

-(C(CH3)2)(C(CH3)2)(CH2)-, -(CH(CH3))(CH(CH3))(C(CH3)2)-, -(CH(CH3))( С(СНз)2)(С(СНз)2)-,

-(С(СНз)2)(СН(СНз))(С(СНз)2)-, (СН(СНз))(С(СНз)2)(СН(СНз))-, -(С(СНз) 2)(С(СНз)2)(СН(СНз))-, (С(СНз)2ХСН(СНз)ХСН(СНз))- and -(С(СНз)2)(С(СНз)2)(С (СНз)2)-.

In some embodiments of compounds of formula (I), L is -O(CH2)(CH2)-, -O(CH2)(CH(CH3))-, -O(CH2)(C(CH3)2)-, - O(CH(CH3))(CH2)-, O(CH(CH3))(CH(CH3))-, -O(CH(CH3)(C(CH3)2)-, -O(C(CH3) 2)(CH2)-, -(CH2)-, -(CH2XCH2)- or -(CH2XCH2XCH2)-. In some embodiments of the compounds of formula (I), L is -O( _CH2 )( _CH2 )-, - (CH ₂ )-, -(CH ₂ )(CH ₂ )- or -(CH2XCH2XCH2)- In other embodiments, L is -O(CH ₂ )(CH ₂ )- or -(CH ₂ )(CH ₂ )(CH ₂ )-. In still other embodiments, L is -O(CH ₂ )(CH ₂ )-. In some embodiments of compounds of formula (I), L is -O(CH2)(CH2)-, - O(CH2)(CH(CH3))-, -O(CH(CH3))(CH2)- or -(CH2ХСН2ХСН2)-.

In some embodiments of compounds of formula (I), A is CH. In certain other embodiments of compounds of formula (I), B is CH. In some other embodiments, B is N.

In some embodiments of compounds of formula (I), a is 0, 1, or 2.

In some embodiments of the compounds of formula (I), each R ^A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, npentyl, CH2CH2CH(CH3 )2, CH(CH3)CH(CH3)2, CF3, CF(CH3)2, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH , cyclopropyl, cyclobutyl and cyclopentyl. In some such embodiments, each ^RA is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, _sec -butyl, CF3 _{, CF2CH3 , CH2CH2F} , _CH2CHF2 , CH ₂ OH, CH(CH ₃ )OH, cyclopropyl, cyclobutyl and cyclopentyl. In some embodiments, where B is CH, each R ^A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, cyclopropyl, cyclobutyl and cyclopentyl. In other embodiments, where B is N, each RA ^is independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF2CH ₃ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ OH, CH(CH ₃ )OH, cyclopropyl and cyclobutyl. In some such embodiments, each R is independently selected from ethyl, isopropyl, and cyclopropyl.

In some embodiments of compounds of formula (I), b is 0 or 1. In some embodiments of compounds of formula (I), R ^B is methyl. In some embodiments of compounds of formula (I), RC is CF ₃ or Cl.

In some embodiments of the compounds of formula (I), R ⁵ and R ⁶ are methyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, tetrahydrofuranyl or tetrahydropyranyl. In some embodiments, R ⁵ and R ⁶ are methyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form cyclobutyl or tetrahydrofuranyl. In some embodiments, R ⁵ and R ⁶ are methyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydrofuranyl.

In some embodiments of compounds of formula (III), (IV), or (V), each R ¹ is independently selected from Cl, F, CN, and CH3, and R ² and R ³ are H. In some such embodiments, each R ⁴ is independently selected from methyl, CF3 and CH ₂ OH, or two R ⁴ groups together with the same carbon atom to which they are attached form unsubstituted cyclopropyl. In some such embodiments, R ⁴ is methyl. In some such embodiments, R ⁴ is ethyl. In some other embodiments, L is -O(CH2)(CH2)- or -(CH2XCH2XCH2)-. In some other embodiments, L is -O(CH2)(CH(CH3))-, O(CH(CH3))(CH2)-. In other similar embodiments, a further aspect A is CH. In yet other similar embodiments, B is CH and each R ^A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF ₂ CH ₃ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , cyclopropyl, cyclobutyl and cyclopentyl. In other similar embodiments, B is N and each R ^A is independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF ₂ CH ₃ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ OH, CH(CH ₃ )OH and cyclopropyl. In some other similar embodiments, each R ^A is ethyl, isopropyl, or cyclopropyl. In other similar embodiments, R ⁵ and R ⁶ are methyl, or R ⁵ and R ⁶ together with the carbon atom to which they

- 11 044376 are added to form cyclobutyl or tetrahydrofuranyl. In some embodiments, R ⁵ and R ⁶ are methyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydrofuranyl.

In some embodiments, compounds of formula (I), (IIa) and (IIb), wherein R ⁿ is H;

each R ¹ is independently selected from Cl, F, Br, CN, -CH ₃ , -CH2CH3 and isopropyl;

each R2 and ^R3 are independently selected from H, substituted or unsubstituted methyl and ethyl, or R2 and ^R3 and the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl;

each R ⁴ is independently selected from substituted or unsubstituted methyl or ethyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R ⁴ groups together with non-adjacent carbon atoms to which they are attached, they form a substituted or unsubstituted 4-7-membered heterocyclyl;

X represents N;

L represents -O(C _1-5 alkyl)- or -(C _1-5 alkyl)-;

n is 0-4;

m equals 0-2;

V represents ’ where A represents N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^{a is} independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3) CH(CH3)2, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CHF2, CH2CF3, CH2OH, cyclopropyl, cyclobutyl and cyclopentyl;

each R ^B is independently selected from halogen and methyl;

R ^C represents halogen or CF ₃ ;

R ⁵ and R ⁶ are methyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl;

and equals 0-3; and b is 0-2.

In some embodiments of compounds of formula (I), (IIa) and (IIb),

R ^N represents H;

each R ¹ is independently selected from Cl, F, Br, CN, -CH ₃ , -CH ₂ CH ₃ and isopropyl;

each R ² and R ³ is independently selected from H, substituted or unsubstituted methyl and ethyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl;

each R ⁴ is independently selected from substituted or unsubstituted methyl or ethyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R ⁴ groups together with non-adjacent carbon atoms to which they are attached, they form a substituted or unsubstituted 4-7-membered heterocyclyl;

X represents N;

L represents -O(CH ₂ ) _p - or -(CH ₂ ) _p -;

n is 0-4;

m equals 0-2;

p equals 1-3;

V represents ' where A represents N, CH, or CR ^A ;

B is N, CH, or CRB;

each R ^A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3) CH(CH3)2, CF3, CF2CH3, CH2CH2F,

- 12 044376

CH2CHF2, CH2CF3, CH2OH, CH( _CH3 )OH, CH2CH2OH, CH( _CH3 )CH2OH, CH2CH( _CH3 )OH, cyclopropyl, cyclobutyl and cyclopentyl;

each R ^B is independently selected from halogen and methyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ represent methyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted cyclobutyl or tetrahydrofuranyl;

and equals 0-3; and b is 0-2.

In certain embodiments of compounds of formula (III), (IV), and (V),

R ⁿ represents H;

each R ¹ is independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl;

each R ² and R ³ is independently selected from H, substituted or unsubstituted methyl and ethyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl;

each R ⁴ is independently selected from substituted or unsubstituted methyl or ethyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R ⁴ groups together with non-adjacent carbon atoms to which they are attached, they form a substituted or unsubstituted 4-7-membered heterocyclyl;

X represents N;

L represents -O(C ₁ . ₅ alkyl)- or -(C ₁ . ₅ alkyl)-;

n is 0-4;

m is 0, 1 or 2;

V represents ’ where A represents N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^{a is} independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3) CH(CH3)2, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl;

each R ^B is independently selected from halogen and methyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ are methyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl;

and equals 0-3; and b is 0-2.

In certain embodiments of compounds of formula (III), (IV), and (V),

R ⁿ represents H;

each R ¹ is independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl;

each R ² and R ³ is independently selected from H, substituted or unsubstituted methyl and ethyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl;

each R ⁴ is independently selected from substituted or unsubstituted methyl or ethyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R ⁴ groups together with non-adjacent carbon atoms to which they are attached, they form a substituted or unsubstituted 4-7-membered heterocycle;

X represents N;

L represents -O(CH ₂ ) _p - or -(CH ₂ ) _p -;

n is 0-4;

m is 0, 1 or 2;

p equals 1-3;

- 13 044376

V represents

where A represents N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^{a is} independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH ₂ CH ₂ CH(CH ₃ ) ₂ , CH( _CH3 )CH( _CH3 ) ₂ , CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH( _CH3 )OH, CH2CH2OH, CH( _CH3 ) _CH2OH , _CH2CH ( _CH3 )OH, cyclopropyl, cyclobutyl and cyclopentyl;

each R ^B is independently selected from halogen and methyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ represent methyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted cyclobutyl or tetrahydrofuranyl;

and equals 0-3; and b is 0-2.

Additional embodiments provided herein include any combination of one or more of the specific embodiments set forth above.

In some embodiments of compounds of formula (I), the compound is a compound from the table.

Representative compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are presented in the table.

The piperidinedione compounds presented in the table were tested and found to be active in the AP-mediated assays described herein. In one embodiment, the piperidinedione compound is a compound as described herein, wherein the compound at a concentration of 1 μM results in degradation of the AP protein by at least about 50% or more.

Methods for preparing piperidinedione compounds.

The piperidinedione compounds described herein can be prepared using conventional organic syntheses and commercially available starting materials or methods presented herein. By way of example, and not limitation, piperidinedione compounds of formula (I) wherein: RN, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , RA , ^RB , ^RC , ^L , V, X , n, m, p, a and b have the meanings specified herein, can be obtained as shown in Schemes 1-8 shown below, as well as in the examples set forth herein. It should be noted that one skilled in the art will understand how to modify the procedures set forth in the illustrative diagrams and examples to obtain the desired products.

Scheme 1

As shown in Scheme 1, piperidinedione compounds of formula (I), where L is -O(C ₁ . ₆ alkyl)-, can be prepared starting from the reaction of a phenol (A is CH or CR ^a ) or a pyridinone derivative (A is is N) V-OH with appropriately derivatized and N-protected piperazinyl (for example, where P ^N is Boc and the leaving group LG ¹ is

- 14 044376 is Br, Cl, OTs or OMs) in the presence of a base in a solvent (for example, CsCO ₃ in DMF or K2CO3 in acetonitrile) at elevated temperature (for example, between about 40°C and about 70°C) to obtain an intermediate connections a. Alternatively, when LG ¹ is -OH, V-OH is treated under Mitsunobu reaction conditions (eg, PPh3 and DIAD or DEAD in a solvent such as THF at room temperature) to yield intermediate a. In yet another embodiment, V-OH may first react with LG2-L-Hal, where Hal is Cl, Br, OMs or OTs, and where LG ² is Br, Cl, OH, and where LG ² is Br or Cl, the reaction is carried out in the presence of a base such as CsCO3 or K2CO3, in a solvent such as DMF or NMP, at an elevated temperature, for example between about 40°C and about 70°C; or when LG2 is OH, perform the Mitsunobu reaction (using PPh3 and DIAD or DEAD in a solvent such as THF at room temperature) to form VL-Hal, which reacts with a suitably protected piperazinyl (in the presence of a base such as CsCO3 or K2CO3, in a solvent such as DMF or NMP, at an elevated temperature, for example, between about 40°C and about 70°C), to obtain intermediate compound a. Removal of the N-protecting group P ^N from intermediate a (eg, when P ^N is Boc, by treatment with an acid in a solvent, such as hydrochloric acid in dioxane or EtOAc, at room temperature, or TFA in DCM, at room temperature), gives the intermediate connection b. By reacting intermediate b with Br-C(R2)(R ³ )COOR (where R is C _1-4 αalkyl, such as methyl, ethyl or t-butyl) in the presence of a base such as TEA, DBU, or DIPEA in a solvent, such as THF, NMP or DMF, optionally at elevated temperature (eg, about 20°C to about 80°C), optionally in the presence of NaI or KI, intermediate c. Alternatively, intermediate c is prepared by reacting VL-Hal (where Hal is Cl, Br, OMs or OTs) with suitably derivatized 2- ₍ piperazin-1-yl)acetate (where R is _C1.4αalkyl , e.g. methyl, ethyl or t-butyl) in the presence of a base such as DIPEA, TEA or DBU, in a solvent such as DMF or NMP at room temperature. Deprotection of the carboxylate intermediate with, wherein R is methyl or ethyl, treatment with a base such as LiOH or NaOH in a solvent such as THF/H2O mixtures or dioxane/H ₂ O mixtures; or, when R is tert-butyl, treatment with an acid in a solvent such as HCl in dioxane/DCM mixtures or TFA in DCM gives intermediate d.

Suitably derivatized 3-((3-aminophenyl)amino)piperidine-2,6-diones h are obtained from R ¹ -derivatized 3-nitroanilines, which are protected by the amino protecting group P ^N (and when P ^N is, for example, Boc, by treating Boc2O in the presence of a base such as TEA, DIPEA or DBU in a solvent such as THF, NMP or DMF) to form intermediate e. The nitro group in intermediate e is reduced (by treatment with a reducing agent such as H2 in the presence of a catalyst such as Pd/C in a solvent such as EtOH or MeOH; or Fe and NH4Cl in a solvent such as EtOH and H2O) to give a monoprotected intermediate derivatized dianiline f. The coupling reaction of intermediate f with 3-bromopiperidine-2,6-dione in the presence of a base in a solvent (eg NaHCO3, CsCO3 or K2CO3, in DMF or NMP, at elevated temperature, for example about 50°C to about 80°C ; or DIPEA in DMF or NMP, at elevated temperature, for example, about 150°C) followed by removal of the protecting group P ^N (for example, when P ^N is Boc, treatment of the acid in a solvent such as TFA in DCM or treatment with HCl in dioxane or EtOAc) yields intermediate h. Alternatively, intermediate h is prepared by iron-catalyzed reductive coupling of intermediate e and 3bromopiperidine-2,6-dione (e.g., reaction in the presence of Zn, TMSCl, _FeCl2-4H2O , in a solvent such as NMP at elevated temperature , for example from about 80°C to about 100°C) followed by removal of the protecting group P ^N (for example, when P ^N is Boc, treatment with an acid in a solvent such as TFA in DCM; or treatment with HCl in dioxane or EtOAc).

The coupling reaction of intermediate d with intermediate h, for example in the presence of a coupling agent such as HATU, HBTU, or EDC, or DCC, optionally in combination with HOBt, in the presence of a base such as DIPEA, NMM or TEA in a solvent such as DCM, DMF or NMP, or mixtures thereof, gives compounds of formula (I) wherein L is -O(C ₁ . ₆ alkyl)-.

- 15 044376

Scheme 2

Alternative approaches to the synthesis of compounds of formula (I) are shown in Scheme 2. In one embodiment, a common intermediate h is reacted with Hal ² -C(R ² ) (R ³ )COY (where Hal ² is Cl or Br) in the presence of Y represents OH, a coupling agent (eg HATU, HBTU or EDC or DCC, optionally in combination with HOBt) and a base (eg DIPEA, TEA or NMM) in a solvent (eg DCM, DMF, NMP or mixtures thereof); or in the presence, when Y is Cl, of a base such as TEA or DIPEA, in a solvent such as DMF or NMP, at a temperature of from about 0°C to about 25°C, to obtain intermediate compound i. Treatment of intermediate i with intermediate b in the presence of a base such as DIPEA, TEA or NMM, in a solvent such as DMF or NMP at an elevated temperature, for example from about 40°C to about 60°C, optionally in the presence of NaI or KI, gives the target compounds of formula (I). In the second embodiment, intermediate h is combined with an N-protected, suitably derivatized 2-(piperazin-1-yl)acetic acid (where P ^N is, for example, Boc) reaction in the presence of a coupling agent (for example, HATU, HBTU or EDC or DCC, optionally in combination with HOBt) and a base (eg DIPEA, TEA or NMM) in a solvent (eg DCM, DMF, NMP or mixtures thereof) to give intermediate j. Alternatively, intermediate j is prepared by reacting intermediate i with an appropriately derivatized protected piperazine (where P ^N is, for example, Boc) in the presence of a base such as DIPEA, TEA or NMM, in a solvent such as DMF or NMP at elevated temperature, for example from about 40°C to about 80°C, optionally in the presence of NaI or KI. In yet another embodiment, intermediate j is prepared by reacting intermediate ae (where P ^N is, for example, Cbz) with Hal-C(R2)(R ³ )COY (where Hal is Cl or Br) in the presence of when Y is OH, a coupling agent (eg HATU, HBTU or EDC or DCC, optionally in combination with HOBt) and a base (eg DIPEA, TEA or NMM) in a solvent (eg DCM, DMF, NMP or mixtures thereof) to get the intermediate af. Treatment of the intermediate af with N-protected, suitably functionalized piperazine (where P ^N is, for example, Boc), in the presence of a base such as DIPEA or TEA, in a solvent such as DMF or NMP, at elevated temperature, e.g. about 60°C to about 90°C, optionally in the presence of NaI or KI, gives intermediate ag. Intermediate ag is deprotected, for example with a reducing agent such as H2 when P ^N is Cbz, in the presence of a catalyst (eg Pd/C, Pt/C or Pd(OH)2) in a solvent such as MeOH or EtOAc to give intermediate ah. The coupling reaction of intermediate ah with 3-bromopiperidine2,6-dione in the presence of a base in a solvent (eg NaHCO ₃ , CsCO ₃ or K ₂ CO ₃ , in DMF or NMP, at elevated temperature, for example from about 50°C to about 80°C; or DIPEA in DMF or NMP, at elevated temperature, eg about 150°C), gives intermediate j. Deprotection of intermediate j (when P ^N is Boc by treatment with an acid in a solvent such as TFA in DCM or HCl in dioxane/DCM or EtOAc) followed by reaction with VL-Hal (where Hal is Cl , Br, OMs or OTs) in the presence of a base, e.g.

DIPEA, TEA or NMM, in a solvent, for example DMF or NMP, at elevated temperature, for example from about 50°C to about 70°C, gives compounds of formula (I).

Scheme 3

An alternative synthesis of intermediate a, where L is -O(C ₁ . ₆ alkyl)-, is shown in Scheme 3. An appropriately derivatized 4-nitrophenol or 5-nitropyridin2-ol is reacted with intermediate I (where LG ² is Br , Cl or OH), and when LG ² is Br or Cl, in the presence of a base in a solvent, at an elevated temperature (for example, the base is CsCO3 or K2CO3, the solvent is acetonitrile, DMF or NMP, and the temperature is from about 50 °C to about 80 °C), to obtain intermediate compound p. When LG ² is OH, carry out the Mitsunobu reaction (using PPh3 and DIAD or DEAD in a solvent such as THF at room temperature) to give intermediate n. Alternatively, when A is N, a suitably derivatized 2-halo-5-nitropyridine is reacted with intermediate m in the presence of a base such as CsCO ₃ or K2CO3 in a solvent such as acetonitrile, DMF, THF or NMP, at elevated temperature, for example from about 50°C to about 70°C, to obtain intermediate compound n. Reduction of the nitro group in intermediate n with a reducing agent in a solvent (e.g. _H2 in EtOH in the presence of a catalyst such as Pd/C; or Fe and _NH4Cl in EtOH and H2O, at elevated temperature, e.g. about 80°C) gives the intermediate O. Reaction of intermediate o with R'OOC-C(R ⁵ )(R ⁶ )Hal (where Hal is Br or Cl and R' is C _1.3 alkyl) _in the presence of a base (for example, DIPEA or TEA) at elevated temperature (for example, from 110°C to about 130°C) gives an intermediate p. Reaction of intermediate p with suitably derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile in the presence of a base such as TEA in a solvent such as EtOAc at elevated temperature, for example from about 70° C. to about 90° C., gives intermediate a. which can be further reacted to _give compounds of formula (I) wherein L is -O( _C1.6alkyl )- as described in the schemes above.

Alternatively, reacting intermediate o with CN-C(R ⁵ )(R ⁶ )OH in the presence of MgSO4 at elevated temperature, eg about 50° C. to about 70° C., gives intermediate q. The CN-C(R ⁵ )(R ⁶ )OH reagents can be formed by reacting C(=O)(R ⁵ )(R ⁶ ) with TMSCN and TMSOTf in a solvent such as DCM. Reaction of intermediate q, with suitably derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile in a solvent such as DMF or DMA, followed by treatment with an acid such as HCl in a solvent such as MeOH or EtOH at elevated temperature, for example from about 70°C to about 80°C gives intermediate a, which is used as described above to prepare compounds of formula (I) wherein L is -O( _C1.6alkyl )-.

Synthesis of intermediates in which R ^A represents substituted or unsubstituted C ₁ . ₆ alkyl, either substituted or unsubstituted C ₃ . ₆ cycloalkyl, shown in Schemes 4, 5 and 6.

- 17 044376

Scheme 4

Intermediate d, where ^P0 is a phenolic protecting group, e.g. acetyl or benzyl, can be treated with R ^A -Zn-Br in the presence of a catalyst and ligand, e.g. CPhosPdG3 and CPhos in a solvent, e.g. toluene, at reduced temperature, e.g. from about 0°C to about 25°C, with the formation of intermediate compound s. Removal of the protecting group ^PO (when ^PO is acetyl, by treatment with a base such as K2CO ₃ in a solvent such as MeOH or EtOH; or when ^PO is benzyl, by treatment with a reducing agent such as H2 in the presence of a catalyst, such as Pd/C, in a solvent such as EtOH or MeOH, or by treatment with a dealkylating agent such as BBr3, in a solvent such as DCM at low temperature, for example about -70°C), gives the intermediate V-OH, where R ^A represents substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C _3-6 cycloalkyl, which can be used in the above schemes. Alternatively, intermediates s where A is CH or CR ^A are formed by starting with hydroxyl protection of a suitably derivatized phenol with an alkylating agent such as bromomethylbenzene in a solvent such as acetonitrile with a base such as K2CO3 at elevated temperature, for example about 80°C, to obtain intermediate compound aw, where A represents CH or CR ^A and P ^O represents a phenolic protecting group such as benzyl. Treatment of the intermediate aw R ^A -B(OH)2B in the presence of a catalyst and a base, for example Pd(dppf)2Cl ₂ and Cs ₂ CO ₃ in a solvent such as a mixture of toluene and water, at elevated temperature, for example about 100°C, gives intermediate connection ah. The nitro group in intermediate ax can be selectively reduced to give intermediate ay using a reducing agent such as iron in the presence of a Lewis acid such as ammonium chloride in a solvent such as a mixture of EtOH and water at an elevated temperature, for example about 60°C. Reaction of intermediate ay with CN-C(R ⁵ )(R ⁶ )OH in the presence of MgSO4 at elevated temperature, eg about 50°C to about 70°C, produces intermediates az. Reaction of intermediate azc with suitably derivatized 4isothiocyanatobenzonitrile (where B is CH or CRB) or 5isothiocyanatopicolinonitrile (where B is N) in a solvent such as DMF or DMA, followed by treatment with an acid such as HCl in a solvent such as MeOH or EtOH , at elevated temperature, for example between about 70°C and about 80°C, gives intermediate compound s. Removal of the protecting group P ^O as described above gives compounds of formula V-OH wherein R ^A is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted C _3-6 cycloalkyl.

Scheme 5

Alternatively, as shown in Scheme 5, R ^A can be introduced by reacting intermediate t with R ^A -Zn-Br in the presence of a catalyst and ligand, e.g. CPhosPdG3 and CPhos, in a solvent, e.g. toluene, at a lower temperature, for example, from about 0°C to about 25°C to form intermediates and, where R ^A is a substituted or unsubstituted C1-6 alkyl, or a substituted or unsubstituted C _3-6 cycloalkyl, and which can be used similarly to intermediate a in the diagrams given above.

- 18 044376

Scheme 6

Intermediates x, where L is -O(C _1-6 alkyl)- and R ^A is as defined below, for use in the schemes above, can be prepared as shown in scheme 6. In the first step 2- bromo-4-nitrophenol or 3-bromo-5-nitropyridin-2-ol, reacts with suitably derivatized and N-protected piperazinyl (e.g. if P ^N is Boc and the leaving group LG ³ is Br, Cl, OTs or OMs) in the presence of a base in a solvent (eg CsCO3 or K2CO3, DMF, NMP or acetonitrile) at elevated temperature (eg about 40°C to about 70°C) to give intermediate v. Alternatively, when LG ³ is -OH, 2-bromo-4-nitrophenol or 3-bromo-5-nitropyridin-2-ol is treated under Mitsunobu conditions (e.g. PPh3 and DIAD or DEAD in a solvent such as THF at room temperature), yielding intermediate v. In yet another embodiment, 2-bromo-4-nitrophenol or 3-bromo-5-nitropyridin-2-ol is reacted with Hal-LHal, where Hal is Br, in the presence of a base (such as K ₂ CO ₃ or CsCO ₃ ) to solvent (such as acetonitrile or DMF) at elevated temperature, for example, from about 80°C to about 100°C, followed by coupling with a suitably derivatized and protected piperazinyl in the presence of a base, for example, DIPEA or TEA, in a solvent, such as DMF or NMP, at elevated temperature, for example, from about 50°C to about 70°C, to obtain intermediate compound v. ^{R _ _} _{_} ⁺ together with the boron atom and the atoms to which they are attached forms a cyclic boronate, for example, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1, 3,2-dioxaborolane) in the presence of a palladium catalyst (such as Pd(dppf)Cl2) and a base (such as K3PO4) in a solvent (such as 1,4-dioxane/aqueous mixtures), to give intermediate w, where R ^A is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C _5-6 cycloalkenyl. Reduction of the nitro group and R ^A of an alkenyl or cycloalkenyl group in an intermediate we using a reducing agent such as H2 in the presence of a catalyst such as Pd/C, in a solvent such as MeOH or EtOH, at a temperature of about 20°C to about 30°C gives intermediates x, wherein R ^A is substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C _5-6 cycloalkyl, which can be used in the schemes above to prepare compounds of formula (I) wherein L is -O(C _1-6 alkyl)- and R ^A is substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C3-6cycloalkyl. Alternatively, intermediate v is treated with R ^a BF3 ^- K ⁺ , where R ^a is substituted or unsubstituted C1-6 alkyl, in the presence of a catalyst and ligand (e.g. cataCXium® A Palladacycle Gen.3 and butyldi-1-adamantylphosphine), in the presence of a base such as Cs2CO3 or K2CO3 in a solvent such as toluene/aqueous mixtures at an elevated temperature, for example from about 90°C to about 110°C, to produce intermediate y, wherein R ^a is substituted or unsubstituted C1-6alkyl. As before, reduction of the nitro group in the intermediate using a reducing agent such as H ₂ in the presence of a catalyst such as Pd/C in a solvent such as MeOH or EtOH at a temperature of about 20°C to about 30°C , gives intermediates x, where R ^A is substituted or unsubstituted C1-6alkyl, which can be used in the schemes above to prepare compounds of formula (I), where L is -O(C1-6alkyl)- and R ^A is substituted or unsubstituted C1-6alkyl.

Scheme 7

The synthesis of ad intermediates used in the synthesis of compounds of formula (I) where L is -(C _2-9 alkyl)- is described in Scheme 7. The V-OH starting material is treated with Tf ₂ O in

- 19 044376 the presence of a base such as DIPEA or TEA in a solvent such as DCM to obtain intermediate aa. Treatment of intermediate aa THP-O-C _2-9 with alkylzinc(II) in the presence of a catalyst and ligand, eg CPhosPdG ₃ and CPhos, in a solvent, eg toluene, at a reduced temperature, eg around 0°C, gives intermediate ab , protected by TNR. After removal of THP (by treatment with an acid such as TsOH in a solvent such as DCM/EtOH mixtures), the ac intermediate is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro -1,2-benziodoxol-3(1H)-one) in a solvent such as DCM at a reduced temperature, for example about 0°C), then combined with the N-protected suitably derivatized piperazinyl by reductive amination using a reducing agent , for example sodium triacetoxyborohydride, in a solvent, for example MeOH, to obtain intermediate ad, which can be used as described in schemes 1 and 2 for intermediate a, to obtain compounds of formula (I), where L is -(C _{2 -9} alkyl)-.

Scheme 8

ai

av

Intermediates c, where L is -O(C _1-6 alkyl)- or -(C _1-9 alkyl)-, can also be prepared as shown in Scheme 8. In one embodiment, a suitably derivatized intermediate ai is subjected to reacting with an alkylating agent such as O-protected LG ⁴ -L-Hal (eg, where the O-protecting group PO is benzyl, LG ⁴ is O, and Hal is Br or Cl) in the presence of a base in a solvent (eg , CsCO3 in DMF or K2CO3 in acetonitrile) at elevated temperature (eg, about 40°C to about 70°C) to give intermediate aj. Reaction of intermediate aj with Hal-C(R2)(R ³ )COOR (where R is C1-4 alkyl, such as methyl, ethyl or tert-butyl, and Hal is Cl or Br) in the presence of a base, such as TEA , DBU or DIPEA, in a solvent such as THF, NMP or DMF, optionally at elevated temperature (eg, about 20° C. to about 80° C.), optionally in the presence of NaI or KI, gives intermediate ak. Removal of the O-protecting group PO in the intermediate ak, where PO is benzyl, is achieved using a reducing agent such as H ₂ in the presence of a catalyst such as Pd/C and Pd(OH) ₂ in a solvent such as MeOH or EtOH, at a temperature of about 20°C to about 30°C, at elevated pressure, for example, at a pressure level of 15 psig, gives the intermediate compound AO.

Alternatively, react a suitably derivatized N-protected piperazyl with Hal-C(R ² )(R ³ )COOR (where R is a C _1-4 alkyl, e.g. methyl, ethyl or t-butyl, P ^N is N- a protecting group such as Boc, and Hal is Br or Cl) in the presence of a base such as TEA, DBU or DIPEA, in a solvent such as THF, NMP or DMF, optionally at an elevated temperature (for example, a temperature of about 20° C to about 80°C), optionally in the presence of NaI or KI, gives intermediate am. Deprotection of intermediate j (when P ^N is Boc by treatment with an acid in a solvent such as TFA in DCM or HCl in dioxane/DCM or EtOAc) followed by reaction with

LG ⁴ -L-Hal (where LG ⁴ is Br, Cl or OH, and Hal is Br or Cl) in the presence of a base, for example DIPEA, TEA or NMM, in a solvent, for example DMF or NMP, at elevated temperature, for example from about 50°C to about 70°C, gives the intermediate compound ao.

The AO intermediate is reacted with a phenolic derivative V-OH where, when LG ⁴ is -OH, the reaction is carried out under Mitsunobu conditions (eg in the presence of PPh3 and DIAD or DEAD, in a solvent such as THF at room temperature) with obtaining an intermediate connection with. When the leaving group LG ⁴ in the intermediate ao is Br, Cl, OTs or OMs (derived from the corresponding alcohol), the reaction with V-OH is carried out in the presence of a base in a solvent (for example, CsCO3 in DMF or K2CO3 in acetonitrile) at elevated temperature (eg, from about 40°C to about 70°C) to obtain intermediate compound c.

The intermediate AO where LG ⁴ is Br, Cl or OH can also be treated with appropriately derivatized 4-nitrophenol (where LG ⁵ is OH and A is CH or CRA) or 5-nitropyridin-2-ol (where LG ⁵ is OH and A is N) (intermediate a) in the presence of a base (eg NaOtBu, CsCO3 or K2CO3), in a solvent (eg acetonitrile, DMF or NMP), at elevated temperature (eg from about 0°C to about 90°C), yielding intermediate as. Alternatively, intermediate ao, where LG ⁴ is OH, is reacted with intermediate ar, where LG ⁵ is OH, under Mitsunobu conditions (by reaction in the presence of PPh3 and DIAD or DEAD, in a solvent such as THF, at room temperature) to obtain intermediate compound as. In a third embodiment, the intermediate AO where LG ⁴ is OH is reacted with suitably derivatized 2-halo-5-nitropyridine (where LG ⁵ is F or Cl and A is N) or 1-halo-4-nitrobenzene (where LG ⁵ is F or Cl and A is CH or CRA) in the presence of a base such as NaOtBu, CsCO3 or K ₂ CO ₃ in a solvent such as acetonitrile, DMF, THF or NMP at elevated temperature, for example, from about 0°C to about 70°C, to obtain intermediate compound as.

In yet another embodiment, suitably derivatized 4-nitrophenol (where A is CH or CRA) or 5-nitropyridin-2-ol (where A is N) (ap intermediate) can be reacted with LG ⁶ -L-Hal (where LG ⁶ is Br or Cl, and Hal is Cl or Br) in the presence of a base (e.g. NaOtBu, CsCO3 or K2CO3), in a solvent (e.g. acetonitrile, DMF or NMP), at elevated temperature (e.g. about 0°C to about 90°C), yielding intermediate aq. The intermediate aq can also be reacted with LG ⁶ -L-Hal, where LG ⁶ is OH, under Mitsunobu conditions (using PPh3 and DIAD or DEAD, in a solvent such as THF, at room temperature) to give intermediate aq. Intermediate aq can then be used to alkylate intermediate an in the presence of a base such as NaOtBu, CsCO3 or K ₂ CO ₃ in a solvent such as acetonitrile, DMF, THF or NMP at elevated temperature, for example from about 0°C to about 70°C, obtaining intermediate compound as.

Reduction of a nitro group in an intermediate as by a reducing agent in a solvent (e.g., H2 in MeOH or EtOH in the presence of a catalyst, e.g., Pd/C at elevated pressure, e.g., 50 psi or Fe and NH ₄ Cl in EtOH and H2O) at elevated temperature, for example, about 80°C gives the intermediate compound at. Reaction of intermediate at with R'OOCC(R5)( ^R6 )Hal (where Hal is Br or Cl and R' is _C1.3alkyl ) in the presence of a base (e.g. _NaHCO3 , DIPEA or TEA) at elevated temperature (eg, from about 90°C to about 130°C) gives intermediate compound av. Reaction of intermediate av with suitably derivatized 4-isothiocyanatobenzonitrile (where B is CH or CRB) or 5-isothiocyanatopicolinonitrile (where B is N) in the presence of a base such as TEA in a solvent such as EtOAc at elevated temperature, for example, from about 60°C to about 90°C, again gives intermediate compounds with, where L represents -O(C ₁ - ₆ alkyl)-, which can be used as described above.

Alternatively, reacting intermediate at with CN-C(R5)(R ⁶ )OH in the presence of MgSO ₄ at elevated temperature, eg, about 50°C to about 70°C, gives intermediate aau. Reaction of intermediate au, with suitably derivatized 4-isothiocyanatobenzonitrile (where B is CH or CRB) or 5-isothiocyanatopicolinonitrile (where B is N) in a solvent such as DMF or DMA, followed by treatment with an acid, such as HCl in the solvent, such as MeOH or EtOH, at elevated temperature, for example from about 70°C to about 80°C, again gives intermediate compound with, where L represents -O(C1_ ₆ alkyl)-.

The intermediate as (when R ^A is Br) can also be used

- 21 044376 for the preparation of intermediate as where R ^A is substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C56 cycloalkyl, by reacting intermediate as (when R ^A is Br) with boronate R ^a [B( OR ⁺ )2] ₂ , (where R ^A represents substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6 cycloalkenyl, and R ⁺ together with the boron atom and the atoms to which they are attached forms a cyclic boronate, for example 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in the presence of a palladium catalyst (for example Pd( dppf)Cl2) and a base (such as K3PO4) in a solvent (such as 1,4dioxane/water) to produce intermediate as, wherein R ^A is substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6cycloalkenyl Reduction of the nitro group and R ^A of an alkenyl or cycloalkenyl group in an intermediate as, using a reducing agent such as H2, in the presence of a catalyst such as Pd/C, in a solvent such as MeOH or EtOH, at a temperature of about 20°C to about 30°C, gives at intermediates where R ^A is substituted or unsubstituted C _{2 -6} alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C _5-6 cycloalkyl, which can be used in the above schemes to produce compounds of formula (I) wherein L is -O(C _{1_6} alkyl) _- .

In some embodiments, chiral resolution (by standard methods and as described herein) of enantiomers of compounds of formula (I) yields compounds of formula (IIa) and formula (IIb).

Alternatively, chiral resolution by standard methods of intermediates h or i, used as described in the schemes above, gives compounds of formula (IIa) or (IIb).

The term protected with respect to amino groups and hydroxyl groups refers to forms of these functional groups that are protected from undesired reaction by protecting groups known to those skilled in the art, for example, those described in Protective Groups in Organic Synthesis, Greene, TW; Wuts, P.G.M., John Wiley & Sons, New York, NY ( ^5th edition, 2014), which may be added or deleted using the procedures contained in this publication.

In one aspect, this document provides methods for preparing a compound of formula (I):

the methods include contacting a compound of formula (h)

with a compound of formula (d)

in the presence of a coupling agent and a base, in a solvent, under conditions suitable for the preparation of the compound of formula (I);

where RN represents H;

each R ¹ is independently selected from halogen, CN, and C ₁ - ₃ alkyl;

- 22 044376

R ² and R ³ are each independently selected from H, and O^alkyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted C _3-6 cycloalkyl;

each R ⁴ independently represents a substituted or unsubstituted C1-3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C 3-6 cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

X represents N;

L represents -O(C _1-6 alkyl)- or -(C _1-9 alkyl)-;

n is 0-4;

m is 0-8;

V represents where A represents N, CH, or CRA; B is N, CH, or CRB;

each R ^a is independently selected from halogen, substituted or unsubstituted C _1-6 alkyl, or substituted and unsubstituted C _3-6 cycloalkyl;

each RA is independently selected from halogen and substituted or unsubstituted C _1-6 alkyl;

RC is halogen or CF ₃ ;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3; and b is 0-2.

In one embodiment, the binding agent is HATU, HBTU, EDC or DCC, optionally in combination with HOBt. In one embodiment, the binding agent is HATU. In another embodiment, the base is DIPEA, NMM or TEA. In one embodiment, the base is DIPEA. In another embodiment, the solvent is DCM, DMF, NMP, or mixtures thereof. In one embodiment, the solvent is DMF.

In the following embodiments, the variables ^RN , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , RA, RB, R ^c , L, V, A, B, n, m, p, a and b are as defined herein unless otherwise stated.

In some embodiments, the methods further comprise preparing a compound of formula (h)

R ⁴ O _Γ γ-ΝΗ (h), methods include deprotection of the compound of formula (g)

under conditions suitable for the preparation of a compound of formula (h), wherein P ^N represents an amino protecting group.

In some embodiments, P ^N is a Boc group. In some such embodiments, deprotection is accomplished by treatment with an acid in a solvent. In some embodiments, the acid is TFA and the solvent is DCM. In other embodiments, the acid is HCl and the solvent is dioxane or EtOAc.

In some embodiments, the methods further comprise preparing a compound of formula (g)

the methods include contacting a compound of formula (f)

- 23 044376

with 3-bromopiperidine-2,6-dione, in the presence of a base, in a solvent, at elevated temperature, under conditions suitable for the preparation of the compound of formula (g).

In some such embodiments, the base is NaHCO ₃ , CsCO ₃ or K ₂ CO ₃ and the solvent is DMF or NMP. In one embodiment, the base is NaHCO3 and the solvent is DMF. In some such embodiments, contacting is carried out at a temperature of from about 50°C to about 80°C. In other embodiments, the base is DIPEA. In some such embodiments, the solvent is DMF or NMP. In some such embodiments, contacting is carried out at a temperature of about 150°C.

In some embodiments, the methods further comprise preparing a compound of formula (f)

the methods involve reducing the nitro group in a compound of formula (e) (e) using a reducing agent, optionally in the presence of a catalyst, in a solvent, under conditions suitable for preparing the compound of formula (f).

In some such embodiments, the reducing agent is H2 and the catalyst is Pd/C. In some such embodiments, the solvent is EtOH or MeOH. In other embodiments, the reducing agent is Fe and NH4Cl. In some such embodiments, the solvent is EtOH and H2O.

In some embodiments, the methods further comprise preparing a compound of formula (e) n

^p st (R'U(e) methods include the protection of nitroaniline of the formula

H/bL „NO·.

IX amino protecting group P ^N , by reaction with a protecting agent in the presence of a base, in a solvent under conditions suitable for preparing the compound of formula (e).

In some such embodiments, the amino protecting group P ^N is Boc, and the protecting agent is Boc ₂ O. In some embodiments, the base is TEA, DIPEA, or DBU. In some embodiments, the base is TEA. In some such embodiments, the solvent is THF, NMP, or DMF. In some embodiments, the solvent is THF.

In some other embodiments, the methods further comprise preparing a compound of formula (g)

the methods include contacting a compound of formula (e)

- 24 044376 n

Zh l „NO-, u...

(e) with 3-bromopiperidine-2,6-dione in the presence of Zn, TMSCl and FeCl ₂ -4H ₂ O, in a solvent, at elevated temperature, under conditions suitable for preparing the compound of formula (g).

In some embodiments, the solvent is HMP. In some embodiments, the temperature is from about 80°C to about 100°C.

In some embodiments, the methods further comprise preparing a compound of formula (d)

methods include deprotection of a compound of formula (c)

where R represents C _{1_4} alkyl, under conditions suitable for _preparing the compound of formula (d).

In some embodiments where R is methyl or ethyl, deprotection is performed by treatment with a base in a solvent. In some embodiments, the base is LiOH or NaOH. In other embodiments, the solvent is THF/H2O mixtures or dioxane/H ₂ O mixtures. In some embodiments, where R is methyl or ethyl, deprotection is accomplished by treatment with an acid in the solvent. In other similar embodiments, the acid is HCl and the solvent is dioxane/DCM mixtures. In other embodiments, the acid is TFA and the solvent is DCM.

In some embodiments, the methods further comprise preparing a compound of formula (c)

with V-L-Hal, wherein the Hal species involves contacting the compound being Cl, Br, OMs or OTs, in the presence of a base, in a solvent under conditions suitable to prepare the compound of formula (c).

In some embodiments, the base is DIPEA, TEA, or DBU. In some embodiments, the base is DIPEA. In other embodiments, the solvent is DMF or NMP. In some embodiments, the solvent is DMF. In some embodiments, contacting is carried out at room temperature. In one embodiment, Hal is Cl or Br.

In some other embodiments, the methods further comprise preparing a compound of formula (c)

the methods include contacting a compound of formula (b)

- 25 044376

with Br-C(R2)(R3)COOR, in the presence of a base, in a solvent under conditions suitable for preparing the compound of formula (c).

In some embodiments, the base is TEA, DBU, or DIPEA. In some embodiments, the base is TEA. In other embodiments, the solvent is THF, NMP, or DMF. In some embodiments, the solvent is THF. In some embodiments, contacting is carried out at an elevated temperature, for example, at a temperature of from about 20°C to about 80°C. In some embodiments, contacting is carried out in the presence of NaI or KI.

In some embodiments, the methods further comprise preparing a compound of formula (b)

methods include deprotection of a compound of formula (a)

where P ^N represents an amino protecting group, under conditions suitable for preparing the compound of formula (b).

In some embodiments, P ^N is Boc. In some such embodiments, deprotection is accomplished by treatment with an acid in a solvent. In some embodiments, the acid is HCl and the solvent is dioxane or EtOAc. In other embodiments, the acid is TFA and the solvent is DCM.

In some embodiments, the methods further comprise preparing a compound of formula (a)

the methods involve contacting the compound with V-L-Hal, where Hal is Cl, Br, OM or OT, in the presence of a base, in a solvent under conditions suitable to prepare the compound of formula (a).

In some embodiments, the base is CsCO3 or K2CO3. In some embodiments, the base is CsCO ₃ . In other embodiments, the solvent is DMF or NMP. In some such embodiments, the solvent is DMF. In some embodiments, contacting is carried out at an elevated temperature, for example, at a temperature of from about 40°C to about 70°C. In one embodiment, Hal is Cl or Br.

In some embodiments, the methods further comprise producing a VL-Hal compound, where L is -O(C _1-6 alkyl)-, the methods include contacting the V-OH compound with LG2-L-Hal, wherein LG2 is a leaving group , selected from Br, Cl and OH under conditions suitable for preparing the VL-Hal compound.

In some embodiments, where LG2 is Br or Cl, contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is CsCO ₃ or K ₂ CO ₃ . In some embodiments, the base is CsCO ₃ . In other embodiments, the solvent is DMF or NMP. In some such embodiments, the solvent is DMF. In some embodiments, contacting is carried out at an elevated temperature, for example, at a temperature of from about 40°C to about 70°C. In other embodiments, LG ² is OH, and contacting is carried out in the presence of PPh ₃ and DIAD or DEAD, in a solvent. In some such embodiments, the solvent is THF. In some embodiments, contacting is carried out at room temperature.

In some embodiments, the methods further comprise preparing a compound of formula (a) pM ^L \r*) _m (a) l ,P ^N

Z N

LG ¹ x J methods involve contacting the compound with V-OH, where LG is a leaving group selected from OH, Br, Cl, OTs and OMs, under conditions suitable to prepare the compound of formula (a).

In some embodiments, LG ¹ is Br, Cl, OTs, or OMs, and contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is CsCO3 and the solvent is DMF. In other embodiments, the base is K2CO3 and the solvent is acetonitrile. In some embodiments, contacting is performed at an elevated temperature. In some such embodiments, the temperature is from about 40°C to about 70°C. In some embodiments, where LG ¹ is OH, contacting is carried out in the presence of PPh3 and DIAD or DEAD, in a solvent. In some such embodiments, the solvent is THF. In some embodiments, contacting is carried out at room temperature.

Methods for preparing compounds of formula (I) are also provided.

(I), the methods include contacting a compound of formula (k)

(k), with V-L-Hal, where Hal represents Br, Cl, OMs or OTs, in the presence of a base, in a solvent under conditions suitable for the preparation of the compound of formula (I);

where R ⁿ represents H;

each R ¹ is independently selected from halogen, CN, and C1_ ₃ alkyl;

R ² and R ³ are each independently selected from H, and C1_3 alkyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted C3_ ₆ cycloalkyl;

each R ⁴ independently represents a substituted or unsubstituted C1_3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3_ ₆ cycloalkyl or two R ⁴ groups together with non-adjacent atoms the carbons to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

X represents N;

L represents -O(C1_balkyl)- or -(C1_9alkyl)-;

η is equal to 0-4;

m is 0-8;

V represents

-27044376 where A is N, CH or CRA;

B represents N, CH or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted C _3-6 cycloalkyl;

each R ^a is independently selected from halogen or substituted or unsubstituted C _1-6 alkyl;

RC is halogen or CF3;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3; and b is 0-2.

In one embodiment, the base is DIPEA, TEA or NMM. In one embodiment, the base is DIPEA. In another embodiment, the solvent is DMF or NMP. In one embodiment, contacting is carried out at an elevated temperature. In one such embodiment, the temperature is from about 50°C to about 70°C. In one embodiment, Hal is Br or Cl.

In some embodiments, the methods further comprise preparing a compound of formula (k)

methods include deprotecting a compound of formula (j)

under conditions suitable for the preparation of a compound of formula (k), wherein P ^N represents an amino protecting group.

In some embodiments, P ^N is a Boc group. In some embodiments, deprotection is performed by treatment with an acid in a solvent. In other such embodiments, the acid is TFA and the solvent is DCM. In other embodiments, the acid is HCl and the solvent is dioxane/DCM or EtOAc.

In some embodiments, the methods further comprise preparing a compound of formula (j)

the methods include contacting a compound of formula (h) with a compound

in the presence of a coupling agent and a base, in a solvent, under conditions suitable for preparing the compound of formula (j).

In one embodiment, the binding agent is HATU, HBTU, EDC or DCC, optionally in combination with HOBt. In one embodiment, the binding agent is HATU. In another embodiment, the base is DIPEA, NMM or TEA. In one embodiment, the base is DIPEA. In another embodiment, the solvent is DCM, DMF, NMP, or mixtures thereof. In one version

- 28 044376 implementation of the solvent is DMF.

Also provided are methods for preparing compounds of formula (I) (I) methods include contacting a compound of formula (i) with a compound of formula (b) (I), (b) wherein Hal is Br, Cl, in the presence of a base, in a solvent under conditions suitable for the preparation of the compound of formula (I);

where R ⁿ represents H;

each R ¹ is independently selected from halogen, CN, and C ₁ . ₃ alkyl;

R ² and R ³ are each independently selected from H, and C1-Zalkylα, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl;

each R ⁴ independently represents substituted or unsubstituted C1.3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

X represents N;

L represents -O(C ₁ . ₆ alkyl)- or -(C ₁ . ₉ alkyl)-;

n is 0-4;

m is 0-8;

V represents ’ where A represents N, CH or CRA;

B represents N, CH or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C ₁ . ₆ alkyl and substituted or unsubstituted C ₃ . ₆ cycloalkyl;

each R ^a is independently selected from halogen or substituted and unsubstituted C ₁ . ₆ alkyl;

RC is halogen or CF3;

R ⁵ and R ⁶ are C1.3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3; and b is 0-2.

In one embodiment, the base is DIPEA, TEA or NMM. In one embodiment, the base is DIPEA. In another embodiment, the solvent is DMF or NMP. In one embodiment, contacting is carried out at an elevated temperature. In one such embodiment, the temperature is from about 40°C to about 60°C. In one embodiment, contacting is carried out in the presence of NaI or KI.

In some embodiments, the methods further comprise preparing a compound of formula (i)

- 29 044376

(i), the methods include contacting a compound of formula (h) R ^N O

(h), with Hal ² -C(R ² )(R ³ )COY, where Y is OH or C1, under conditions suitable for preparing the compound of formula (i).

In some embodiments, where Y is OH, contacting is carried out in the presence of a coupling agent and a base, in a solvent. In one embodiment, the binding agent is HATU, HBTU, EDC or DCC, optionally in combination with HOBt. In one embodiment, the binding agent is HATU. In some embodiments, the base is DIPEA, TEA, or NMM. In one embodiment, the base is DIPEA. In one embodiment, the solvent is DCM, DMF, IMI, or mixtures thereof. In one embodiment, the solvent is DMF. In other embodiments, where Y is C1, contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is TEA or DIPEA. In other embodiments, the solvent is DMF or IMI. In some embodiments, contacting is carried out at a temperature of from about 0°C to about 25°C.

In some embodiments, the methods further comprise preparing a compound of formula (j)

b) the methods include contacting a compound of formula (i)

(i), with a compound wherein P ^N is an amino protecting group, in the presence of a base, in a solvent, under conditions suitable for preparing the compound of formula (j). In one embodiment, P ^N represents a Boc group.

In one embodiment, the base is DIPEA, NMM or TEA. In one embodiment, the base is DIPEA. In another embodiment, the solvent is DMF, ΗΜΠ, or a mixture thereof. In one such embodiment, contacting is carried out at a temperature of from about 40°C to about 80°C. In one embodiment, contacting is carried out in the presence of Nai or KI.

In one embodiment, the methods presented herein include preparing a compound of formula (j)

b) where the method includes bringing into contact a connection (ah)

-30044376

_N where P ^N represents an amino protecting group, with 3-bromopiperidine-2,6-dione in the presence of a base, in a solvent under conditions suitable for preparing the compound of formula (j). In one embodiment, P ^N represents a Boc group.

In one embodiment, the base is NaHCO ₃ , CsCO ₃ or K2CO3. In another embodiment, the solvent is DMF, NMP, or a mixture thereof. In one such embodiment, contacting is carried out at a temperature of from about 50°C to about 80°C. In one embodiment, the base is NaHCO ₃ , CsCO ₃ or K2CO3, the solvent is DMF or NMP, and contacting is carried out at a temperature of from about 50°C to about 80°C.

In one embodiment, the base is DIPEA. In another embodiment, the solvent is DMF, NMP, or a mixture thereof. In one such embodiment, contacting is carried out at a temperature of about 150°C. In one embodiment, the base is DIPEA, the solvent is DMF or NMP, and contacting is carried out at a temperature of about 150°C.

In one embodiment, the methods presented herein include preparing a compound of formula (j)

where the method includes bringing into contact a connection (ah)

with 3-bromopiperidine-2,6-dione in the presence of a base, in a solvent under conditions suitable for preparing the compound of formula (j).

In one embodiment, the methods presented herein include preparing a compound of formula (ah)

where the method involves unprotecting the connection (ag)

using a reducing agent under conditions suitable for preparing the compound of formula (ah).

In one embodiment, the reducing agent is H2. In one embodiment, PN' is Cbz and deprotection is carried out in the presence of a Pd/C, Pt/C or Pd(OH)2 catalyst in a solvent. In one embodiment, the solvent is MeOH or EtOAc.

In one embodiment, the methods presented herein include preparing a compound of formula (ag)

- 31 044376

where the method includes bringing into contact a connection (af)

with N-protected piperazine, wherein P ^N represents a protecting group, in the presence of a base, in a solvent, under conditions suitable for preparing the compound of formula (ag).

In one embodiment, P ^N represents a Boc group. In one embodiment, the base is DIPEA or TEA. In another embodiment, the solvent is DMF or NMP. In one such embodiment, contacting is carried out at a temperature of from about 60°C to about 90°C. In one embodiment, contacting is carried out in the presence of NaI or KI.

In one embodiment, the methods presented herein include preparing a compound of formula (af),

(af) where the method includes bringing into contact a connection (ae)

with Hal ² -C(R ² )(R ³ )COY, where Y is OH or Cl, under conditions suitable for preparing the compound of formula (af).

In some embodiments, where Y is OH, contacting is carried out in the presence of a coupling agent and a base, in a solvent. In one embodiment, the binding agent is HATU, HBTU, EDC or DCC, optionally in combination with HOBt. In some embodiments, the base is DIPEA, TEA, or NMM. In one embodiment, the solvent is DCM, DMF, NMP, or a mixture thereof.

In other embodiments, where Y is Cl, contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is TEA or DIPEA. In other embodiments, the solvent is DMF or NMP. In some embodiments, contacting is carried out at a temperature of from about 0°C to about 25°C.

In some embodiments, the methods further comprise preparing a compound of formula (a)

the methods include contacting a compound of formula (q)

- 32 044376 with connection

in a first solvent followed by treatment with an acid in a second solvent, under conditions suitable to prepare a compound of formula (a) wherein L is -O(C _1-6 alkyl)-.

In some embodiments, the first solvent is DMF or DMA. In some embodiments, the acid is HCl. In some such embodiments, the second solvent is MeOH or EtOH. In some embodiments, the acid contacting is performed at an elevated temperature. In some such embodiments, the temperature is from about 70°C to about 80°C.

In some embodiments, the methods further comprise preparing a compound of formula (q)

the methods involve contacting a compound of formula (o)

with CN-C(R ⁵ )(R ⁶ )OH, in the presence of a drying agent, under conditions suitable for preparing the compound of formula (q).

In some embodiments, the drying agent is MgSO ₄ . In some embodiments, contacting is performed at an elevated temperature. In some such embodiments, the temperature is from about 50°C to about 70°C.

In some embodiments, the methods further comprise preparing a compound of formula (a)

the methods involve contacting a compound of formula (p) with a compound

wherein R' is C _1-3 alkyl, in the presence of a base, in a solvent under conditions suitable for the preparation of a compound of formula (a), wherein L is -O(C _1-6 alkyl)-.

In some embodiments, the base is TEA. In other embodiments, the solvent is EtOAc. In some embodiments, contacting is performed at an elevated temperature. In some such embodiments, the temperature is from about 70°C to about 90°C.

- 33 044376

In some embodiments, the methods further comprise preparing a compound of formula (p)

(Ρλ methods include bringing into contact a compound of formula (o)

(o), with R'OOC-C(R ⁵ )(R ⁶ )Hal, where Hal is Br or Cl, in the presence of a base under conditions suitable for preparing the compound of formula (p).

In some embodiments, Hal is Br. In some embodiments, the base is DIPEA or TEA. In some embodiments, contacting is performed at an elevated temperature. In some such embodiments, the temperature is from about 110°C to about 130°C.

In some embodiments, the methods further comprise preparing a compound of formula (o)

methods include reduction of a compound of formula (n)

using a reducing agent, in a solvent, under conditions suitable for preparing the compound of formula (o).

In some embodiments, the reducing agent is H2. In some such embodiments, contacting is carried out in the presence of a catalyst. In some embodiments, the catalyst is Pd/C. In some such embodiments, the solvent is EtOH. In other embodiments, the reducing agent is Fe and NH4Cl. In some such embodiments, the solvent is EtOH and H ₂ O. In some such embodiments, the contacting is performed at an elevated temperature. In some embodiments, the temperature is about 80°C.

In some embodiments, the methods further comprise preparing a compound of formula (n)

the methods include contacting a compound of formula (m)

with connection

where A is N, in the presence of a base, in a solvent, under conditions suitable for preparing the compound of formula (n), where A is N.

In some embodiments, the base is CsCO ₃ or K2CO3. In some embodiments, the base is K2CO3. In some embodiments, the solvent is acetonitrile, DMF, THF, or NMP. In some embodiments, the solvent is acetonitrile. In some embodiments, contacting is performed at an elevated temperature. In some such embodiments, the temperature is from about 50°C to about 70°C.

In some other embodiments, the methods further comprise preparing a compound of formula (n)

NO ₂ Jin 1Д ί AL (η), methods include bringing into contact a compound of formula (l) (1), νο ₂ ;ιη

XX with a compound ^{A he} where LG ² represents Br, Cl or OH, under conditions suitable for the preparation of a compound of formula (n) where A represents N.

In some embodiments, LG ² is Br or Cl, and contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is CsCO3 or K2CO3. In some embodiments, the base is CsCO3. In some embodiments, the solvent is acetonitrile, DMF, or NMP. In some embodiments, the solvent is acetonitrile. In some embodiments, contacting is performed at an elevated temperature. In some embodiments, the temperature is from about 50°C to about 80°C. In some embodiments, Hal is Br, the base is CsCO3, the solvent is DMF, and the temperature is about 70°C. In other embodiments, Hal is Cl, the base is K2CO3, the solvent is acetonitrile, and the temperature is about 60°C. In some embodiments, LG ² is OH, and contacting is carried out in the presence of PPh3 and DIAD or DEAD, in a solvent. In some embodiments, the solvent is THF. In some embodiments, contacting is carried out at room temperature.

In some embodiments, the methods further comprise preparing a compound of formula V-OH

methods include deprotecting the compound of formula (s). 9 ^Ri R ^s

AL n ra

G X (R ^B )b D ^L 0-P° (s) where R ^a represents a substituted or unsubstituted C _1-6 alkyl, or a substituted or unsubstituted C _3-6 cycloalkyl, and P ^O represents a phenolic protecting group, in conditions suitable for preparing the compound of formula V-OH.

In some embodiments, P ^O is acetyl and deprotection is accomplished by treatment with a base in a solvent. In some embodiments, the base is such as K2CO3. In some embodiments, the solvent is MeOH or EtOH. In other embodiments, PO is benzyl and deprotection is accomplished by treatment with a reducing agent in a solvent. In some embodiments, the reducing agent is H ₂ and the contacting is carried out in the presence of a catalyst. In one embodiment, the catalyst is Pd/C. In some embodiments, the solvent is EtOH or MeOH.

In some embodiments, the methods further comprise preparing a compound of formula (s)

the methods include contacting a compound of formula (r)

(d) with R ^A -Zn-Br, where R ^A is substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted C _3-6 cycloalkyl, in the presence of a catalyst and ligand, in a solvent, under conditions suitable for the preparation compounds of formula (s).

In some embodiments, the catalyst and ligand are CPhosPdG ₃ and CPhos. In some embodiments, the solvent is Toluene. In some embodiments, contacting is carried out at a lower temperature. In some such embodiments, the temperature is from about 0°C to about 25°C.

In some embodiments, the methods further include preparing a compound of formula (s) “RYrf (R% ^b % _d ^< _o _pO (s) where A is CH or CR ^A and PO is a phenolic protecting group, the methods include contacting the compound formulas (az) _I N .

^{rs cn} Χα,ρ» (az), ^R y

NC-Z y-NCS with the compound wherein B is CH, CRB or N, in a solvent, followed by treatment with an acid in the solvent under conditions suitable to obtain the compound of formula (s).

In one embodiment, PO is a benzyl group. In one embodiment, the solvent is DMF or DMA. In one embodiment, the acid is HCl. In one embodiment, the acid is in a solvent such as MeOH or EtOH. In one embodiment, contacting is carried out at a temperature of from about 70°C to about 80°C.

In one embodiment, provided herein is a method for preparing compound (az)

(az) where the method includes bringing into contact a connection (ay)

- 36 044376

with CN-C(R ⁵ )(R ⁶ )OH, in the presence of MgSO ₄ , under conditions suitable for preparing the compound of formula (az).

In one embodiment, contacting is carried out at a temperature of from about 50°C to about 70°C.

In one embodiment, provided herein is a method for preparing a compound ⁽ au)

wherein the method includes bringing into contact the connection(s)

with a reducing agent in the presence of a Lewis acid in a solvent under conditions suitable for preparing the compound of formula (ay).

In one embodiment, the reducing agent is iron. In one embodiment, the Lewis acid is ammonium chloride. In one embodiment, the solvent is a mixture of EtOH and water. In one embodiment, contacting is carried out at a temperature of about 60°C.

In one embodiment, provided herein is a method for preparing compound ^(s)

where the method involves bringing into contact a connection (aw)

(aw) with R ^A -B(OH)2 in the presence of a catalyst and a base in a solvent, under conditions suitable for preparing the compound of formula (ah).

In one embodiment, the catalyst is Pd(dppf)2Cl2. In one embodiment, the base is Cs ₂ CO ₃ . In one embodiment, the solvent is a mixture of toluene and water. In one embodiment, contacting is carried out at a temperature of about 100°C.

In one embodiment, provided herein is a method for producing a compound (aw)

wherein the method comprises contacting the compound with an alkylating agent in a solvent with a base, under conditions suitable for preparing the compound of formula (aw).

In one embodiment, the alkylating agent is bromomethylbenzene. In one embodiment, the solvent is acetonitrile. In one embodiment, the base is K2CO3. In one embodiment, contacting is carried out at a temperature of about 80°C.

In some embodiments, the methods further comprise preparing a compound of formula (u)

- 37 044376

(u) the methods include contacting a compound of formula (t)

(t) with R ^A -Zn-Br, where R ^A represents substituted or unsubstituted C^alkyl or substituted or unsubstituted C ₃ . ₆ cycloalkyl, in the presence of a catalyst and ligand, in a solvent, under conditions suitable for the preparation of the compound of formula (i).

In some embodiments, the catalyst and ligand are CPhosPdG ₃ and CPhos. In some embodiments, the solvent is toluene. In some embodiments, contacting is carried out at a lower temperature. In some such embodiments, the temperature is from about 0°C to about 25°C.

In some embodiments, the methods further comprise preparing a compound of formula (x)

(x) the methods involve the reduction of a compound of formula (y)

(y) with a reducing agent, where L represents -O(C1.balkyl)-, and R ^A represents substituted or unsubstituted C1. ₆ alkyl, in a solvent, under conditions suitable for preparing the compound of formula (x).

In some embodiments, the reducing agent is H ₂ in the presence of a catalyst. In some embodiments, the catalyst is Pd/C. In some embodiments, the solvent is MeOH or EtOH. In some embodiments, contacting is carried out at a temperature of from about 20°C to about 30°C.

In some embodiments, the methods further comprise preparing a compound of formula (y)

NO _: . pi * rch '11 T j; ) ^A L _iR 4)_ (y) methods include bringing into contact a compound of formula (ν)

(ν) with R ^a BF ₃ 'K ⁺ , where R ^a represents a substituted or unsubstituted Ci-balkyl, in the presence of a catalyst and ligand, in the presence of a base, in a solvent, under conditions suitable for the preparation of the compound of formula (y).

In some embodiments, the catalyst and ligand are cataCXium® A Pa1ladacycle Gen. 3 and butyldi-1-adamantylphosphine. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is

Cs2CO3. In some embodiments, the solvent is a toluene/water mixture. In some embodiments, contacting is performed at an elevated temperature. In some embodiments, the temperature is from about 90°C to about 110°C.

In some embodiments, the methods further comprise preparing a compound of formula (x)

ΝΗ ₃ ρΛ ρΝ ιύ xQ ^Α XR ⁴ )(x) methods involve bringing into contact a compound of formula (w)

Νθζ. p' ^J h 'Γί' ^N _A ' ^{1 ,s} I nN (w) with a reducing agent, where L is -O(C _1-6 alkyl)-, and R ^A is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6cycloalkenyl, in a solvent, under conditions suitable for the preparation of a compound of formula (x), wherein R ^A is substituted or unsubstituted C2-6alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted _C5-6 cycloalkyl, under conditions suitable for preparing the compound of formula (x).

In some embodiments, the reducing agent is H2, in the presence of a catalyst. In some embodiments, the catalyst is Pd/C. In some embodiments, the solvent is MeOH or EtOH. In some embodiments, contacting is carried out at a temperature of from about 20°C to about 30°C.

In some embodiments, the methods further comprise preparing a compound of formula (w)

Νθζ Λ. R ^a Λ. ,R ^h CX -x XAP (w) methods involve bringing into contact a compound of formula (v)

ΝΟ ₂ Λ Br R ^h Ίΐ Ν' ^{Α L} ''(R ⁴ )c R ^a [B(OR ⁺ )2]2, where R ^a is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C _5-6 cycloalkenyl, and R ⁺ together with the boron atom and the atoms to which they are attached forms a cyclic boronate, for example, 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane, in the presence of a catalyst and a base, in a solvent, under conditions suitable for the preparation of the compound of formula (w).

In some embodiments, the catalyst is Pd(dppf)Cl ₂ . In some embodiments, the base is K ₃ PO ₄ . In some embodiments, the solvent is a 1,4-dioxane/water mixture.

In some embodiments, the methods further comprise preparing a compound of formula (v)

NO^ Br l. R ^h

CX ί x (V)

methods include bringing a connection into contact with a connection

- 39 044376

wherein Hal represents Br, in the presence of a base, in a solvent, under conditions suitable for preparing the compound of formula (v).

In some embodiments, the base is DIPEA or TEA. In some embodiments, the solvent is DMF, or NMP. In some embodiments, contacting is performed at an elevated temperature. In some embodiments, the temperature is from about 50°C to about 70°C.

In some embodiments, the methods further comprise obtaining a compound

formulas; methods include bringing the connection into contact

with HalL-Hal, where Hal is Br, in the presence of a base, in a solvent, under conditions suitable

to obtain a compound of the formula

In some embodiments, the base is K2CO ₃ or CsCO ₃ . In some embodiments, the solvent is acetonitrile, or DMF. In some embodiments, contacting is performed at an elevated temperature. In some embodiments, the temperature is from about 80°C to about 100°C.

In some embodiments, the methods further comprise preparing a compound of formula (v)

methods include bringing the connection into contact

with connection

where LG ³ represents OH, Br, Cl, OT or OM under conditions suitable for preparing the compound of formula (y).

In some embodiments, LG ³ is Br, Cl, OTs, or OMs, and contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is CsCO3 or K2CO3. In some embodiments, the solvent is DMF NMP or acetonitrile. In some embodiments, contacting is performed at an elevated temperature. In some embodiments, the temperature is from about 40°C to about 70°C. In other embodiments, LG ³ is OH, and contacting is carried out in the presence of PPh3 and DIAD or DEAD, in a solvent. In some embodiments, the solvent is THF. In some embodiments, contacting is carried out at room temperature.

In some embodiments, the methods further comprise preparing a compound of formula (ad)

the methods involve contacting the compound with Y-(C _1-9 alkyl)-C(=O)H, where P ^N represents an amino protecting group, in the presence of a reducing agent, in a solvent, under conditions suitable to obtain the compound of formula (ad ).

In some embodiments, the reducing agent is sodium triacetoxyborohydride. In other embodiments, the solvent is MeOH.

In some embodiments, the methods further comprise obtaining a compound

- 40 044376 formula V-(C _1- 9alkyl)-C(=O)H, methods include bringing into contact a compound of formula (ac)

V-(C ₂ - ₉ alkyl)-OH (ac) with an oxidizing agent, in a solvent, under conditions suitable for preparing a compound of the formula N-(C _1-9 alkyl)-C(=O)H.

In some embodiments, the oxidizing agent is DessaMartin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one). In other embodiments, the solvent is DCM. In some embodiments, contacting is carried out at a lower temperature. In one embodiment, the temperature is about 0°C.

In some embodiments, the methods further comprise preparing a compound of formula (ac)

V-(C ₂ -9 alkyl)-OH (ac) methods include deprotection of a compound of formula (ab) V ₂ . ₃ alkyl)-' ⁰

(ab) under conditions suitable for preparing the compound of formula (ac).

In some embodiments, deprotection is accomplished by treatment with an acid in a solvent. In one embodiment, the acid is TsOH. In another embodiment, the solvent is a DCM/EtOH mixture.

In some embodiments, the methods further comprise preparing a compound of formula (ab)

ViC^alkylJ^Y ⁰ ^ (ab) methods involve bringing into contact a compound of formula (aa)

V-OTf (aa) with THP-O(C _2-9 alkyl)-zinc(P) in the presence of a catalyst and ligand, in a solvent, under conditions suitable for preparing the compound of formula (ab).

In some embodiments, the catalyst and ligand are CPhosPdG ₃ and CPhos. In some embodiments, the solvent is toluene. In some embodiments, contacting is carried out at a lower temperature. In some embodiments, the temperature is about 0°C.

In some embodiments, the methods further comprise preparing a compound of formula (aa)

V-OTf(aa) methods involve contacting V-OH with Tf ₂ O in the presence of a base, in a solvent, under conditions suitable to prepare a compound of formula (aa).

In some embodiments, the base is DIPEA or TEA. In other embodiments, the solvent is DCM.

In one embodiment, provided herein is a method for preparing a compound ^(ao)

R ² R ³

(ao) where the method includes bringing into contact a connection (ak)

- 41 044376

R ² R ³

(ak) where P ^O represents an O-protecting group, with a reducing agent in the presence of a catalyst, under conditions suitable for preparing the compound of formula (ao).

In one embodiment, contacting compound (ak) with a reducing agent in the presence of a catalyst is carried out in a solvent at a temperature of from about 20°C to about 30°C under elevated pressure.

In one embodiment, P ^O is a benzyl group. In one embodiment, the reducing agent is H2. In one embodiment, the catalyst is Pd/C or Pd(OH) ₂ . In one embodiment, the solvent is MeOH or EtOAc. In one embodiment, the pressure is increased to about 15 psi.

In one embodiment, the methods presented herein include preparing a compound of formula (ak)

where the method includes bringing into contact a connection (aj)

where R represents alkyl, and Hal represents Cl or Br, under conditions suitable for preparing the compound of formula (ak).

In some embodiments, R is C _1-4 alkyl. In one embodiment, R is methyl, ethyl or butyl. In other embodiments, contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is TEA, DBU, or DIEA. In one embodiment, the solvent is THF, NMP, or DMF. In one embodiment, contacting is carried out at a temperature of from about 20°C to about 80°C. In one embodiment, contacting is carried out in the presence of NaI or KI.

In one embodiment, the methods presented herein include preparing a compound of formula (aj),

wherein the method comprises contacting compound (ai) pI H^^r^ (ai) with an alkylating agent ^Ha1 ' where P ^O represents an O-protecting group, under conditions suitable for preparing the compound of formula (aj).

In one embodiment, P ^O represents a benzyl group, LG ⁴ represents O, and Hal represents Br or Cl. In one embodiment, contacting is carried out in the presence of a base, in a solvent. In one embodiment, contacting is carried out in the presence of CsCO ₃ in DMF or K ₂ CO ₃ in acetonitrile. In one embodiment

- 42 044376 bringing into contact is carried out at elevated temperature. In one embodiment, the temperature is from about 40°C to about 70°C.

In one embodiment, provided herein is a method for preparing a compound ^(ao)

(ao) where the method includes bringing into contact a connection (an)

(ap) with LG ⁴ -L-Hal, where LG ⁴ represents Br, Cl or OH, and Hal represents Br or Cl, in the presence of a base, in a solvent under conditions suitable for preparing the compound of formula (ao).

In one embodiment, the base is DIPEA, TEA or NMM. In one embodiment, the solvent is DMF or NMP. In one embodiment, contacting is carried out at a temperature of from about 50°C to about 70°C.

In one embodiment, provided herein is a method for preparing compound ^(an)

(ap) where the method involves bringing into contact a connection (am)

(am) where P ^N represents a Boc group, with an acid in a solvent, under conditions suitable for preparing the compound of formula (an).

In some embodiments, the acid is TFA or HCl. In one embodiment, the solvent is DCM, dioxane, MeOH or EtOH. In one embodiment, the acid and solvent are TFA in DCM or HCl in dioxane/DCM, MeOH or EtOAc.

In one embodiment, the methods presented herein include preparing a compound of formula (am),

(am) where the method includes contacting an N-protected piperazyl compound

ABOUT

c' where P ^N represents an N-protecting group, R represents alkyl, and Hal represents Cl or Br, under conditions suitable for preparing the compound of formula (am).

In one embodiment, P ^N represents a Boc group. In some embodiments, R is C _1-4 alkyl. In one embodiment, R is methyl, ethyl or butyl. In other embodiments, contacting is carried out in the presence of a base, in a solvent. In some embodiments, the base is TEA, DBU, or DIEA. In one embodiment, the solvent is THF, NMP, or

- 43 044376

DMF. In one embodiment, contacting is carried out at a temperature of from about 20°C to about 80°C. In one embodiment, contacting is carried out in the presence of NaI or

KI.

In one embodiment, the methods presented herein include preparing a compound of formula (c),

(c) where the method includes bringing into contact a connection (ao)

R ² R ²

with V-OH, where LG ⁴ represents a leaving group and R represents alkyl, under conditions suitable for preparing the compound of formula (c).

In one embodiment, LG ⁴ is -OH and contacting (ao) with V-OH is carried out under Mitsunobu conditions, for example, in the presence of Pph3 and DIAD or DEAD, in a solvent such as THF at room temperature. In one embodiment, the leaving group of LG ⁴ in the compound (ao) is Br, Cl, OTs or OMs, and the reaction with V-OH is carried out in the presence of a base, in a solvent. In one embodiment, the base is CsCO3 and the solvent is DMF. In other embodiments, the base is K ₂ CO ₃ and the solvent is acetonitrile. In one embodiment, the reaction is carried out at elevated temperature. In one embodiment, the reaction is carried out at a temperature of from about 40°C to about 70°C.

In one embodiment, the methods presented herein include preparing a compound of formula (as),

(as) where the method includes bringing into contact a connection (ao) R ² R ³

X U. O

L· ;R ) _m (ao) with connection (ar)

NO? .schgch. ϊ Ί Ί G ⁵ (ag) where LG ⁴ represents Br, Cl or OH, LG ⁵ represents OH, and A represents CH, CRA or N, under conditions suitable for preparing the compound of formula (as).

In one embodiment, the LG ⁴ in compound (ao) is OH and the reaction is carried out in the presence of a base in a solvent. In one embodiment, the base is NaOtBu, CsCO ₃ or K ₂ CO ₃ . In one embodiment, the solvent is acetonitrile, DMF, or NMP. In one embodiment, the reaction is carried out at a temperature of from about 0°C to about 70°C.

In one embodiment, the LG ⁴ in compound (ao) is OH, and contacting compound (ao) and compound (ar) is carried out under Mitsunobu conditions, for example, in the presence of PPh ₃ and DIAD or DEAD, in a solvent such as THF , at room temperature to obtain compound (as).

In one embodiment, in compound (ao), LG ⁴ is OH; in compound (ar), LG is F or Cl, and A is N; and contacting the compound (ao) and the compound (ar) is carried out in the presence of a base, in a solvent at a temperature of from about 0°C to about 70°C to obtain the compound (as). In one embodiment, the base is

- 44 044376

NaOtBu, CSCO3 or K2CO3. In one embodiment, the solvent is acetonitrile, DMF, THF or NMP.

In one embodiment, in compound (ao), LG ⁴ is OH; in compound (ag) LG ⁵ represents F or C1, and A represents CH or CR ^A ; and contacting the compound (ao) and the compound (ag) is carried out in the presence of a base, in a solvent at a temperature of from about 0°C to about 70°C to obtain the compound (as). In one embodiment, the base is NaOtBu, CsCO ₃ or K ₂ CO ₃ . In one embodiment, the solvent is acetonitrile, DMF, THF or NMP.

In one embodiment, the methods presented herein include preparing a compound of formula (as),

(as) where the method involves bringing into contact a connection (ap)

R ² _R 2 n-Msch,. ⁰ with connection (aq) (ap)

NO?

(aq) in the presence of a base, in a solvent under conditions suitable for preparing the compound of formula (as).

In one embodiment, the base is NaOtBu, CSCO3 or K2CO3. In one embodiment, the solvent is acetonitrile, DMF, THF, or NMP. In one embodiment, contacting is carried out at a temperature of from about 0°C to about 70°C.

In one embodiment, the methods provided herein include preparing a compound of formula (aq),

(aq) where the method includes bringing into contact a connection (ap)

(ap) where A represents CH, CR ^A or N;

with LG ⁶ -L-Hal in a solvent, under conditions suitable for preparing the compound of formula (aq).

In one embodiment, LG ⁶ is Br or Cl, and Hal is Cl or Br, and contacting is carried out in the presence of a base. In some such embodiments, the base is NaOtBu, CsCO ₃ or K ₂ CO ₃ . In one embodiment, the solvent is acetonitrile, DMF, THF or NMP. In one embodiment, contacting is carried out at a temperature of from about 0°C to about 90°C.

In some embodiments, LG ⁶ is OH, and contacting is carried out in the presence of PPh ₃ and DIAD or DEAD. In one embodiment, the solvent is DMF. In one embodiment, contacting is carried out at room temperature.

In one embodiment, the methods presented herein include preparing a compound of formula (c),

-45 044376

where L represents -O(C ₁ . ₆ alkyl)-, the method includes contacting a compound of formula (av) with a compound

wherein B is CH, CR ^B or N with a base in a solvent, under conditions suitable for preparing the compound of formula (c).

In one embodiment, the solvent is EtOAc. In one embodiment, the base is TEA. In one embodiment, contacting is carried out at a temperature of from about 60°C to about 90°C.

In some embodiments, the methods provided herein include preparing a compound of formula (av)

the methods involve contacting a compound of formula (at)

with R'OOC-C(R ⁵ )(R ⁶ )Hal, where Hal represents Br or Cl, and R' represents C1.3alkyl, in the presence of a base under conditions suitable for preparing the compound of formula (av).

In one embodiment, the base is NaHCO3, DIPEA or TEA. In one embodiment, contacting is carried out at a temperature of from about 90°C to about 130°C.

In some embodiments, the methods provided herein include preparing a compound of formula (at)

the methods involve contacting a compound of formula (as)

with a reducing agent, in a solvent in the presence of a catalyst at elevated pressure, under conditions suitable for the preparation of the compound of formula (at).

In one embodiment, the reducing agent is H2 in MeOH or EtOH. In one embodiment, the catalyst is Pd/C. In one embodiment, the pressure is about 50 psi. In one embodiment, contacting is carried out at a temperature of about 80°C.

In one embodiment, the methods presented herein include preparing a compound of formula (c),

- 46 044376

(c) where L is -O(C _1-6 alkyl)-, the methods include contacting a compound of formula (au)

(au)

R® nc-Y%ncs with the compound * wherein B is CH, CR ^B or N, in a solvent followed by treatment with an acid in the solvent, under conditions suitable to obtain the compound of formula (c).

In one embodiment, the solvent is DMF or DMA. In one embodiment, the acid is HCl. In one embodiment, the acid is in a solvent such as MeOH or EtOH. In one embodiment, contacting is carried out at a temperature of from about 70°C to about 80°C.

In some embodiments, the methods provided herein include preparing a compound of formula (at)

„A. ^(a0 - -, where R ^a represents substituted or unsubstituted C _2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C _5-6 cycloalkyl, and L represents -O(C _1-6 alkyl)-, methods involve bringing into contact a compound of formula (as)

(as) with a reducing agent, in a solvent in the presence of a catalyst, under conditions suitable for preparing the compound of formula (at).

In one embodiment, the reducing agent is H ₂ in MeOH or EtOH. In one embodiment, the catalyst is Pd/C. In one embodiment, contacting is carried out at a temperature of from about 20°C to about 30°C.

In some embodiments, the methods provided herein include preparing a compound of formula (as)

(as) where R ^a represents substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C _5-6 cycloalkenyl;

the methods involve contacting a compound of formula (as)

(as) ' + where R ^a represents Br, with boronate R ^A [B(OR ⁺ ) ₂ ] ₂ ,

- 47 044376 where R ^a represents substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C5-6cycloalkenyl, and R+ together with the boron atom and the atoms to which they are attached forms a cyclic boronate in the presence of a palladium catalyst and a base in a solvent under conditions suitable for preparing a compound of formula (as) wherein R ^a is substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted _C5-6 cycloalkenyl.

In one embodiment, the cyclic boronate is 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane). In one embodiment, the catalyst is Pd(dppf) ₂ Cl ₂ . In one embodiment, the base is K3PO4. In one embodiment, the solvent is a 1,4-dioxane/water mixture.

In one embodiment, provided herein are compounds having the following formula (V-L-Hal):

V I Hal or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (a) wherein A is N, CH, or CR ^A ;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C _3-6 cycloalkyl;

each R ^B is independently selected from halogen and substituted or unsubstituted C _1-6 alkyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3;

b equals 0-2

L represents -O(C _1-6 alkyl)- or -(C _1-9 alkyl)-; And

Hal represents Cl, Br, OMs or OTs;

In one embodiment, provided herein are compounds having the following formula (a):

(a) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (a) wherein A is N, CH, or CR ^A ;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C _3-6 cycloalkyl;

each R ^B is independently selected from halogen and substituted or unsubstituted C _1-6 alkyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl; and equals 0-3;

b equals 0-2

X represents N;

L represents -O(C _1-6 alkyl)- or -(C _1-9 alkyl)-;

each R ⁴ independently represents a substituted or unsubstituted C1-3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C 3-6 cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

- 48 044376 m equals 0-8; And

P ^N represents an amino protecting group.

In one embodiment, P ^N is tert-butyloxycarbonyl or carboxybenzyl.

In one embodiment, provided herein are compounds having the following formula (ai):

or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein R ^x is C _1-4 alkyl and other variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (ai) wherein A is N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C _3-6 cycloalkyl;

each R ^B is independently selected from halogen and substituted or unsubstituted C _1-6 alkyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl; and equals 0-3;

b equals 0-2

X represents N;

L represents -O(C _1-6 alkyl)- or -(C _1-9 alkyl)-;

each R ⁴ independently represents a substituted or unsubstituted C1-3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C 3-6 cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

m is 0-8; And

R ^x represents C _1-4 alkyl.

In one embodiment, provided herein are compounds having the following formula (b):

or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (b), wherein A is N, CH, or CR ^A ;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C _3-6 cycloalkyl;

each R ^B is independently selected from halogen and substituted or unsubstituted C _1-6 alkyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl; and equals 0-3;

b equals 0-2

X represents N;

L represents -O(C _1-6 alkyl)- or -(C _1- 9 alkyl)-;

each R ⁴ independently represents a substituted or unsubstituted C1-3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or two R ⁴ groups together with

- 49 044376 non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl; and m is 0-8.

In one embodiment, provided herein are compounds having the following formula (c):

(c) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (c) wherein A is N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C ₁ . ₆ alkyl and substituted or unsubstituted C3. ₆ cycloalkyl;

each ^RB is independently selected from halogen and substituted or unsubstituted C ₁ . ₆ alkyl;

RC is halogen or CF3;

R ⁵ and R ⁶ are C1.3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3; b equals 0-2

X represents N;

L represents -O(C ₁ . ₆ alkyl)- or -(C ₁ . ₉ alkyl)-;

each R ⁴ independently represents a substituted or unsubstituted C1.3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

m is 0-8;

R ² and R ³ are each independently selected from H, and C1.3alkyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl; And

R represents C ₁ . ₄ alkyl.

In one embodiment, provided herein are compounds having the following formula (d):

(d) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (d), wherein A is N, CH, or CR ^A ;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C ₁ . ₆ alkyl and substituted or unsubstituted C ₃ . ₆ cycloalkyl;

each ^RB is independently selected from halogen and substituted or unsubstituted C ₁ . ₆ alkyl;

RC is halogen or CF3;

R ⁵ and R ⁶ are C1.3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl or 3-6 membered heterocyclyl; and equals 0-3; b equals 0-2

X represents N; L represents -O(C ₁ . ₆ alkyl)- or -(C ₁ . ₉ alkyl)-;

each R ⁴ independently represents substituted or unsubstituted C1.3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3. ₆ cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

m is 0-8; And

- 50 044376

R ² and R ³ are each independently selected from H and C _1-3 alkyl, or R ² and R ³ and the carbon atom to which they are attached form a substituted or unsubstituted C _3-6 cycloalkyl.

In one embodiment, provided herein are compounds having the following formula (t):

(t) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (t) wherein A is N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^B is independently selected from halogen and substituted or unsubstituted C _1-6 alkyl;

R ^C represents halogen or CF ₃ ;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl;

b equals 0-2

X represents N;

L represents -O(C _1-6 alkyl)- or -(C _1-9 αlkyl)-;

each R ⁴ independently represents a substituted or unsubstituted C1-3alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

m is 0-8; And

P ^N represents an amino protecting group.

In one embodiment, P ^N is tert-butyloxycarbonyl or carboxybenzyl.

In one embodiment, provided herein are compounds having the following formula (u):

(and) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (u) wherein A is N, CH, or CRA;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C _3-6 cycloalkyl;

each R ^B is independently selected from halogen and substituted or unsubstituted C _1-6 alkyl;

R ^C represents halogen or CF3;

R ⁵ and R ⁶ represent C1-3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or 3-6 membered heterocyclyl;

b equals 0-2

X represents N;

L represents -O(C _1-6 alkyl)- or -(C _1-9 αlkyl)-;

each R ⁴ independently represents a substituted or unsubstituted C1-3alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

m is 0-8; And

P ^N represents an amino protecting group.

In one embodiment, P ^N is tert-butyloxycarbonyl or carboxybenzyl.

In one embodiment, provided herein are compounds having the following formula (ab):

(ab) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (ab), wherein A is N, CH, or CR ^A ;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C ^ alkyl, and substituted or unsubstituted C ₃ bcycloalkyl;

each R ^B is independently selected from halogen and substituted or unsubstituted C1. ₆ alkyl;

R represents halogen or CF ₃ ;

R ⁵ and R ⁶ represent C1.3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3.b Cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3; and b is 0-2.

In one embodiment, provided herein are compounds having the following formula(s):

(ac) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (ac) wherein A is N, CH, or CR ^A ;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C ^ alkyl, and substituted or unsubstituted C ₃ . ₆ cycloalkyl;

each R ^B is independently selected from halogen and substituted or unsubstituted C1. ₆ alkyl;

R represents halogen or CF ₃ ;

R ⁵ and R ⁶ represent C1.3 alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C3.b Cycloalkyl or 3-6 membered heterocyclyl;

and equals 0-3; and b is 0-2.

In one embodiment, provided herein are compounds having the following formula (ad):

(ad) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof, wherein the variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of formula (ad), wherein A is N, CH, or CR ^A ;

B represents N, CH, or CR ^B ;

each R ^a is independently selected from halogen, substituted or unsubstituted C ^ alkyl, and substituted or unsubstituted C ₃ .b Cycloalkyl;

each R is independently selected from halogen and substituted or unsubstituted C1. ₆ alkyl;

R ^c represents halogen or CF ₃ ;

-52044376

R ⁵ and R ⁶ represent O^alkyl or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a substituted or unsubstituted C ₃ - ₆ cycloalkyl or 3-6-membered heterocyclyl;

and equals 0-3; b equals 0-2

X represents N;

each R ⁴ independently represents a substituted or unsubstituted C1-3 alkyl, or two R ⁴ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C3-6 cycloalkyl or two R ⁴ groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl;

m is 0-8; And

P ^N represents an amino protecting group.

In one embodiment, P ^N is tert-butyloxycarbonyl or carboxybenzyl.

Methods of application.

In one embodiment, the compounds described herein can be used as pharmaceuticals to treat, prevent, or improve conditions in animals or humans. The piperidinedione compounds described herein can be used as pharmaceuticals to treat, prevent, or ameliorate conditions in animals or humans. Accordingly, a variety of uses of piperidinedione compounds are provided herein, including the treatment or prevention of the diseases described below. In one embodiment, the methods provided herein include administering an effective amount of a compound to a subject in need thereof.

The methods presented herein involve administering an effective amount of one or more piperidinedione compounds to a subject in need thereof.

Provided herein are methods of treating or preventing an androgen receptor (AR)-mediated disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein.

Provided herein are methods of treating or preventing AR-mediated diseases in a subject, the method comprising administering to a subject in need thereof an effective amount of a piperidinedione compound as described herein.

In another aspect, provided herein are compounds for use in the treatment or prevention of an AR-mediated disease in a subject, comprising administering to the subject in need thereof an effective amount of a piperidinedione compound as described herein. In some embodiments, provided herein are compounds for use in treating an AR-mediated disease in a subject, comprising administering to the subject in need thereof an effective amount of a piperidinedione compound as described herein. In some embodiments, provided herein are compounds for use in the prevention of an AR-mediated disease in a subject, comprising administering to the subject in need thereof an effective amount of a piperidinedione compound as described herein.

In some embodiments, the compound used in these methods is a piperidinedione compound as described herein. In some embodiments, the compound is a compound of formula (I). In some embodiments, the compound is a compound of formula (II). In some embodiments, the compound is a compound of formula (III). In some embodiments, the compound is a compound of formula (IV). In some embodiments, the compound is a compound of formula (V). In some embodiments, the compound is a compound of formula (VI). In some embodiments, the compound is a compound of formula (VII). In some embodiments, the compound is a compound of formula (VIII). In some embodiments, the compound is a compound of formula (IX). In some embodiments, the compound is a compound of formula (X). In some embodiments, the compound is a compound of formula (a). In some embodiments, the compound is a compound of formula (b). In some embodiments, the compound is a compound of Formula (c). In some embodiments, the compound is a compound of formula (d). In some embodiments, the compound is a compound of formula (t). In some embodiments, the compound is a compound of formula (u). In some embodiments, the compound is a compound of formula (ab). In some embodiments, the compound is a compound of formula (ac). In some embodiments, the compound is a compound of formula (ad). In some embodiments, the connection is a table connection.

In some embodiments, the AR-mediated disease is a wild-type AR-mediated disease. In other embodiments, AR-mediated disease is the result of AR amplification.

In certain embodiments, the AR-mediated disease is prostate cancer. In some such embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some such embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In yet another embodiment, the prostate cancer is non-metastatic CRPC (nmCRPC). In some embodiments, the prostate cancer is hormonally refractory. In some embodiments, the prostate cancer is resistant to AR antagonist treatment. For example, prostate cancer is resistant to treatment with enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole or spironolactone.

Provided herein are methods of reducing AR levels, the method comprising administering to a subject an effective amount of a piperidinedione compound. Also provided herein are piperidinedione compounds for use in methods of reducing AR levels in a cell in vivo, ex vivo or in vitro, comprising contacting the cell with an effective amount of a piperidinedione compound. In one embodiment, the cell is located in the patient. In one embodiment, the cell is not located in the patient. In one embodiment, provided herein are methods of reducing wild-type AR levels in a tumor, the method comprising administering a therapeutically effective amount of a piperidinedione compound to reduce wild-type AR levels in a tumor. In one embodiment, provided herein are methods of reducing AR-full length (AR-FL) levels within a tumor, the method comprising administering a therapeutically effective amount of a piperidinedione compound to reduce AR-full length (AR-FL) levels within a tumor. In some embodiments, AR levels are reduced compared to AR levels before administration of the piperidinedione compound. In some embodiments, AR levels are reduced by 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% compared to AR levels before administration of the piperidinedione compound.

Also provided herein are methods of regulating the activity of an AR protein in a patient in need thereof, comprising administering to said patient a specified amount of a piperidinedione compound. In certain such embodiments, provided herein are methods of reducing AR protein activity in a patient in need thereof, comprising administering to said patient an amount of a piperidinedione compound. In some embodiments, the activity of the AP protein is reduced compared to the activity of the AP protein before administration of the piperidinedione compound. In some embodiments, the AP protein activity is reduced by 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% compared to the AP protein activity before administration of the piperidinedione compound.

In some embodiments of the methods described herein, the methods further comprise administering one or more second agents selected from an AR antagonist (such as cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), a 5a-reductase inhibitor (such as finasteride and dutasteride), a CYP17A1 inhibitor (eg, abiraterone acetate), a gonadotropin-releasing hormone (GnRH) analogue (eg, leuprorelin and cetrorelix), and an antigonadotropin (eg, megestrol and medroxyprogesterone acetate).

In some embodiments, the compounds provided herein can be used in any of the above methods.

In some embodiments, the piperidinedione compound provided herein can be used in any of the above methods.

The pharmaceutical compositions and methods of administering the compound provided herein can be administered to a subject orally, topically or parenterally in conventional formulation form, such as capsules, microcapsules, tablets, granules, powder, lozenges, pills, suppositories, injections, suspensions, syrups, patches , creams, lotions, ointments, gels, sprays, solutions and emulsions.

The piperidinedione compounds may be administered orally, topically or parenterally to a subject in conventional formulation forms such as capsules, microcapsules, tablets, granules, powder, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays , solutions and emulsions. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as filler (for example, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binder (for example, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum acacia, polyethylene glycol, sucrose or starch), disintegrant (e.g. starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricant (e.g. magnesium stearate , light anhydrous silicic acid, talc or sodium lauryl sulfate), flavor (such as citric acid, menthol, glycine or orange powder), preservative (such as sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizer (such as citric acid, citrate sodium or acetic acid), suspending agent (e.g.

- 54 044376 methylcellulose, polyvinylpyrroliclone or aluminum stearate), dispersing agent (eg hydroxypropyl methylcellulose), diluent (eg water) and base wax (eg cocoa butter, white petrolatum or polyethylene glycol). The effective amount of piperidinedione compounds in the pharmaceutical composition may be at a level to provide the desired effect; for example, from about 0.005 mg/kg of the subject's body weight to about 10 mg/kg of the subject's body weight in a unit dosage for both oral and parenteral administration.

The dose of the piperidinedione compound administered to a subject varies widely and may depend on the judgment of the practitioner. In general, piperidinedione compounds can be administered one to four times daily at a dose of from about 0.001 mg/kg of the subject's body weight to about 10 mg/kg of the subject's body weight, but the above dosage may be appropriately adjusted depending on the age, weight body and health status of the subject and type of administration. In one embodiment, the dose is from about 0.001 mg/kg of the subject's body weight to about 5 mg/kg of the subject's body weight, from about 0.01 mg/kg of the subject's body weight to about 5 mg/kg of the subject's body weight, from about 0. 05 mg/kg of the subject's body weight to about 1 mg/kg of the subject's body weight, from about 0.1 mg/kg of the subject's body weight to about 0.75 mg/kg of the subject's body weight, or from about 0.25 mg/kg of the subject's body weight subject to about 0.5 mg/kg of the subject's body weight. In one embodiment, one dose is administered per day. In any particular case, the amount of piperidinedione compound administered will depend on factors such as the solubility of the active component, the formulation used, and the route of administration.

In another embodiment, provided herein are methods of treating or preventing a disease or disorder, comprising administering from about 0.01 mg/day to about 750 mg/day, from about 0.1 mg/day to about 375 mg/day, from about 0.1 mg/day to about 150 mg/day, from about 0.1 mg/day to about 75 mg/day, from about 0.1 mg/day to about 50 mg/day, from about 0.1 mg/day day to about 25 mg/day or about 0.1 mg/day to about 10 mg/day of the piperidinedione compound to a subject in need thereof.

In another embodiment, provided herein are unit dosage forms that contain from about 0.1 to 500 mg, from about 1 to 250 mg, from about 1 to about 100 mg, about 1 and about 50 mg, about 1 and about 25 mg or from about 1 to about 10 mg of a piperidinedione compound.

In a specific embodiment, provided herein are unit dosage forms containing about 0.1 mg or 100 mg of a piperidinedione compound.

In another embodiment, unit dosage forms provided herein include 0.5, 1, 5, 10, 15, 20, 30, 35, 50, 70, 100, 125, 140, 175, 20θ, 250, 280, 350, 500, 560, 700, 750, 1000 or 1400 mg of piperidinedione compound.

The piperidinedione compound may be administered one, two, three, four or more times per day. In a specific embodiment, doses of 100 mg or less are administered as a single daily dose, and doses greater than 100 mg are administered twice daily in an amount equal to half the total daily dose.

For reasons of convenience, the piperidinedione compound can be administered orally. In one embodiment, when administered orally, the piperidinedione compound is administered with food and water. In another embodiment, the piperidinedione compound is dispersed in water or juice (eg, apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

The piperidinedione compound may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, skin. The route of administration is at the discretion of the practitioner and may depend in part on the site of disease.

In one embodiment, provided herein are capsules containing a piperidinedione compound without additional carrier, excipient or base.

In another embodiment, provided herein are compositions comprising an effective amount of a piperidinedione compound and a pharmaceutically acceptable carrier or base, wherein the pharmaceutically acceptable carrier or base may include an excipient, a diluent, or a mixture thereof. In one embodiment, said composition is a pharmaceutical composition.

The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose or a suitable portion of a daily dose in a dosage unit, which may be one tablet or capsule or a suitable volume of liquid. In one embodiment, solutions are prepared from water-soluble salts, such as a hydrochloride salt. In general, all compositions are prepared in accordance with methods known in pharmaceutical chemistry. Capsules can be prepared by mixing the piperidinedione compound with a suitable carrier or diluent and filling the capsules with the required amount of the mixture. Common carriers and diluents include, but are not limited to, inert powdered substances such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline

- 55 044376 cellulose, sugars such as fructose, mannitol and sucrose, cereal flour and similar food powders.

Tablets can be prepared by direct compression, wet granulation or dry granulation. Their formulations typically include diluents, binders, lubricants and disintegrants, and a compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders are starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including gum arabic, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

The tablet formulation may require a lubricant to prevent the tablet and stamps from sticking to the dye. The lubricant may be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, breaking the tablet and releasing a compound. These include starches, clays, celluloses, algins and gums. In particular, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and, for example, carboxymethylcellulose, as well as sodium lauryl sulfate can be used. Tablets may be coated with sugar as a flavoring and sealant or with film-forming protective agents to modify the dissolution properties of the tablet. The compositions may also be formulated as chewable tablets, for example using substances such as mannitol.

If it is desired to administer the piperidinedione compound as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base that can be modified by adding wax to slightly increase the melting point. Water-miscible suppository bases containing, in particular, polyethylene glycols of various molecular weights are widely used.

The effect of the piperidinedione compound can be delayed or prolonged through proper formulation. For example, a slowly dissolving granule of the piperidinedione compound may be prepared and included in a tablet or capsule or in a slow release implantable device. The method also involves making granules with several different dissolution rates and filling capsules with a mixture of said granules. Tablets or capsules may be coated with a film that resists dissolution for a predictable period of time. Even parenteral preparations can be made long-acting by dissolving or suspending the piperidinedione compound in oily or emulsified vehicles that allow it to disperse slowly in serum.

Examples

The following examples are provided by way of illustration and not limitation. Compound names are given using the automatic name generation tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures with support for Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art may modify the procedures set forth in the illustrative examples to obtain the desired products.

Salts of the compounds described herein can be prepared by standard methods, such as incorporating an acid (e.g., TFA, formic acid or HCl) into the mobile phases during chromatographic purification or mixing the chromatographic purification products with a solution of acid (e.g., aqueous HCl) .

Abbreviations used:__________________________________________

Vos tert-butoxycarbonyl Vosgo di-tert-butyl dicarbonate nBuLi n-Butyllithium

- 56 044376

CataCXium®A Palladacycle Gen. 3 Adduct of methanesulfonato(diadamantyl-nbutylphosphino)-2'-amino-1, G-biphenyl-2yl)palladium (II) with dichloromethane Cbz Carboxybenzyl CPhos 2-(2-Dicyclohexylphosphanylphenyl)- IgbAbP-tetramethyl-benzene-1,3-diamine CPhosPdG3 [(2-dicyclohexylphosphino-2',6'-bis(I, N dimethylamino)-1,1 '-biphenyl)-2-(2'-amino-1, Γbiphenyl)] palladium(P) methanesulfonate DXM Dichloromethane DIAD Diisopropyl azodicarboxylate DEAD Diethyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMS0 Dimethyl sulfoxide IER Electrospray ionization EtOH Ethanol EtOAc Ethyl acetate _FeCl2 Ferric chloride(P) HATU 1 - [Bis(d ymethylamino)methylene] -1 Η-1,2,3 triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High performance liquid chromatography HTRF Time-resolved homogeneous fluorescence LCMS Liquid chromatography - mass spectrometry MeOH Methanol M.C. Mass spectrometry MTBE Methyl tert-butyl ether NML N-Methylpyrrolidone NMR Nuclear magnetic resonance

- 57 044376

OMs Mesilate OTs Tosylate Pd/C Palladium on coal Pd(dppf) ₂ Cl ₂ [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(P) PPh ₃ Triphenylphosphine TEA Triethylamine TFU Trifluoroacetic acid _Tf2O Triflate anhydride THF Tetrahydrofuran TGP Tetrahydropyran those Thin layer chromatography TMSC1 Trimethylsilyl chloride TMSCN Trimethylsilyl cyanide TMSOTf Trimethylsilyl trifluoromethanesulfonate TsOH p-Toluenesulfonic acid

Synthesis of compounds

Example 1: 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) phenoxy)ethyl)pinerazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide formate

5-Isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile.

To a solution of thiocarbonyl dichloride (75.9 g, 0.66 mol) in water (1000 ml), 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (95.0 g, 0.508 mol) was added slowly in portions. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was extracted with EtOAc (1000 mlx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to give 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (86.0 g, 73.9% yield) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.66 (d, J=2.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H).

2-(4-Hydroxyanilino)-2-methylpropanenitrile.

To a solution of 4-aminophenol (80.0 g, 0.733 mmol) in DCM (1600 ml) and acetone (400 ml) was added trimethylsilyl trifluoromethanesulfonate (8.15 g, 36.7 mmol) and trimethylsilylformonitrile (102 g, 1.03 mol) . The reaction mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated under reduced pressure and the residue was purified by recrystallization from MTBE (500 ml) and dried to give 2-(4-hydroxyanilino)-2-methylpropanenitrile (85.0 g, yield 65.8%) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.90 (s, 1H), 6.78-6.77 (m, 2H), 6.66-6.63 (m, 2H), 5.20 (s, 1H), 1.51 (s, 6H).

5-[3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-3(trifluoromethyl)pyridine-2-carbonitrile.

To a solution of 2-(4-hydroxyanilino)-2-methylpropanenitrile (53.0 g, 0.301 mol) in DMA (500 ml) was added 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (72.4 g, 0.316 mol) at 28°C. The reaction mixture was stirred at 28°C for 2 hours. The reaction solution was mixed with MeOH (500 ml) and aqueous HCl (2 M, 500 ml) and heated to 70°C. After stirring for 2 hours, the reaction solution was cooled to 30°C, mixed with water (500 ml) and extracted with EtOAc (1000 mlx2). The combined organic phases were washed with saturated sodium chloride solution (500 mlx2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from EtOAc (100 ml) to give 5-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-58 044376 oxo-2-thioxoimidazolidin-1-yl]-3 -(trifluoromethyl)pyridine-2-carbonitrile (41.5 g, 33.9% yield) as a white solid.

¹ H NMR (400 MHz, CDCL3) δ ppm 9.10 (s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.17 (dd, J=2.0, 6.4 Hz, 2H), 6.97 (dd , J=2.0, 6.4 Hz, 2H), 5.23 (s, 1H), 1.59 (s, 6H).

tert-Butyl-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy) ethyl)piperazine-1-carboxylate.

5-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile (2.00 g, 4.92 mmol), tert-butyl -4-(2-bromoethyl)piperazine-1-carboxylate (1.44 g, 4.92 mmol) and cesium carbonate (2.40 g, 7.38 mmol) were combined in DMF (12 ml) and the mixture was heated to 45°C. in a scintillation vial with a screw cap. After 48 hours, the solution was filtered, the solid was washed with additional MeOH in DCM, and the combined filtrate was concentrated under reduced pressure to give a yellow oil that partially solidified. The solid was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give the title compound as an off-white solid (0.971 g, 1.57 mmol, 31.9% yield). MS (ESI) m/z 619[M+1]+.

5-(4,4-Dimethyl-5-oxo-3-(4-(2-(piperazin-1-yl)ethoxy)phenyl)-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile trihydrochloride.

tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy)ethyl )piperazine-1-carboxylate (0.971 g, 1.57 mmol) was dissolved in DCM (4 ml) and a 4.0 M solution of HCl in dioxane (0.572 ml, 18.8 mmol) was added. After 90 min, the solution was concentrated under reduced pressure to give the title compound as a yellow solid (1.07 g, 1.7 mmol, quantitative yield). MS (ESI) m/z 519 [M+1] ⁺ .

Methyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy) ethyl)piperazin-1-yl)acetate.

5-(4,4-Dimethyl-5-oxo-3-(4-(2-(piperazin-1-yl)ethoxy)phenyl)-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile trihydrochloride (0.400 g, 0.637 mmol) and TEA (0.444 mL, 3.19 mmol) were combined in THF (3 mL). After stirring for 2 min, methyl 2-bromoacetate (0.065 mL, 0.637 mmol) was added and the mixture was stirred at ambient temperature in a screw cap flask. After 30 min, the solution was loaded onto a silica gel column for purification chromatography (0-100% EtOAc in hexanes, then 10% MeOH in EtOAc) to give the title compound (θ.273 g, 0.462 mmol, 72.6% yield). MS (ESI) m/z 591 [M+1] ⁺ .

2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)phenoxy)ethyl )piperazin-1-yl)acetic acid.

Methyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy) ethyl)piperazin-1-yl)acetate (0.273 g, 0.462 mmol) was dissolved in THF (1 ml) and treated with a solution of lithium hydroxide hydroxide (0.213 g, 5.08 mmol) in water (1.000 ml). The mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. Water (3 ml) and 3.0 M aqueous HCl solution were added to the resulting yellow oil to lower the pH to 4-5. The material was partitioned between 15% MeOH in DCM and water (75 ml). The aqueous phase was extracted with DCM and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an off-white solid (0.135 g, 0.234 mmol, 51.0% yield). MS (ESI) m/z 577 [M+1] ⁺ .

tert-Butyl N-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]carbamate.

To a solution of 3-bromopiperidine-2,6-dione (120 g, 0.470 mol) in DMF (1 L) was added tert-butyl N-(3aminophenyl)carbamate (81.4 g, 0.390 mol) and the mixture was stirred at 80° C for 12 hours, then slowly poured into water (2500 ml) and filtered. The solid was washed with EtOAc (200 mL) and dried to give tert-butyl-N-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]carbamate (56.0 g, crude) as blue solid matter.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.78 (s, 1H), 9.04 (s, 1H), 6.96-6.92 (m, 1H), 6.87 (s, 1H), 6.67 (d, J=8, 0 Hz, 1H), 6.31 (dd, J=1.6 Hz, 8.0 Hz, 1H), 5.79 (s, 1H), 4.23-4.21 (m, 1H), 2 .74-2.62 (m, 1H), 2.61-2.58 (m, 1H), 2.10-2.08 (m, 1H), 1.91-1.87 (m, 1H) , 1.47 (s, 9H).

3-(3-Aminoanilino)piperidine-2,6-dione.

To a solution of tert-butyl N-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]carbamate (55.6 g, 0.17 mol) in DCM (550 ml) add TFA (385 g, 3.38 mol, 250 ml) at 0-5°C. The reaction mixture was stirred at 25°C for 10 hours, then concentrated to a residue. MTBE (600 mL) was added to the residue, resulting in a blue solid. 3-(3-Aminoanilino)piperidine-2,6-dione trifluoroacetate (52.0 g, 89.6% yield) was collected by filtration.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.83 (s, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 6.50-6.43 (m, 1H), 4.33 (dd, J=5.2 Hz, 11.6 Hz, 1H), 2.76-2.73 (m, 1H), 2.63 -2.58 (m, 1H), 2.13-2.07 (m, 1H), 1.97-1.93 (m, 1H).

2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine- 59 044376

1-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide formate.

2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl) was added to the scintillation vial )phenoxy)ethyl)piperazin-1-yl)acetic acid (0.135 g, 0.234 mmol), 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.074 g, 0.234 mmol) and DIPEA (0.123 ml , 0.702 mmol) in DMF (1 ml). HATU (0.089 g, 0.234 mmol) was added last and the solution was stirred at ambient temperature. After 30 min, the solution was diluted with DMSO (0.5 mL) and the mixture was purified by standard methods to give the title compound (0.050 g, 0.064 mmol, 27.5% yield). MS (ESI) m/z 778 [M+1]+.

¹ H NMR (400 MHz, DMSO-06) δ ppm 10.78 (s, 1H), 9.36-9.44 (m, 1H), 9.24 (d, J=1.22 Hz, 1H), 8.82 (d, J=1.83 Hz , 1H), 8.13 (s, 1H), 7.28 (m, J=8.68 Hz, 2H), 7.12 (m, J=8.56 Hz, 2H), 6.96-7 .03 (m, 2H), 6.81 (br.d., J=8.07 Hz, 1H), 6.52 (s, 1H), 6.39 (d., J=7.35 Hz, 1H), 5.88 (br.d., J=8.68 Hz, 1H), 4.25 (dt, J=7.15, 5.35 Hz, 1H), 4.08-4.20 ( m, 2H), 3.37 (br.s, 1H), 3.24 (br.s, 1H), 2.95-3.19 (m, 3H), 2.58-2.87 (m, 1H), 2.54-2.81 (m, 10H), 2.37-2.44 (m, 1H), 2.33 (br. s, 1H), 2.04-2.14 (m , 1H), 1.82-1.95 (m, 1H), 1.46-1.54 (m, 7 N), 1.25 (br.d, J=1.47 Hz, 1H), 0 .04 (br. s, 1H), -0.04 (br. d, J=3.18 Hz, 1H).

Example 2: (2S)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine- 1-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)propanamide hydrochloride

2-(3-Chloro-4-hydroxyanilino)-2-methylpropanenitrile.

To a solution of 4-amino-2-chlorophenol (45.0 g, 0.310 mol) in DCM (450 ml) and acetone (225 ml) was added trimethylsilyl trifluoromethanesulfonate (3.48 g, 16.0 mmol) and trimethylsilylformonitrile (43.5 g , 0.440 mol) at 10°C. After addition, the reaction mixture was stirred at 25°C for 16 hours, then concentrated to a residue, which was purified by silica gel column chromatography (petroleum ether and EtOAc, 15:1 ~ 7:1), to give 2-(3-chloro-4 -hydroxy-anilino)-2-methyl-propanenitrile (41.5 g, 62.8% yield) as a colorless solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 9.52 (s, 1H), 6.89-6.84 (m, 2H), 6.76-6.73 (m, 1H), 5.52 (s, 1H), 1.54 (s, 6H).

4-[3-(3-Chloro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2(trifluoromethyl)benzonitrile.

4-Isothiocyanato-2-(trifluoromethyl)benzonitrile ( 19.0 g, 83.0 mmol) at 20°C. After stirring at 20°C for 2 hours, the reaction mixture was diluted with MeOH (150 ml) and aqueous HCl (2 M, 150 ml) at 20°C and stirred at 70°C for 5 hours. The reaction mixture was cooled to 10°C and filtered. The filter residue was washed with water (200 ml) and dried to give 4-[3-(3-chloro-4hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2 -(trifluoromethyl)benzonitrile (20.0 g, 65.6% yield) as a white solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 10.72 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.07 (dd, J=1 .6 Hz, 8.0 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.15-7.10 (m, 2H), 1.49 (s, 6H).

tert-Butyl 4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy)ethyl )piperazine-1-carboxylate.

tert-Butyl 4-(2-chloroethyl)piperazine-1-carboxylate (0.424 g, 1.70 mmol, 1.50 eq.) was dissolved in DMF (8.42 ml, 0.135 mol). Add cesium carbonate (0.556 g, 1.70 mmol, 1.50 eq.) and 4-(3-(3-chloro-4hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile (0.500 g, 1.14 mmol, 1 eq.) and the reaction mixture was heated to 60°C for 18 hours. The reaction was quenched with water and diluted with EtOAc, and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (010% MeOH in DCM) and the appropriate fractions were combined and concentrated to give tert-butyl4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)phenoxy)ethyl)piperazine-1-carboxylate (0.792 g, 1.07 mmol, 95% yield) as a yellow oil. MS (ESI) m/z 652.2 [M] ⁺ .

4-(3-(3-Chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)2-(trifluoromethyl) benzonitrile hydrochloride.

tert-Butyl 4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy)ethyl )piperazine-1-carboxylate (0.701 g, 1.07 mmol, 1 eq.) was suspended in DCM (4.75 mL, 0.226 mol) and treated with a solution of HCl in dioxane (4.03 mL, 16.1 mmol, 15 eq. .). The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give 4-(3-(3-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5- oxo-2- 60 044376 thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.633 g, 1.08 mmol, yield

100%) as a white solid. MS (ESI) m/z 552.2 [M] ⁺ .

(S)-Methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1 - yl)phenoxy)ethyl)piperazin-1-yl)propanoate.

(R)-Methyl 2-chloropropanoate (0.033 mL, 0.31 mmol, 1.2 eq.) was added to the stirred mixture of 4(3-(3-chloro-4-(2-(piperazin-1-yl)ethoxy) phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile hydrochloride (0.150 g, 0.255 mmol, 1 eq.), THF (2.179 ml, 0.117 mol) and TEA (0.142 ml, 1.02 mmol, 4 eq.). The reaction mixture was stirred for 18 hours at 60°C, then heated at 80°C for 36 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (0-80% EtOAc in hexanes) to give (S) -methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy )ethyl)piperazin-1-yl)propanoate (0.078 g, 0.122 mmol, 48.0% yield) as a yellow solid. MS (ESI) m/z 638.2 [M] ⁺ .

(S)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )phenoxy)ethyl)piperazin-1-yl)propanoic acid.

K (B)-methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1 -yl)phenoxy)ethyl)piperazin-1-yl)propanoate (0.078 g, 0.12 mmol, 1 eq.) suspended in a 3:1 mixture of THF (0.811 ml) and water (0.270 ml) (0.113 mol), lithium hydroxide (0.031 g, 1.30 mmol, 10 eq.) was added. The reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc and water, the pH was reduced to ~3 by adding 6 M aqueous HCl. The organic layer was extracted with EtOAc, dried over sodium sulfate, filtered and concentrated to give (S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)- 5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoic acid (0.117 g, 0.127 mmol, 104% yield) as a beige solid. MS (ESI) m/z 624.2 [M] ⁺ .

(28)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)propanamide hydrochloride.

(S)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )phenoxy)ethyl)piperazin-1-yl)propane. acid (0.076 g, 0.12 mmol, 1 eq.) was combined with 3-((3-aminophenyl)amino)piperidine-2,6-dione trifluoroacetate salt (0.041 g, 0.12 mmol, 1 eq.), HATU (0.051 g, 0.134 mmol, 1.1 eq.), DIPEA (0.085 mL, 0.49 mmol, 4 eq.) and DMF (0.609 mL, 0.2 M), and the reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and diluted with EtOAc, and the aqueous layer was extracted with EtOAc. The combined extracts were concentrated and the residue was purified by standard methods to give (2S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5- dimethyl 4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)propanamide hydrochloride (0.022 g , 0.027 mmol, yield 22%). MS (ESI) m/z 825.2 [M] ⁺ .

1H NMR (400 MHz, DMSO-th ₆ ) δ ppm 10.79 (s, 1H), 10.12 (br. s, 1H), 8.40 (d, J=8.31 Hz, 1H), 8.27 (d, J=1.83 Hz, 1H ), 8.06 (dd, J=1.59, 8.19 Hz, 1H), 7.54-7.57 (m, 1H), 7.38 (s, 3H), 6.96-7, 06 (m, 2H), 6.85 (br. d, J=7.83 Hz, 1H), 6.45 (dd, J=1.47, 8.19 Hz, 1H), 4.55 (br. s, 2H), 4.26 (ush dd, J=4.34, 11.19 Hz, 1H), 3.23-3.46 (m, 9H), 2.69-2.80 (m, 1H ), 2.55-2.64 (m, 1H), 2.54 (s, 2H), 2.08-2.14 (m, 1H), 1.90 (ush dq, J=4.46, 12.08 Hz, 1H), 1.52 (s, 6H), 1.39 (br.s, 3H).

Example 3: 2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy )ethyl)piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3yl)amino)-2-fluorophenyl)acetamide hydrochloride

tert-Butyl (2-fluoro-5-nitrophenyl)carbamate, tert-butyl N-tert-butoxycarbonyl-N-(2-fluoro-5nitro-phenyl)carbamate.

To a solution of 2-fluoro-5-nitroaniline (100.0 g, 640.6 mmol, 1.00 eq.) and Boc ₂ O (279.6 g, 1.28 mol, 294 ml, 2.00 eq.) to THF (600 mL) add 4-dimethylaminopyridine (7.83 g, 64.1 mmol, 0.10 eq.) in one portion. The mixture was stirred at 50°C under nitrogen atmosphere for 12 hours. The mixture was cooled to 15°C and concentrated under reduced pressure to obtain a residue. The residue was diluted with water (1500 ml) and extracted with EtOAc (500 mlx3). The combined organic layers were washed with brine (500 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether). A mixture of tert-butyl (2-fluoro-5-nitrophenyl)carbamate and tert-butyl N-tert-butoxycarbonyl-N-(2-fluoro-5nitro-phenyl)carbamate (200 g) was obtained as a colorless oil.

- 61 044376 tert-Butyl (5-amino-2-fluorophenyl)carbamate, tert-butyl N-(5-αamino-2-fluorophenyl)-N-tertbutoxycarbonylcarbamate.

To a mixture of tert-butyl (2-fluoro-5-nitrophenyl)carbamate and tert-butyl N-tert-butoxycarbonyl-N-(2fluoro-5-nitrophenyl)carbamate (80.0 g, 224.5 mmol, 1. 00 eq.) in MeOH (800 ml) was added palladium on alumina (10.0 g, 224.5 mmol, 5% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 15°C for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to leave a residue. A mixture of tert-butyl (5-amino-2-fluorophenyl)carbamate and tert-butyl N-(5-αmino-2fluorophenyl)-N-tert-butoxycarbonylcarbamate (70 g) was obtained as a colorless oil. The mixture was used in the next step without further purification. MS (ESI) m/z 171.1 [M-55] ⁺ .

tert-Butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamate, tert-butyl N-tertbutoxycarbonyl-N[5-[(2,6-dioxo-3-piperidyl) amino]-2-fluorophenyl]carbamate.

To a mixture of tert-butyl (5-amino-2-fluorophenyl)carbamate and tert-butyl N-(5-amino-2-fluorophenyl)-Ntert-butoxycarbonyl-carbamate (30.00 g, 132.6 mmol, 1.00 eq.) and sodium bicarbonate (22.28 g, 265.2 mmol, 2.00 eq.) in DMF (250 ml) was added 3-bromopiperidine-2,6-dione (30.00 g, 156.2 mmol, 1.18 eq.) per serving. The reaction mixture was stirred at 50°C under nitrogen atmosphere for 12 hours, then diluted with water (1000 ml) and extracted with EtOAc (300 mlx4). The combined organic layers were washed with brine (400 mlx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (10~35% EtOAc in petroleum ether). A mixture of tert-butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2fluorophenyl)carbamate and tert-butyl N-tert-butoxycarbonyl-N-[5-[(2,6-dioxo-3- piperidyl)amino]-2fluorophenyl]carbamate (43.00 g) was obtained as a light yellow solid. MS (ESI) m/z 282.1 [M-55] ⁺ .

3-(3-Amino-4-fluorophenylamino)piperidine-2,6-dione.

To a mixture of tert-butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamate and tert-butyl Ntert-butoxycarbonyl-N-[5-[(2,6-dioxo-3 -piperidyl)amino]-2-fluorophenyl]carbamate (30.00 g, 68.58 mmol, 1.00 eq.) in DCM (300 mL) added TFA (60.0 mL, 11.8 eq.) in one portion at 0°C. The mixture was stirred at 0°C for 0.5 hours and then stirred at 20°C for 2 hours. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure at 40°C to remove DCM. Saturated sodium bicarbonate solution (500 ml) and solid sodium bicarbonate were then added to the mixture to adjust the pH to 7. The suspension was filtered and the filter cake was collected. The filter cake was washed with EtOAc (200x5) and dried under reduced pressure to obtain a gray solid. The compound 3-(3-amino-4-fluorophenylamino)piperidine-2,6-dione (10.02 g, 41.53 mmol, 60.6% yield) was obtained as a gray solid. MS (ESI) m/z 238.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (s, 1H), 6.69 (dd, J=8.7, 11.2 Hz, 1H), 6.08 (dd, J=2.7, 7.9 Hz, 1H), 5 .84 (td, J=3.1, 8.7 Hz, 1H), 5.40 (d, J=7.3 Hz, 1H), 4.81 (s, 2H), 4.16-4, 07 (m, 1H), 2.76-2.65 (m, 1H), 2.61-2.53 (m, 1H), 2.13-2.04 (m, 1H), 1.83 ( dk, J=4.7, 12.0 Hz, 1H).

4-(2-(4-((1-Methoxy-2-methyl-1-oxopropan-2-yl)amino)-2-vinylphenoxy)ethyl)piperazine-1carboxylate.

Mixture of tert-butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (1.00 g, 2 .00 mmol, 1 eq.), 4,4,5,5-tetramethyl-2vinyl-1,3,2-dioxaborolane (0.616 g, 4.00 mmol, 2 eq.), potassium phosphate (2.12 g, 9.99 mmol, 5 eq.), (1,1'bis(diphenylphosphino)ferrocene)-dichloropalladium(P) (0.292 g, 0.399 mmol, 0.2 eq.) in dioxane (1 ml) and water (0. 5 ml) was degassed and purged with nitrogen 3 times. The mixture was stirred at 120°C for 12 hours under a nitrogen atmosphere, then concentrated under reduced pressure at 40°C. The residue was poured into ice water (50 ml). The aqueous phase was extracted with EtOAc (50 mlx3). The combined organic phase was washed with brine (100 mlx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20-33% EtOAc in petroleum ether) to give tert-butyl 4-(2-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)- 2vinylphenoxy)ethyl)piperazine-1-carboxylate (0.500 g, 1.12 mmol, 55.9% yield) as a yellow oil. MS (ESI) m/z 448.1 [M+1] ⁺ .

tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl) piperazine-1-carboxylate.

K astute tert-butyl 4-(2-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)-2vinylphenoxy)ethyl)piperazine-1-carboxylate (0.500 g, 1.12 mmol , 1 eq.) in MeOH (10 ml) was added Pd-C (10%, 0.200 g) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 40°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(2-(2-ethyl-4((1-methoxy- 2-Methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.320 g, 0.712 mmol, 63.7% yield) as a yellow oil. MS (ESI) m/z 450.3 [M+1] ⁺ .

tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2

- 62 044376 thioxoimidazolidin-1 -yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate.

To a mixture of tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.319 g, 0.710 mmol , 1 eq.) and 4-isothiocyanato-2(trifluoromethyl)benzonitrile (0.486 g, 2.130 mmol, 3 eq.) in EtOAc (2 ml) was added TEA (0.359 g, 3.550 mmol, 5 eq.). The mixture was stirred at 80°C for 12 hours, then concentrated under reduced pressure. The residue was purified by preparative TLC (67% EtOAc in petroleum ether) to give tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2 -thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)piperazine-1-carboxylate (0.315 g, 0.488 mmol, 68.8% yield) as a yellow solid. MS (ESI) m/z 646.4 [M+1]+.

4-(3-(3-Ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)2-(trifluoromethyl) benzonitrile hydrochloride.

To a solution of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy) ethyl)piperazine-1-carboxylate (0.315 g, 0.488 mmol, 1 eq.) in EtOAc (2 ml) was added with HCl in dioxane (4 M, 10 ml). The mixture was stirred at 25°C for 30 minutes, then concentrated under reduced pressure to give 4-(3-(3-ethyl-4-(2-(piperazin-1yl)ethoxy)phenyl)-4,4-dimethyl-5 -oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.300 g, crude) as a yellow solid. MS (ESI) m/z 546.1 [M+1] ⁺ .

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl) piperazin-1-yl)acetic acid hydrochloride.

To a solution of 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl )benzonitrile hydrochloride (1.00 g, 1.72 mmol) in THF (10 ml) was added DIPEA (1.20 ml, 6.87 mmol), then tert-butyl 2-bromoacetate (0.266 ml, 1.80 mmol) . The resulting mixture was stirred overnight at ambient temperature, then diluted with EtOAc (125 ml), water (20 ml) and brine (20 ml). The solvent layers were separated and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was dissolved in DCM (25 ml), treated with TFA (2.65 ml, 34.4 mmol), and the solution was stirred overnight at ambient temperature. A 4.0 M solution of HCl in dioxane (5 ml) was added and stirring was continued at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residual oil was treated with 4.0 M HCl in dioxane (5 ml). The resulting precipitate was collected by filtration, suspended and triturated in diethyl ether for 3 hours. The material was collected by filtration, washed with hexane and dried in a vacuum oven overnight at 45°C to obtain 2-(4-(2-(4-(3 -(4-cyano-3-(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)acetic acid hydrochloride (0.989 g , 1.54 mmol, yield 90.0%). MS (IER) m/z 604.2 [M+1] ⁺ .

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl) piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride.

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl) piperazin-1-yl)acetic acid hydrochloride (0.100 g, 0.156 mmol), 3-((3-amino-4fluorophenyl)amino)piperidine-2,6-dione 2,2,2-trifluoroacetate (0.055 g, 0.156 mmol) , DIPEA (0.164 ml, 0.937 mmol) and DMF (1 ml) were combined and stirred for 5 min. HATU (0.065 g, 0.17 mmol) was added and the resulting mixture was stirred at ambient temperature. After 6 hours, the reaction mixture was filtered and purified by standard methods to give 2-(4-(2-(4-(3-(4-Cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride (0.011 g, 0.013 mmol , yield 8.2%). MS (ESI) m/z 823.2 [M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-de) δ ppm 10.67-10.89 (m, 1H), 8.35-8.47 (m, 1H), 8.24-8.35 (m, 1H), 8.028.14 (m, 1H), 7, 10-7.28 (m, 4H), 6.90-7.10 (m, 1H), 6.38-6.55 (m, 1H), 4.40-4.55 (m, 3H), 4.18-4.29 (m, 2H), 3.49-3.81 (m, 5H), 2.56-2.79 (m, 4H), 2.01-2.15 (m, 1H ), 1.81-1.98 (m, 1H), 1.40-1.57 (m, 6H), 1.00-1.25 (m, 4H).

Example 4: 2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-fluorophenoxy )ethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride

Ν

tert-Butyl N-(3-bromo-5-nitrophenyl)-N-tert-butoxycarbonyl carbamate.

- 63 044376

To a solution of 3-bromo-5-nitroaniline (5.50 g, 25.3 mmol, 1.00 eq.) in pyridine (50 ml) was added Boc ₂ O (27.66 g, 126.7 mmol, 5.00 eq.). The mixture was stirred at 25°C for 12 hours, then diluted with water (30 ml) and EtOAc (60 mlx3). The combined organic extracts were washed with brine (20 mlx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3% EtOAc in petroleum ether) to give tert-butyl K-(3-bromo-5-nitro-phenyl)-K tert-butoxycarbonyl carbamate (8.00 g, 19.2 mmol , yield 76.0%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (t, J=1.8 Hz, 1H), 8.20 (t, J=1.8 Hz, 1H), 8.12 (t, J=1.6 Hz, 1H), 1, 40 (s, 18H).

tert-Butyl (3-cyano-5-nitrophenyl) carbamate.

To a mixture of tert-butyl K-(3-bromo-5-nitro-phenyl)-K-tert-butoxycarbonyl carbamate (4.30 g, 10.31 mmol, 1.00 eq.) in DMF (5 ml) was added zinc cyanide (2.42 g, 20.61 mmol, 2.00 eq.), tetrakis[triphenylphosphine]palladium(0) (2.38 g, 2.06 mmol, 0.20 eq.), and the mixture was stirred at 100°C for 10 hours in a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and the product was extracted with EtOAc (30 mlx3). The combined organic extracts were washed with brine (15 mlx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (4% EtOAc in petroleum ether) to give tert-butyl (3-cyano5-nitrophenyl) carbamate (1.10 g, 4.09 mmol, 30.0% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 1.50 (s, 9H).

tert-Butyl (3-amino-5-cyanophenyl)carbamate.

Iron nitrate ( 1.40 g, 25.1 mmol, 6.00 eq.) and ammonium chloride (2.24 g, 41.8 mmol, 10.00 eq.) at 25°C. The mixture was heated to 80°C, stirred for 10 hours under a nitrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (3-amino5-cyanophenyl)carbamate (0.95 g, 4.07 mmol, 97.0% yield) as a black-brown oil. MS (ESI) m/z 178.1 [M-55] ⁺ .

3,5-Diaminobeshonitrile.

To a solution of tert-butyl (3-amino-5-cyanophenyl)carbamate (0.200 g, 0.857 mmol, 1.00 eq.) in EtOAc (2 ml) was added a 4.0 M solution of HCl in 1,4-dioxane (2, 14 ml, 10.00 eq.). The mixture was stirred at 25°C for 1 hour, then poured into saturated aqueous sodium bicarbonate (50 ml) and the mixture was extracted with EtOAc (50 ml x 3). The combined organic extracts were washed with brine (50 mlx3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3,5-diaminobenzonitrile (0.100 g, 0.751 mmol, 88.0% yield) as a white solid. MS (ESI) m/z 134.2 [M+1] ⁺ .

3-Amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile.

To a solution of 3,5-diaminobenzonitrile (0.100 g, 0.75 mmol, 1.00 eq.) and 3-bromopiperidine-2,6-dione (0.288 g, 1.50 mmol, 2.00 eq.) in DMF ( 1 ml) sodium bicarbonate was added. (0.094 g, 1.13 mmol, 1.50 eq.). The mixture was stirred at 50°C for 12 hours. The mixture was poured into ice water (20 ml) and the aqueous phase was extracted with EtOAc (20 ml x 3). The combined organic extracts were washed with brine (20 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by preparative TLC (50% EtOAc in petroleum ether) to give 3-amino-5-((2,6dioxopiperidin-3-yl)amino)benzonitrile (0.050 g, 0.204 mmol, 27.0% yield) as a white solid substances. MS (ESI) m/z 245.2 [M+1] ⁺ .

2-(Difluoromethyl-fluoranyl)-4-isothiocyanato-benzonitrile.

To a solution of thiocarbonyl dichloride (44.2 g, 385 mmol, 29.5 mL) in water (500 mL) was added 4-amino2-(difluoromethylfluoranyl)benzonitrile (48.0 g, 256 mmol) at 15°C. After addition, the reaction mixture was stirred at 28°C for 12 hours. The resulting material was then extracted with DCM (3x300 ml). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (0-5% EtOAc in petroleum ether) to give 2-(difluoromethylfluoranyl)-4isothiocyanatobenzonitrile (52.0 g, 88.4% yield) as a brown solid.

1H NMR (400 MHz, CDCl·,) δ ppm 7.87 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.51-7.48 (m, 1H).

2-(3-Fluoro-4-hydroxyanilino)-2-methylpropanenitrile.

To a solution of 4-amino-2-fluorophenol (25.0 g, 197 mmol) in DCM (250 ml) and acetone (125 ml) was added trimethylsilylformonitrile (27.3 g, 275 mmol, 34.57 ml) and trifluoromethanesulfonate (2 .19 g, 9.83 mmol, 1.78 ml) at 0-5°C. After addition, the reaction mixture was stirred at 20°C for 16 hours, then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% EtOAc in petroleum ether) to give 2-(3-fluoro-4-hydroxy-anilino) -2methylpropanenitrile (20.0 g, 53.4% yield) as a white solid.

1H NMR (400 MHz, CDC13) δ ppm 6.93 (t, J=8.8 Hz, 1H), 6.82 (dd, J=2.8 Hz, 12.0 Hz, 1H), 6.78-6.71 (m, 1H), 4.99 (s, 1H), 3.41 (s, 1H), 1.62 (s, 6H).

4-[3-(3-Fluoro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-64 044376 (trifluoromethyl)benzonitrile.

A solution of 2-(3-fluoro-4-hydroxy-anilino)-2-methylpropanenitrile (20.0 g, 103 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (31 g, 134 mmol) in DMA (300 ml ) was stirred for 3 h at 18°C, then diluted with MeOH (200 ml) and aqueous HCl (2 M, 200 ml) and heated to 70°C. After 2 hours, the reaction mixture was cooled to room temperature 18°C, mixed with water (150 ml) and extracted with EtOAc (200 mlx3). The organic phases were washed with brine (100 mlx2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (11-16% EtOAc in petroleum ether) to give 4-[3-(3-fluoro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo -2-thioxo-imidazolidin-1-yl]-2(trifluoromethyl)benzonitrile (19 g, 43.6% yield) as a light yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.00-7.96 (m, 2H), 7.85-7.82 (m, 1H), 7.16 (t, J=8.8 Hz, 1H), 7.09-7.06 ( m, 1H), 7.02-7.00 (m, 1H), 5.84 (s, 1H), 1.60 (s, 6H).

tert-Butyl 4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl]-2-fluorophenoxy]ethyl] piperazine-1-carboxylate.

To a solution of 4-[3-(3-fluoro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2(trifluoromethyl)benzonitrile (11.4 g, 26 .9 mmol) and cesium carbonate (13.1 g, 40.3 mmol) in DMF (330 ml) was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (10 g, 40.3 mmol) at 18°C. The reaction mixture was stirred at 60°C for 10 hours, then diluted with water (500 ml) and extracted with EtOAc (300 mlx3). The combined organic phases were washed with brine (300 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product (20 g) was purified by preparative HPLC to give tert-butyl 4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5dimethyl-4-oxo-2- thioxo-imidazolidin-1-yl]-2-fluorophenoxy]ethyl]piperazine-1-carboxylate (12.4 g, 72.6% yield) as a light yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 7.99-7.96 (m, 2H), 7.85-7.82 (m, 1H), 7.10-7.05 (m, 3H), 4.24 (t, J=5.6 Hz, 2H), 3.46 (t, J=4.4 Hz, 4H), 2.89 (t, J=5.2 Hz, 2H), 2.56 (t, J=4.8 Hz, 4H), 1.59 (s, 6H), 1.47 (s, 9H).

4-[3-[3-Fluoro-4-(2-piperazin-1-ylethoxy)phenyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1 -yl]2-(trifluoromethyl)benzonitrile.

To a solution of tert-butyl-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl]-2-fluorophenoxy ]ethyl]piperazine-1-carboxylate (16.4 g, 25.8 mmol) in DCM (100 ml) was added TFA (26.5 mg, 232 mmol, 17.2 ml) at 0°C. The reaction mixture was stirred at 20°C for 10 hours and then concentrated in vacuo. The resulting oil was dissolved in acetonitrile (20 ml), the pH was adjusted to pH 8~9 with saturated aqueous sodium bicarbonate, and the resulting solution was concentrated in vacuo. The aqueous phase was extracted with DCM (100 mlx2). The combined organic phases were washed with water (100 mlx2), dried over sodium sulfate, filtered and concentrated to a light yellow oil. The residue was lyophilized to give 4-[3-[3fluoro-4-(2-piperazin-1-ylethoxy)phenyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1 -yl]-2(trifluoromethyl)benzonitrile (12.1 g, 87.5% yield) as a light yellow solid.

1H NMR (400 MHz, CDCl·,) δ ppm 7.99-7.96 (m, 2H), 7.84-7.82 (m, 1H), 7.10-7.04 (m, 3H), 4.24 (t, J=5.6 Hz, 2H), 2.94-2.86 (m, 6H), 2.59 (s, 4H), 1.59 (s, 6H).

Methyl 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2-fluorophenoxy)ethyl )piperazin-1-yl)acetate. 4-(3-(-3-Fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl) Benzonitrile (0.250 g, 0.467 mmol) was combined with methyl 2-bromoacetate (0.047 ml, 0.47 mmol) in THF (4 ml). The solution was stirred at ambient temperature in a screw cap vial for 30 minutes. The reaction mixture was diluted with DCM and the organic layers were washed with water and brine. Organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography (0-100% EtOAc in hexanes, then 5% MeOH in EtOAc (500 mL)) to give the title compound (0.230 g, 0.379 mmol, 81.0% yield). MS (ESI) m/z 608 [M+1]+.

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2fluorophenoxy)ethyl) piperazin-1-yl)acetic acid.

A solution of methyl 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-fluorophenoxy) ethyl)piperazin-1-yl)acetate (0.230 g, 0.379 mmol) in THF (2 ml) was treated with a solution of lithium hydroxide hydrate (0.159 g, 3.79 mmol) in water (2.00 ml). After 30 min, the pH was adjusted to 5 with 2.0 M aqueous HCl, and the mixture was diluted with DCM (100 ml) and water (30 ml). The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (0.183 g, 0.308 mmol, 81% yield). MS (ESI) m/z 594 [M+1] ⁺ .

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2fluorophenoxy)ethyl) piperazin-1-yl)-K-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

- 65 044376 hydrochloride.

To a solution of 3-amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile (0.040 g, 0.16 mmol, 1.0 eq.) and 2-(4-(2-(4- (3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)2-fluorophenoxy)ethyl)piperazin-1-yl)acetic acid (0.097 g, 0.16 mmol, 1.0 eq.) in DMF (1 ml) was added HATU (0.093 g, 0.24 mmol, 1.5 eq.) and DIPEA (0.064 g, 0.49 mmol, 3.0 eq.), and the mixture was stirred at 25°C for 1 hour under a nitrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to give 2-(4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.050 g, 0.060 mmol, yield 37.0%). MS (ESI) m/z 820.2 [M+1]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.82 (s, 1H), 10.51 (br. s, 1H), 8.40 (d, J=8.2 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H ), 8.07 (d, J=8.2 Hz, 1H), 7.45-7.35 (m, 2H), 7.29-7.20 (m, 3H), 6.82 (s, 1H), 4.57 (ush s, 2H), 4.40 (ush dd, J=4.8, 11.8 Hz, 1H), 4.19-3.76 (m, 7H), 3.60 (br.s, 5H), 3.40 (br.s, 2H), 2.81-2.69 (m, 1H), 2.64-2.54 (m, 1H), 2.14-2 .03 (m, 1H), 2.00-1.86 (m, 1H), 1.52 (s, 6H).

Example 5: N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-((5-(3-(4-cyano-3 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-3-ethylpyridin-2yl)oxy)ethyl)piperazin-1-yl)acetamide hydrochloride

6-Chloro-5-vinylpyridin-3-amine.

Mixture of 5-bromo-6-chloropyridin-3-amine (0.750 g, 3.62 mmol, 1 eq.), tributylstannylethylene (1.52 mL, 5.19 mmol, 1.43 eq.), tetrakis(triphenylphosphine) palladium (0) (0.209 g, 0.181 mmol, 5 mol%) and lithium chloride (0.476 g, 11.2 mmol, 3.10 eq.) in dioxane (19.0 ml, 0.190 mol) were refluxed for 24 h, then cooled to room temperature, diluted with water and extracted with DCM. The organic layer was concentrated under reduced pressure and the resulting residue was purified by column chromatography (0-15% MeOH in DCM) to give 6-chloro-5-vinylpyridin-3amine (0.804 g, 3.20 mmol, 89.0% yield) in as a yellow solid. MS (ESI) m/z 155.0 [M+1] ⁺ .

6-Chloro-5-ethylpyridin-3-amine hydrochloride.

A solution of 6-chloro-5-vinylpyridin-3-amine (0.194 g, 1.25 mmol, 1 eq.) in EtOH (12.5 ml, 0.1 mol) was purged with nitrogen gas and treated with 10% Pd/C (0.099 g 0.094 mmol, 7.5 mol.%). The suspension was purged with hydrogen gas and stirred for 30 minutes at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to give a pale yellow oil, which was suspended in DCM (5.17 ml, 0.226 mol), treated with a solution of HCl in dioxane (4.38 ml, 17.53 mmol, 15 eq.) and left stir at room temperature for 6 hours. The reaction mixture was concentrated to give 6-chloro-5-ethylpyridin-3-amine hydrochloride (0.226 g, 1.171 mmol, 93.7% yield) as a pale yellow solid. MS (ESI) m/z 157.0 [M+1] ⁺ .

2-((6-Chloro-5-ethylpyridin-3-yl)amino)-2-methylpropanenitrile.

Acetone cyanohydrin (0.307 ml, 3.36 mmol, 2.87 eq.) and magnesium sulfate (0.324 g, 2.69 mmol, 2.3 eq.) were added to 6-chloro-5-ethylpyridin-3-amine hydrochloride (0.226 g, 1.17 mmol, 1 eq.), TEA (0.280 ml, 1.17 mmol, 1 eq.), and the mixture was stirred at 80°C for 18 hours. The reaction mixture was quenched with saturated aqueous sodium chloride and the aqueous phase washed with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate, dried with sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-80% EtOAc in hexanes) to give 2-((6-chloro-5-ethylpyridin-3-yl)amino)-2-methylpropanenitrile (0.232 g, 1.04 mmol, yield 30.9%) as a yellow residue. MS (IER) m/z 224.2 [M+1] ⁺ .

4-(3-(6-Chloro-5-ethylpyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

To a solution of 2-((6-chloro-5-ethylpyridin-3-yl)amino)-2-methylpropanenitrile (0.232 g, 1.04 mmol, 1 eq.) in DMA (2.19 ml) was added 2-(trifluoromethyl)benzonitrile (0.284 g, 1.24 mmol, 1.19 eq.) at 25°C, and the reaction mixture was stirred at room temperature for 18 hours, then at 70°C for 4 hours. MeOH (2.188 mL, 0.474 mol) and 3 M aqueous HCl (1.46 mL, 4.38 mmol, 4.22 eq.) were added to the reaction solution, and heating was resumed to 70°C. After 18 hours, the reaction was quenched with water and diluted with EtOAc, and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-10% MeOH in DCM). The appropriate fractions were combined and concentrated to give 4-(3-(6-chloro-5-ethylpyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-66 044376 ( trifluoromethyl)benzonitrile (0.117 g, 0.258 mmol, 24.91% yield) as an orange solid.

MS (ESI) m/z 453.2 [M+1]+.

tert-Butyl 4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)-3-ethylpyridin-2 -yl)oxy)ethyl)piperazine-1-carboxylate.

tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.028 g, 0.12 mmol, 1 eq.) and 4-(3-(6-chloro5-ethylpyridin-3-yl)-4,4- Dimethyl 5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.056 g, 0.12 mmol, 1 eq.) was dissolved in THF (2.86 ml, 0.043 mol). A 1.0 M solution of potassium tert-butoxide in THF (0.618 mL, 0.62 mmol, 5 eq.) was added and the reaction mixture was heated to 60° C. for 36 h, resulting in partial deprotection of the product. The reaction mixture was cooled to 25°C and Boc ₂ O (0.034 ml, 0.15 mmol, 1.2 eq.) was added. After 4 h, the reaction was quenched with water, diluted with DCM, and the aqueous phase was extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated, and the crude material was purified by silica gel column chromatography (0-4% MeOH in DCM). The appropriate fractions were combined and concentrated to give tert-butyl 4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl )-3-ethylpyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate (0.033 g, 0.051 mmol, 41.3% yield) as a pale yellow solid. MS (ESI) m/z 647.2 [M+1] ⁺ .

4-(3-(5-Ethyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile hydrochloride.

Suspension of tert-butyl-4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-3-ethylpyridine -2-yl)oxy)ethyl)piperazine-1-carboxylate (0.033 g, 0.051 mmol, 1 eq.) in DCM (0.226 ml, 0.226 mol) was treated with a solution of HCl in dioxane (0.191 ml, 0.765 mmol, 15 eq.) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-(3-(5-ethyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3yl)-4,4 -dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.030 g, 0.051 mmol, 101% yield) as a beige solid. MS (ESI) m/z 547.2 [M+1] ⁺ .

tert-Butyl 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-3- ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetate.

tert-Butyl-2-bromoacetate (9.97 µl, 0.062 mmol, 1.2 eq.) was added to the stirred mixture of 4-(3(5-ethyl-6-(2-(piperazin-1-yl)ethoxy)pyridine -3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile hydrochloride (0.030 g, 0.051 mmol, 1 eq.), THF (0.440 ml, 0.117 mol ) and TEA (0.029 ml, 0.206 mmol, 4 eq.). The reaction mixture was stirred for 18 hours at 60°C. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography (0-4% MeOH in DCM) to give tert-butyl 2-(4-(2-((5-(3-(4-cyano-3(trifluoromethyl) )phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-3-ethylpyridin-2yl)oxy)ethyl)piperazin-1-yl)acetate (0.0142 g, 0.021 mmol, yield 41.8%) as a pale yellow solid. MS (ESI) m/z 661.4 [M+1] ⁺ .

2-(4-(2-((5-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)3-ethylpyridin- 2-yl)oxy)ethyl)piperazin-1-yl)acetic acid hydrochloride.

Suspension of tert-butyl 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-3 -ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetate (0.014 g, 0.021 mmol, 1 eq.) in DCM (0.500 ml) was treated with a solution of hydrochloric acid in dioxane (0.081 ml, 0.322 mmol, 15 eq. .) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5, 5-dimethyl-4oxo-2-thioxoimidazolidin-1 -yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1 -yl)acetic acid hydrochloride (0.014 g, 0.022 mmol, 102% yield) as beige solid matter. MS (ESI) m/z 605.2 [M+1] ⁺ .

K-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-((5-(3-(4-cyano-3(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-3-ethylpyridin-2yl)oxy)ethyl)piperazin-1-yl)acetamide hydrochloride.

2-(4-(2-((5-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)3-ethylpyridin- 2-yl)oxy)ethyl)piperazin-1-yl)acetic acid hydrochloride (14 mg, 0.023 mmol, 1 eq.) was combined with 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6- dione trifluoroacetate salt (8.51 mg, 0.023 mmol, 1 eq.), HATU (9.68 mg, 0.025 mmol, 1.1 eq.), DIPEA (0.016 ml, 0.093 mmol, 4 eq.) and DMF (0.116 ml) , and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water, diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic extracts were concentrated and the residue was purified by standard methods to give K-(3-chloro-5-((2,6dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-((5-(3 -(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1 -yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1 -yl)acetamide hydrochloride (5 mg, 5.47 µmol, yield 23.6%). MS (iEr) m/z 840.2 [M+1] ⁺ .

1H NMR (500 MHz, acetonitrile-d ₃ ) δ ppm 9.12 (br s, 1H), 8.7-8.8 (m, 1H), 8.1-8.2 (m, 3H), 7.9-8.0 (m, 2H), 7 .50 (d, 1H, J=2.5 Hz), 7.03 (s, 1H), 6.95 (s, 1H), 6.49 (s, 1H), 5.04 (ind, 1H , J=6.6 Hz), 4.54 (t, 2H, J=5.5 Hz), 4.24 (ddd, 1H, J=5.2, 6.7, 12.1 Hz), 3 .06 (s, 2H), 2.86 (ush t, 2H, J=5.7 Hz), 2.77 (ddd, 2H, J=5.4,

- 67 044376

12.6, 17.3 Hz), 2.7-2.7 (m, 4H), 2.67 (k, 4H, J=7.3 Hz), 2.60 (ush s, 4H), 1 .57 (s, 6H), 1.25 (t, 3H, J=7.6 Hz).

Example 6: 2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thiokeoimidazolidin-1-yl) -2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)-N-(5-((2,6dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)acetamide

2-(1,1-Difluoroethyl)-4-nitrophenol.

A solution of 1-(2-hydroxy-5-nitrophenyl)ethanone (1.27 g, 7.00 mmol) in DCM (18 ml) was cooled to 0°C and bis(2-methoxyethyl) amino sulfur trifluoride (Deoxo-Fluor®, 2.58 ml, 14.0 mmol) was added dropwise over 2 min. The mixture was stirred for 2.5 hours, during which the temperature was gradually increased to 20°C. The mixture was poured into ice water (30 ml) and stirred for 5 minutes. The organic layer was removed, the aqueous layer was extracted with DCM, and the combined organic extracts were dried over sodium sulfate and activated carbon. The solution was filtered, concentrated and the solid purified by silica gel column chromatography (10-40% EtOAc in hexanes) to give the title compound as a light beige solid (1.23 g, 86.0% yield).

1H NMR (400 MHz, CDC13) δ ppm 8.33 (d, J=2.57 Hz, 1H), 8.24 (dd, J=8.99, 2.63 Hz, 1H), 7.06 (d, J=9.05 Hz, 1H ), 6.51-6.92 (br.s, 1H), 2.08 (t, J=18.9 Hz, 3H).

tert-Butyl-4-(2-(2-(1,1-difluoroethyl)-4-nitrophenoxy)ethyl)piperazine-1-carboxylate.

To a solution of 2-(1,1-difluoroethyl)-4-nitrophenol (1.20 g, 5.91 mmol) and tert-butyl 4-(2bromoethyl)piperazine-1-carboxylate (2.08 g, 7.09 mmol) in dry DMF (12 ml), cesium carbonate (3.85 g, 11.81 mmol) was added and the mixture was stirred under nitrogen at 65°C for 4 hours. The mixture was cooled to ambient temperature, poured into ice water (60 ml) and stirred. The mixture was extracted with EtOAc and the combined extracts were washed with water, brine and dried over magnesium sulfate with activated carbon. The solution was filtered through a silica gel plug, eluted with EtOAc, concentrated and the residue dried in vacuo to give tert-butyl 4-(2-(2-(1,1-difluoroethyl)-4nitrophenoxy)ethyl)piperazine-1-carboxylate as light brown solid (2.33 g, 95% yield). MS (ESI) m/z 416.2 [M+1]+.

1H NMR (400 MHz, CDCI3) δ ppm 8.44 (d, J=2.81 Hz, 1H), 8.30 (dd, J=9.11, 2.75 Hz, 1H), 7.03 (d, J=9.17 Hz, 1H ), 4.26 (t, J=5.56 Hz, 2H), 3.40-3.47 (m, 4H), 2.88 (t, J=5.56 Hz, 2H), 2.49 -2.58 (m, 4H), 2.00 (t, J=18.8 Hz, 3H), 1.46 (s, 9H).

tert-Butyl-4-(2-(4-amino-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate.

To a solution of tert-butyl 4-(2-(2-(1,1-difluoroethyl)-4-nitrophenoxy)ethyl)piperazine-1-carboxylate (2.30 g, 5.54 mmol) in MeOH (20 ml) 10% Pd/C with 50 wt% water (1.18 g, 0.554 mmol) was added and the mixture was purged with H ₂ gas. The reaction mixture was stirred under H ₂ atmosphere (balloon) for 3 hours at ambient temperature. The mixture was purged with nitrogen gas, filtered through compacted celite and concentrated. The residual syrup was dissolved in diethyl ether, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (25-100% EtOAc in hexanes) to give tert-butyl 4-(2-(4-amino-2-(1,1difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate as a clear golden syrup (1.85 g, yield 87.0%). MS (ESI) m/z 386.2 [M+1] ⁺ .

1H NMR (400 MHz, CDC13) δ ppm 6.87 (d, J=2.81 Hz, 1H), 6.78 (d, J=8.68 Hz, 1H), 6.68 (d, J=8.61 Hz, 1H), 4, 05 (t, J=5.69 Hz, 2H), 3.51 (lat. s, 2H), 3.38-3.46 (m, 4H), 2.78 (t, J=5.69 Hz , 2H), 2.44-2.58 (m, 4H), 1.99 (t, J=18.8 Hz, 3H), 1.46 (s, 9H).

tert-Butyl-4-(2-(4-((2-cyanopropan-2-yl)amino)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1carboxylate.

A solution of tert-butyl 4-(2-(4-amino-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (1.59 g, 4.13 mmol) in acetone (15 ml) cooled to 0°C and trimethylsilyl cyanide (0.774 mL, 6.19 mmol) was added followed by trimethylsilyl trifluoromethylsulfonate (0.037 mL, 0.21 mmol). The mixture was stirred for 7 hours, during which time the reaction mixture reached ambient temperature after approximately 2 hours. The mixture was concentrated and the residue was partitioned into saturated aqueous sodium bicarbonate and EtOAc and stirred. The organic layer was removed and the aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over magnesium sulfate-charcoal and filtered through a silica gel plug, eluting with EtOAc. The solution was concentrated and the residue was dried in vacuo to give tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)-2-(1,1difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate as a pale pink solid (1.77 g, 95.0% yield). MS (ESI) m/z 453.4 [M+1] ⁺ .

1H NMR (400 MHz, CDCI3) δ ppm 7.02-7.19 (m, 2H), 6.89 (d, J=8.68 Hz, 1H), 4.11 (t, J=5.56 Hz, 2H),

- 68 044376

3.35-3.52 (m, 4H), 2.82 (t, J=5.62 Hz, 2H), 2.44-2.60 (m, 4H), 2.01 (t, J= 18.8 Hz, 3H), 1.64 (s, 6H), 1.46 (s,

9H).

4-(3-(3-(1,1-Difluoroethyl)-4-(2-(piperazin-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile.

To a solution of tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)-2-(1,1difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.200 g, 0.442 mmol) in DMF (1.0 ml), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.121 g, 0.530 mmol) was added and the mixture was stirred at 60°C for 3 hours. Additionally, 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.020 g) was added ), and the mixture was heated at 60°C for 30 minutes. The reaction mixture was cooled to ambient temperature and diluted with MeOH (3 ml). 2.0 M aqueous HCl solution (1.11 ml, 2.21 mmol) was added and the mixture was stirred at 60°C for 23 hours. The mixture was concentrated, the remaining syrup was dissolved in 5.0 M aqueous HCl in isopropyl alcohol (3 ml) and stirred for 90 min at ambient temperature. The mixture was concentrated, the residue was partitioned into EtOAc and water and cooled to 0°C. The mixture was treated with 1.0 M aqueous sodium hydroxide to pH 9-10, the organic layer was removed, and the aqueous layer was extracted with EtOAc. The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (20-100% EtOAc in hexanes, then 5-50% MeOH in DCM) to give 4-(3-(3-(1,1-difluoroethyl)-4-(2(piperazine- 1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile as a white solid (0.112 g, 44.0% yield). MS (ESI) m/z 582.2 [M+1]+.

tert-Butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate.

To a solution of 5-(3-(3-(1,1-difluoroethyl)-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl )-3-(trifluoromethyl)picolinonitrile (0.140 g, 0.240 mmol) and DIPEA (0.092 mL, 0.529 mmol) in dry THF (2 mL), tert-butyl 2-bromoacetate (0.039 mL, 0.264 mmol) was added and the mixture was stirred at ambient temperature for 6 hours. The mixture was diluted with EtOAc (4 ml), added to water (10 ml) and stirred. The organic layer was removed and the aqueous layer was extracted with EtOAc. The organic fractions were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% 10% ammonium hydroxide in MeOH in DCM) to give tert-butyl 2-(4-(2-(4-(3-(6-cyano-5(trifluoromethyl) pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate in the form of a colorless foam (0.085 g, yield 51.0%). MS (ESI) m/z 697.2 [M+1] ⁺ .

2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1 -yl)-2- (1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid trifluoroacetate.

To a solution of tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo2-thioxoimidazolidin-1 - yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate (0.083 g, 0.12 mmol) in DCM (1 ml), TFA (2 ml) was added and the mixture was stirred at environment for 3 hours. The reaction mixture was concentrated and the residue in the flask was sonicated in diethyl ether to obtain a granular solid. The solid was collected, washed with diethyl ether and dried under vacuum to give 2-(4-(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4 -oxo-2-thioxoimidazolidin-1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid trifluoroacetate as a white solid (0.083 g, 92.0% yield). MS (ESI) m/z 641.2 [M+1] ⁺ .

bis-tert-Butyl (N-3-nitro-5,6-difluorophenyl)iminodicarbonate.

2,3-Difluoro-5-nitroaniline (1.0 g, 5.74 mmol) was placed in a vial with Boc ₂ O (3.33 ml, 14.36 mmol), (±)-2,2'-bis( diphenylphosphino)-1,1'-binaphthalene (0.351 g, 2.87 mmol), TEA (1.60 ml, 11.49 mmol) and THF (50.0 ml). The reaction mixture was stirred at 25°C for 18 hours. Volatile organic compounds were removed under reduced pressure to obtain a dark orange oil. The oil was dissolved in EtOAc and purified by silica gel column chromatography (0-100% EtOAc in hexanes). Fractions containing the desired product were combined and VOCs were removed under reduced pressure to give bis-tert-butyl (N-3-nitro-5,6-difluorophenyl)iminodicarbonate (1.29 g, 3.45 mmol, 60% yield). 0%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (ddd, J=2.81, 6.72, 9.78 Hz, 1H), 8.42 (td, J=2.34, 5.84 Hz, 1H), 1.34-1.46 (m, 18H); MS (ESI) m/z 397.0 [M+Na]+.

bis-tert-Butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)iminodicarbonate.

bis-tert-Butyl (N-3-nitro-5,6-difluorophenyl)iminodicarbonate (0.200 g, 0.534 mmol), 3-bromopiperidine-2,6-dione (0.513 g, 2.67 mmol), zinc (0.175 g, 2 .67 mmol) and iron(II) chloride tetrahydrate (0.032 g, 0.16 mmol) were combined in NMP (1.5 ml). After degassing with argon for several minutes and treatment with trimethylsilyl chloride (0.171 ml, 1.34 mmol), the reaction mixture was sealed overnight at 90°C, then diluted with EtOAc (100 ml) and water (15 ml). Two-phase

- 69 044376 the mixture was filtered through celite. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (50 ml) followed by brine (2x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to a dark green oil. The oil was dissolved in EtOAc and purified by silica gel column chromatography (0-80% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated under reduced pressure to give bis-tert-butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)iminodicarbonate (0.075 g, 0.16 mmol , yield 30.8%) as a yellow oil. MS (ESI) m/z 300.0 [M -(Boc+m-butyl)] ⁺ .

3-((3-amino-4,5-difluorophenyl)amino)piperidine-2,6-dione dihydrochloride.

bis-tert-Butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)iminodicarbonate (0.075 g, 0.165 mmol) in solution in DCM (1.0 ml) was treated with 4. 0 M HCl in dioxane (1.0 ml, 4.00 mmol). The reaction mixture was stirred at 25°C for 18 hours. Volatile organic compounds were removed under reduced pressure to give 3-((3-amino-4,5-difluorophenyl)amino)piperidine-2,6dione hydrochloride (0.074 g, 0.23 mmol, yield 137%) as a light orange solid. MS (ESI) m/z 256.0 [M+1] ⁺ .

2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- (1,1-difluoroethyl)phenoxy)ethyl)ninerazin-1-yl)-N-(5-((2,6-dioxopineridin-3-yl)αmino)-2,3difluorophenyl)acetamide.

To a solution of 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid trifluoroacetate (0.113 g, 0.150 mmol) and 3-((3-amino-4,5-difluorophenyl)amino)piperidine-2, 6-Dione dihydrochloride (0.054 g, 0.165 mmol) in dry DMF (1.0 mL), HATU (0.068 g, 0.180 mmol) and DIPEA (0.131 mL, 0.749 mmol) were added successively and the mixture was stirred at ambient temperature for 16 additional 3-((3-amino-4,5-difluorophenyl)amino)piperidine-2,6dione dihydrochloride (0.025 g), HATU (0.035 g) and DIPEA (0.070 ml) were used and the mixture was stirred for an additional 3 h. The reaction mixture was slowly poured into ice water (10 ml) with stirring and the resulting suspension was filtered. The collected solid was washed with water and diethyl ether and dissolved in 25% formic acid in DMSO (2 ml). The solution was filtered (45 μm nylon membrane) and purified by standard methods to give 2-(4-(2-(4-(3-(6-cyano5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4 -oxo-2-thioxoimidazolidin-1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)piperazin-1-yl)-N(5-((2,6-dioxopiperidin-3-yl)amino)-2 ,3difluorophenyl)acetamide (0.010 g, 8.0% yield). MS (ESI) m/z 878.0 [M+1] ⁺ ;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.82 (US s, 1H), 9.81 (US s, 1H), 9.26 (US s, 1H), 8.83 (US s, 1H), 7.17-7.65 (m, 4H), 6.98 (br s, 1H), 6.22 (br s, 1H), 4.48 (br s, 2H), 4.28 (br s, 1H), 3.08-3.16 (m, 4H), 2.67-2.77 (m, 4H), 2.02-2.16 (m, 5H), 1.90 (USS, 3H), 1.55 (USS, 9H) .

Example 7: 2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-N(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

1-(Benzyloxy)-2-bromo-4-nitrobenzene.

To a mixture of 2-bromo-4-nitrophenol (30.00 g, 137.61 mmol, 1 eq.) and potassium carbonate (57.06 g, 412.8 mmol, 3 eq.) in acetonitrile (300 ml) was added ( bromomethyl)benzene (25.89 g, 151.4 mmol, 17.98 mL, 1.1 eq.) under nitrogen. The reaction mixture was stirred at 80°C for 2 hours, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (520% EtOAc in petroleum ether) to give the product, 1-(benzyloxy)-2-bromo-4-nitrobenzene (35.80 g, 116.2 mmol, 84.4% yield) as yellow solid. MS (ESI) m/z 332.0 [M+Na] ⁺ .

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 8.44 (d, J=2.7 Hz, 1H), 8.27 (dd, J=2.8, 9.2 Hz, 1H), 7.52-7.46 (m, 2H), 7 .45-7.40 (m, 3H), 7.38-7.34 (m, 1H), 5.37 (s, 2H).

1-(Benzyloxy)-4-nitro-2-vinylbenzene.

To a mixture of 1-(benzyloxy)-2-bromo-4-nitrobenzene (20.00 g, 64.91 mmol, 1 eq.), 4,4,5,5-tetramethyl-2vinyl-1,3,2-dioxaborolane (19.99 g, 129.82 mmol, 22.02 mL, 2.0 eq.) and potassium phosphate (41.33 g, 194.72 mmol, 3 eq.) in dioxane (300 mL) and water (150 ml) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.75 g, 6.49 mmol, 0.1 eq.) was added at room temperature (25°C). The reaction mixture was degassed and then heated to 100°C for 12 hours under a nitrogen atmosphere, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-1% EtOAc in petroleum ether) to give the product: 1-(benzyloxy)-4-nitro-2-vinylbenzene (12.50 g, 48.97 mmol, 75.4% yield) . as a yellow solid. MS (ESI): m/z 278.1 [M+Na] ⁺ .

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4-Amino-2-ethylphenol.

To a solution of 1-(benzyloxy)-4-nitro-2-vinylbenzene (12.50 g, 48.97 mmol, 1 eq.) in MeOH (50 ml) and

THF (50 ml) was added to Pd/C (2.00 g, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen. The reaction mixture was stirred under hydrogen atmosphere (50 psi) at 50°C for 12 hours, filtered, and the filtrate was concentrated in vacuo.

The residue was purified by silica gel column chromatography (0-2% EtOAc in petroleum ether) to give the product, 4-amino-2-ethylphenol (6.40 g, 46.65 mmol, 95.3% yield) as a brown solid. MS (ESI) m/z 170.2 [M+Na]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.13 (s, 1H), 6.46 (d, J=8.3 Hz, 1H), 6.34 (d, J=2.6 Hz, 1H), 6.23 (dd, J=2 ,8, 8.3 Hz, 1H), 4.28 (s, 1H), 2.41 (k, J=7.5 Hz, 2H), 1.07 (t, J=7.5 Hz, 3H ).

5-Isothiocyanato-3-(trifluoromethyl)picolinonitrile.

To a solution of 5-amino-3-(trifluoromethyl)picolinonitrile (20.00 g, 106.88 mmol, 1 eq.) in toluene (200 ml) was added thiocarbonyl dichloride (24.58 g, 213.76 mmol, 16.39 ml , 2 eq.). The reaction mixture was stirred at 110°C for 12 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% EtOAc in petroleum ether) to give the product, 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (18.90 g, 82.47 mmol, 77.2% yield), which was obtained in the form of a yellow liquid. MS (ESI) m/z 230.1 [M+1] ⁺ .

2-((3-Ethyl-4-hydroxyphenyl)amino)-2-methylpropanenitrile.

To a solution of 2-hydroxy-2-methylpropanenitrile (18.64 g, 219.00 mmol, 20 mL, 4.69 eq.) in 4-amino-2ethylphenol (6.400 g, 46.65 mmol, 1 eq.) was added magnesium (14.04 g, 116.62 mmol, 2.5 eq.). The reaction mixture was stirred at 60°C for 12 hours, then poured into EtOAc-water (v/v=1/1, 100 ml) and stirred for 15 minutes. The organic phase was separated and the aqueous phase was extracted with EtOAc (100 mlx2). The combined organic extracts were washed with brine (200 mlx5), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. 2-((3-Ethyl-4hydroxyphenyl)amino)-2-methylpropanenitrile (12.00 g, crude) was obtained as a brown solid. MS (ESI) m/z 205.1 [M+1] ⁺ .

5-(3-(-3-Ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

A solution of 2-((3-ethyl-4-hydroxyphenyl)amino)-2-methylpropanenitrile (9.50 g, 46.51 mmol, 1 eq.) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (8.53 g, 37 .21 mmol, 0.8 eq.) in DMF (100 ml) was stirred at 20°C for 1 hour. Then 4.0 M HCl/MeOH solution (100 ml, 2.15 eq.) was added. The resulting mixture was stirred at 70°C for 12 hours, then concentrated in vacuo to remove MeOH. The resulting mixture was diluted with water (200 ml) and extracted with EtOAc (200 mlx2). The combined organic extracts were washed with brine (50 mlx2), dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-30% EtOAc in petroleum ether) to give the product 5-(3-(3-ethyl-4-hydroxyphenyl)-4,4dimethyl-5-oxo-2-thioxoimidazolidin-1-yl) -3-(trifluoromethyl)picolinonitrile (13.30 g, 30.61 mmol, 65.8% yield) as a brown solid. MS (ESI) m/z 457.2 [M+Na] ⁺ .

tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate.

5-(3-(3-Ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile (0.800 g, 1.84 mmol), tert -butyl 4-(2-bromoethyl)-2,2-dimethylpiperazine 1-carboxylate (0.887 g, 2.76 mmol), sodium iodide (0.276 g, 1.84 mmol) and cesium carbonate (0.900 g, 2.76 mmol) combined in DMF (7.366 ml) and heated to 60°C for 1.5 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (150 ml) and water (50 ml). After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The crude material was purified by silica gel column chromatography (0-50% EtOAc in hexanes). The fractions were combined and concentrated under reduced pressure to obtain tert-butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate (1.45 g, 2.15 mmol, 117% yield) as an oil. MS (ESI) m/z 675.4 [M+1] ⁺ .

tert-butyl 4-(2-bromoethyl)-2,2-dimethylpiperazine-1-carboxylate.

tert-Butyl 2,2-dimethylpiperazine-1-carboxylate (3.60 g, 16.8 mmol) and potassium phosphate (10.70 g, 50.4 mmol) were combined in THF (168 ml). To this mixture was added 1,2-dibromoethane (21.7 mL, 252 mmol). The reaction mixture was stirred at 60°C for 48 hours, filtered and concentrated under reduced pressure to an oil, which was dissolved in a minimal amount of DCM and purified by silica gel column chromatography (0-70% EtOAc in hexanes). Fractions containing the product were combined and concentrated to give tert-butyl 4-(2-bromoethyl)-2,2dimethylpiperazine-1-carboxylate (2.93 g, 9.12 mmol, 54.3% yield) as an oil. which was dried overnight under vacuum. MS (ESI) m/z 321.2, 323.2 [M+1, M+3] ⁺ .

5-(3-(4-(2-(3,3-Dimethylpiperazin-1 -yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2

- 71 044376 thioxoimidazolidin-1 -yl)-3-(trifluoromethyl)picolinonitrile hydrochloride.

tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)-2- ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate (1.456 g, 2.158 mmol) was dissolved in DCM (40 ml) and a 4.0 M solution of HCl in dioxane (10.8 ml, 43.2 mmol) was added. The mixture was stirred at ambient temperature for 2 hours, then concentrated to an oil under reduced pressure, which was then triturated in diethyl ether at ambient temperature overnight. The resulting solid was 5-(3-(4-(2-(3,3-dimethylpiperazin-1-yl)ethoxy)3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl) -3-(trifluoromethyl)picolinonitrile hydrochloride (1.24 g, 2.02 mmol, 94.0% yield) was collected by filtration and dried in a vacuum oven for 1.5 h. MS (ESI) m/z 575.2 [ M+1]+.

tert-Butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetate.

5-(3-(4-(2-(3,3-Dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-3-( trifluoromethyl)picolinonitrile hydrochloride (1.24 g, 2.02 mmol) was dissolved in THF (15 ml) and treated with DIPEA (1.77 ml, 10.11 mmol) followed by tert-butyl 2-bromoacetate (0.314 ml, 2 .12 mmol). The reaction mixture was stirred overnight at 50°C. To this mixture was added sodium iodide (0.303 g, 2.02 mmol, 1 eq), DMF (1 ml) and 0.75 equivalent of DIPEA and tert-butyl 2 bromoacetate, and heated again to 50° C. overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridine -3-yl)-5,5-dimethyl-4-oxo2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetate (1.32 g, 1.92 mmol, yield 95.0%) in the form of an oil, which was used without further purification. MS (ESI) m/z 689.3 [M+1] ⁺ .

2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetic acid trihydrochloride.

A solution of tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetate (1.32 g, 1.92 mmol) in DCM (10 ml) was treated with 4.0 M HCl in dioxane (15.6 ml, 62.3 mmol). After 6 hours, the temperature was raised to 45-50°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3 -yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetic acid trihydrochloride as a tan solid (1 .37 g, 1.84 mmol, yield 96.0%). MS (ESI) m/z 633 [M+1] ⁺ .

2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetic acid trihydrochloride (0.125 g, 0.168 mmol, 1 eq.) was combined with 3-((3-aminophenyl)amino)piperidine-2,6-dione trifluoroacetate salt (0.056 g, 0.17 mmol, 1 eq), HATU (0.070 g, 0.18 mmol, 1.1 eq), DIPEA (0.177 mL, 1.01 mmol, 6 eq), and DMF (0.842 ml, 0.2 M), and the reaction was stirred at 25°C for 1 hour. The reaction was quenched with water and the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were concentrated under reduced pressure. The residue was purified by standard methods to give 2-(4(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- 1-yl)-2ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-ul)-N-(3-((2,6-dioxopiperidin-3 yl)amino)phenyl)acetamide hydrochloride (0.063 g, 0.076 mmol, yield 45.1%). MS (ESI) m/z 834.4 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 10.14 (us s, 1H), 9.25 (d, 1H, J=1.7 Hz), 8.82 (d, 1H, J=2.1 Hz) , 7.1-7.2 (m, 3H), 7.04 (t, 1H, J=8.1 Hz), 7.01 (ush s, 1H), 6.83 (ush d, 1H, J =8.3 Hz), 6.45 (dd, 1H, J=1.8, 8.0 Hz), 4.42 (ush s, 2H), 4.27 (ush dd, 1H, J=4, 8, 11.4 Hz), 3.3-3.5 (m, 6H), 3.2-3.3 (m, 4H), 2.6-2.8 (m, 5H), 2.10 (td, 1H, J=4.1, 8.5 Hz), 1.91 (dk, 1H, J=4.8, 12.1 Hz), 1.52 (s, 6H), 1.41 ( ush s, 3H), 1.35 (ush s, 3H), 1.18 (t, 3H, J = 7.5 Hz).

Example 8: N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(7-(2-(4-(3 -(4-cyano-3 ( trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-4,7diazaspiro[2.5]octan-4-yl)acetamide hydrochloride

- 72 044376

2-Bromo-1-(2-bromoethoxy)-4-nitrobenzene.

To a solution of 2-bromo-4-nitrophenol (10 g, 45.9 mmol) in DMF (115 ml) was added cesium carbonate (29.9 g, 92 mmol), followed by 1,2-dibromoethane (39.5 ml, 460 mmol), and the mixture was stirred overnight at 70°C. The reaction mixture was diluted with EtOAc (400 ml), water (75 ml) and brine (75 ml). The layers were separated and the organic layer was washed with brine (3x100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The resulting oil was purified by silica gel column chromatography (0-30% EtOAc in hexanes) to give the title compound (9.20 g, 28.3 mmol, 61.7% yield). MS (ESI) m/z 325.9 [M+1]+.

tert-Butyl 7-(2-(2-bromo-4-nitrophenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

To a solution of 2-bromo-1-(2-bromoethoxy)-4-nitrobenzene (6.20 g, 19.08 mmol) in DMF (47.7 mL) was added DIPEA (6.66 mL, 38.2 mmol) and tert-butyl-4,7-diazaspiro[2,5]octane-4-carboxylate (4.86 g, 22.90 mmol) and the mixture was stirred at 60°C for 5 hours. The reaction mixture was then cooled to ambient temperature medium and diluted with EtOAc (400 ml), water (75 ml) and brine (75 ml). The layers were separated and the organic layer was washed with brine (3x100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification (8.29 g, 18.18 mmol, 95% yield .0%). MS (ESI) m/z 456.2 [M+1] ⁺ .

tert-Butyl 7-(2-(4-nitro-2-vinylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

tert-Butyl 7-(2-(2-bromo-4-nitrophenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (8.71 g, 19.1 mmol), trifluoro(vinyl)borate potassium (7.67 g, 57.3 mmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.12 g, 3.82 mmol) and cesium carbonate (18.66 g, 57. 3 mmol) were combined in a 4:1 mixture of THF (100 ml) and water (25 ml) and heated for 6 h at 70°C under nitrogen atmosphere and then cooled to ambient temperature overnight. The reaction mixture was diluted with EtOAc (500 ml), water (100 ml) and brine (100 ml). The solvent layers were separated and the organic layer was washed with brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil under reduced pressure. The crude material was purified by silica gel column chromatography [0-70% EtOAc (containing 10% 7 N ammonia in MeOH solution) in hexanes] to give the title compound based on theoretical yield. MS (ESI) m/z 404.2 [M+1] ⁺ .

tert-Butyl 7-(2-(4-amino-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

Solution of tert-butyl 7-(2-(4-nitro-2-vinylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (7.92 g, 19.63 mmol in MeOH (196 ml) purged with nitrogen and treated with humidified 10% Pd/C (2.09 g, 1.96 mmol). The reaction mixture was stirred under hydrogen at ambient temperature overnight. Additional humidification with 10% palladium (2 g) and 12 h stirring at room temperature under a hydrogen atmosphere were necessary to achieve complete conversion.The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure to give tert-butyl 7-(2-(4-amino-2-ethylphenoxy)ethyl)-4,7-diazaspiro [2,5]octane-4-carboxylate (6.52 g, 17.36 mmol, 88% yield), MS (ESI) m/z 376.2 [M+1] ⁺ .

4-(3-(4-(2-(4,7-Diazaspiro[2.5]octan-7-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl) -2-(trifluoromethyl)benzonitrile hydrochloride.

tert-Butyl 7-(2-(4-((2-cyanopropan-2-yl)amino)-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4carboxylate (3.50 g, 7. 91 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.80 g, 7.91 mmol) were combined in DMA (26.4 ml) and stirred at ambient temperature. The reaction mixture was treated with MeOH (10 ml) and 3N aqueous HCl (10 ml) and stirred at 70°C for 6 hours, then diluted with EtOAc (400 ml) and water (50 ml), and saturated aqueous sodium bicarbonate ( 50 ml). The solvent layers were separated and the pH of the aqueous layer was checked to ensure its basicity. The organic layer was washed with brine (2x75 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil under reduced pressure. The resulting oil was dissolved in DCM (30 ml) and a 4 N solution of HCl in dioxane (29.6 ml, 119 mmol) was added. The mixture was stirred at ambient temperature for 1 hour and concentrated to dryness under reduced pressure. The material was triturated with diethyl ether overnight at ambient temperature. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (3.193 g, 5.25 mmol, 66.5% yield). MS (ESI) m/z 572.2 [M+1] ⁺ .

5-Chlorobenzene-1,3-diamine.

1,3-Dibromo-5-chlorobenzene (30.00 g, 111 mmol, 1 eq.), diphenylmethanimine (44.7 ml, 266 mmol, 2.4

- 73 044376 eq.), tris(dibenzylideneacetone)dipalladium(0) (2.03 g, 2.22 mmol, 2 mol.%), (±)-2,2'bis(diphenylphosphino)-1,1'- binaphthalene (4.15 g, 6.66 mmol, 6 mol%) and sodium tert-butoxide (27.7 g, 289 mmol, 2.6 eq.) in toluene (556 ml, 0.067 M) were heated to 80° C for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was dissolved in THF (444 mL, 0.049 mol), treated with 1.0 N aqueous HCl (388 mL, 388 mmol, 3.5 eq.) and stirred for 5 min. The reaction mixture was diluted with a 3:1 mixture of EtOAc and hexane, and the aqueous layer was washed with a 3:1 mixture of EtOAc and hexane. The pH of the aqueous layer was adjusted to 11 with 1.0 N aqueous NaOH and extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 5-chlorobenzene-1,3-diamine (13.48 g, 95 mmol, 85.0% yield) as a beige solid. MS (ESI) m/z 143.0 [M+1]+.

3-((3-Amino-5-chlorophenyl)amino)piperidine-2,6-dione.

5-Chlorobenzene-1,3-diamine (13.48 g, 95 mmol, 1 eq.), 3-bromopiperidine-2,6-dione (18.15 g, 95 mmol, 1 eq.) and sodium bicarbonate (9 .53 g, 113 mmol, 1.2 eq.) were combined in DMF (95 ml, 1 mol) and heated at 50°C for 3 days. The reaction mixture was partitioned between EtOAc and brine. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0100% EtOAc in hexanes, then 20% MeOH in EtOAc) to give 3-((3-amino-5chlorophenyl)amino)piperidine-2,6-dione. (2.38 g, 9.37 mmol, 9.9% yield) as a blue-green solid. MS (PER) m/z 254.0 [M+1] ⁺ .

2-Chloro-N-(3-chloro-5-((2,6-diokCOpiperidin-3-yl)amino)phenyl)acetamide.

3-((3-Amino-5-chlorophenyl)amino)piperidine-2,6-dione (3.74 g, 14.74 mmol, 1 eq.), 2-chloroacetic acid (1.06 ml, 17.69 mmol, 1.2 eq.), HATU (8.41 g, 22.11 mmol, 1.5 eq.) and DIPEA (7.72 ml, 44.2 mmol, 3 eq.) were combined in DMF (42, 1 ml, 0.350 mol) and stirred at room temperature. After 10 min, the reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography (50-100% EtOAc in hexanes) to give a green oil, which was triturated in DCM and hexanes. After removing the solvents under reduced pressure and further drying under high vacuum, 2-chloro-N-(3-chloro-5-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide (3.25 g, 9.84 mmol, yield 66.7%) was isolated as a light green solid. MS (ESI) m/z 330.0 [M] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 10.19 (s, 1H), 6.92 (t, 1H, J=1.7 Hz), 6.82 (t, 1H, J=1.8 Hz), 6, 47 (t, 1H, J=1.9 Hz), 6.32 (d, 1H, J=8.1 Hz), 4.3-4.4 (m, 1H), 4.22 (s, 2H ), 2.7-2.8 (m, 1H), 2.5-2.6 (m, 1H), 2.0-2.1 (m, 1H), 1.90 (dk, 1H, J =4.7, 12.4 Hz).

N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(7-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-4,7diazaspiro[2.5]octan-4-yl)acetamide hydrochloride.

2-Chloro-N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.285 g, 0.863 mmol, 1.5 eq.) was added to the stirred mixture of 4-( 3-(4-(2-(4,7-diazaspiro[2.5]octan-7-yl)ethoxy)-3ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile hydrochloride (0.350 g, 0.576 mmol, 1 eq.), sodium iodide (0.129 g, 0.863 mmol, 1.5 eq.), DMF (4.80 ml, 0.12 mol) and DIPEA (0.402 ml , 2.302 mmol, 4 eq.). The reaction mixture was stirred for 20 min at 60°C. The solution was then cooled to room temperature, filtered, concentrated under reduced pressure, and the crude material was purified by standard methods to give N-(3-χλορ5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(7 -(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-4,7 -diazaspiro[2.5]octan-4-yl) acetamide hydrochloride (0.122 g, 0.141 mmol, 24.5% yield). MS (ESI) m/z 865.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 10.58 (us s, 1H), 9.49 (s, 1H), 8.39 (d, 1H, J=8.3 Hz), 8.29 (d, 1H, J=1.7 Hz), 8.08 (dd, 1H, J=1.6, 8.2 Hz), 7.1-7.2 (m, 3H), 6.9-7.0 (m, 2H), 6.45 (t, 1H, J=1.8 Hz), 4.4-4.6 (m, 2H), 4.32 (dd, 1H, J=4.8, 11.7 Hz), 3.3-3.5 (m , 6H), 3.11 (br.d., 1H, J=12.8 Hz), 2.92 (br.d., 1H, J=12.1 Hz), 2.5-2.8 (m, 4H) , 2.5-2.5 (m, 2H), 2.0-2.1 (m, 1H), 1.90 (dk, 1H, J=4.9, 12.3 Hz), 1.50 (s, 6H), 1.17 (t, 3H, J=7.5 Hz), 1.02 (br s, 1H), 0.87 (br s, 2H), 0.6-0.7 ( m, 1H).

Example 9: K-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-(4-(3-(4-cyano-3( trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin1 -yl)-2-methylpropanamide hydrochloride

- 74 044376

4-(2-(4-(( 1 -Methoxy-2-methyl-1 -oxopropan-2-yl)amino)-2-vinylphenoxy)ethyl)piperazine-1 carboxylate.

Mixture of tert-butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (1.00 g, 2 .00 mmol, 1 eq.), 4,4,5,5-tetramethyl-2vinyl-1,3,2-dioxaborolane (0.62 g, 4.00 mmol, 2 eq.), potassium phosphate (2.12 g, 9.99 mmol, 5 eq.), (1,1'bis(diphenylphosphino)ferrocene)-dichloropalladium(P) (0.29 g, 0.40 mmol, 0.2 eq.) in dioxane (1 ml ) and water (0.5 ml) were degassed and purged with nitrogen 3 times. The mixture was stirred at 120°C for 12 hours under a nitrogen atmosphere, then concentrated under reduced pressure at 40°C. The residue was poured into ice water (50 ml). The aqueous phase was extracted with EtOAc (50 mlx3). The combined organic phase was washed with brine (100 mlx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20%-33% EtOAc in petroleum ether) to give tert-butyl 4-(2-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino) -2vinylphenoxy)ethyl)piperazine-1-carboxylate (0.50 g, 1.12 mmol, 55.9% yield) as a yellow oil. MS (ESI) m/z 448.1 [M+1]+.

tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl) piperazine-1-carboxylate.

To a solution of tert-butyl 4-(2-(4-(( 1 -methoxy-2-methyl-1 -oxopropan-2-yl)amino)-2vinylphenoxy)ethyl)piperazine-1-carboxylate (0.500 g, 1.120 mmol, 1 eq.) in MeOH (10 ml) was added Pd-C (10%, 0.2 g) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 40°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(2-(2-ethyl-4((1-methoxy- 2-Methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.320 g, 0.712 mmol, 63.7% yield), which was obtained as a yellow oil. MS (ESI) m/z 450.3 [M+1] ⁺ .

tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl) piperazine-1-carboxylate.

To a mixture of tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.319 g, 0. 71 mmol, 1 eq.) and 4-isothiocyanato-2(trifluoromethyl)benzonitrile (0.486 g, 2.13 mmol, 3 eq.) in EtOAc (2 ml) was added TEA (0.359 g, 3.55 mmol, 5 eq. ). The mixture was stirred at 80°C for 12 hours, then concentrated under reduced pressure. The residue was purified by preparative TLC (66.7% EtOAc in petroleum ether). tert-Butyl 4-(2(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)piperazine -1-carboxylate (0.315 g, 0.488 mmol, 68.8% yield) was obtained as a yellow solid. MS (ESI) m/z 646.4 [M+1] ⁺ .

4-(3-(3 -Ethyl-4-(2-(piperazin-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1 -yl)2-(trifluoromethyl) benzonitrile hydrochloride.

To a solution of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy) ethyl)piperazine-1-carboxylate (0.315 g, 0.488 mmol, 1 eq.) in EtOAc (2 ml) was added with HCl/dioxane (4 M, 10 ml). The mixture was stirred at 25°C for 30 minutes, then concentrated under reduced pressure. The crude material was used without further purification to give 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl )-2-(trifluoromethyl)benzonitrile hydrochloride (0.300 g, crude) as a yellow solid. MS (ESI) m/z 546.1 [M+1] ⁺ .

tert-Butyl 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy )ethyl)piperazin-1-yl)-2-methylpropanoate.

tert-Butyl 2-bromo-2-methylpropanoate (0.077 mL, 0.41 mmol, 1.2 eq.) was added to the stirred mixture of 4-(3-(3-ethyl-4-(2-(piperazin-1-yl )ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)2-(trifluoromethyl)benzonitrile hydrochloride (0.200 g, 0.34 mmol, 1 eq.), THF (2.94 ml, 0.12 mol) and TEA (0.192 ml, 1.37 mmol, 4 eq.). The reaction mixture was stirred for 4 days at 85°C. An additional 4.8 equiv of tert-butyl 2-bromo-2-methylpropanoate was added to the reaction mixture, and the reaction mixture was stirred at 85°C for an additional 4 days. The reaction mixture was concentrated and purified by silica gel column chromatography (20-100% EtOAc in hexanes, then 0-5% MeOH in DCM) to give tert-butyl-2-(4-(2-(4-(3-(4- cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoate (0.026 g, 0.038 mmol, yield 11.0%) as a beige solid contaminated with some hydrant product. MS (ESI) m/z 688.2 [M+1] ⁺ .

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl) piperazin-1-yl)-2-methylpropanoic acid trihydrochloride.

Suspension of tert-butyl-2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2 -ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoate (0.026 g, 0.038 mmol, 1 eq.) in DCM (0.170 ml, 0.226 M) was treated with a solution of HCl in dioxane (142 μl. 0.567 mmol, 15 eq. ) and stirred at room temperature for 4 days. The reaction mixture was concentrated to give 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1 -yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoic acid trihydrochloride (0.028 g, 0.038 mmol, 100% yield) as a brown solid. MS (IER) m/z 632.2

[M+1]+.

N-(3 -Chloro-5-((2,6-dioxopiperidin-3 -yl)amino)phenyl)-2-(4-(2 -(4-(3 -(4-cyano-3 (trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin1 -yl)-2-methylpropanamide hydrochloride.

Mixture of 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2-ethylphenoxy)ethyl )piperazin-1-yl)-2-methylpropanoic acid trihydrochloride (0.028 g, 0.038 mmol, 1 eq.) combined with 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione (0.011 g, 0.038 mmol, 1 eq.), HATU (0.016 g, 0.042 mmol, 1.1 eq.), DIPEA (0.040 ml, 0.23 mmol, 6 eq.) and DMF (0.189 ml, 0.2 mol) stirred at 25°C for 4 days. The reaction was quenched with water and the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were concentrated. The material was purified by standard methods to obtain N-(3-chloro-5-((2,6-dioxopiperidin-3yl)amino)phenyl)-2-(4-(2-(4-(3-(4-cyano-3 -(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanamide hydrochloride (0.002 g 0.002 mmol, yield 5, 2%). MS (ESI) m/z 867.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 10.40 (br s, 1H), 9.48 (br s, 1H), 8.39 (d, 1H, J=8.2 Hz), 8.29 (d , 1H, J=1.6 Hz), 8.07 (dd, 1H, J=1.8, 8.3 Hz), 7.1-7.2 (m, 4H), 6.86 (s, 1H), 6.46 (s, 1H), 4.48 (br s, 2H), 4.35 (br dd, 1H, J=4.7, 11.7 Hz), 3.6-3.6 (m, 4H), 3.2-3.3 (m, 4H), 2.9-3.0 (m, 2H), 2.7-2.8 (m, 1H), 2.67 (k , 2H, J=7.5 Hz), 2.62 (td, 1H, J=4.0, 13.6 Hz), 2.07 (td, 1H, J=3.9, 8.1 Hz) , 1.90 (dk, 1H, J=4.0, 11.9 Hz), 1.50 (s, 6H), 1.2-1.2 (m, 6H), 1.17 (ush t, 3H, J=7.5 Hz).

Example 10: 1 -(4-(2-(4-(3 -(4-Cyano-3 -(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy )ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)cyclopropanecarboxamide hydrochloride

Ethyl 1-(4-benzylpiperazin-1-yl)cyclopropanecarboxylate.

Ethyl 1-aminocyclopropanecarboxylate hydrochloride (0.500 g, 3.02 mmol, 1 eq.) was added to a stirred mixture of N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (0.886 g, 3.30 mmol, 1 eq. 09 eq.), EtOH (6.66 ml, 0.453 mol) and DIPEA (5.30 ml, 30.3 mmol, 10.05 eq.). The reaction mixture was stirred for 18 hours at 78°C, then concentrated under reduced pressure. The crude material was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were concentrated under reduced pressure and the crude material was purified by silica gel column chromatography (5-10% EtOAc in hexanes) to give ethyl 1-(4benzylpiperazin-1-yl)cyclopropanecarboxylate (0.409 g, 1.42 mmol, yield 47.0 %) as a yellow oil. MS (ESI) m/z 289.2 [M+1] ⁺ .

Ethyl 1-(piperazin-1-yl)cyclopropanecarboxylate hydrochloride.

To a solution of ethyl 1-(4-benzylpiperazin-1-yl)cyclopropanecarboxylate (0.200 g, 0.694 mmol, 1 eq.) in anhydrous DCM (1.692 ml, 0.410 mol), cooled to 0°C, was slowly added 1-chloroethyl carbonochloridate (0.110 ml, 1.02 mmol, 1.465 eq.) while maintaining the temperature below 0°C. The mixture was stirred at 18°C for 1 hour. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOH (1.69 ml, 0.410 M). The resulting solution was stirred at 78°C for 18 hours. The reaction mixture was concentrated to dryness. The residue was then stirred in a 5:1 mixture of EtOH and MTBE, and the precipitate was collected by filtration to give ethyl 1-(piperazin-1-yl)cyclopropanecarboxylate hydrochloride (0.107 g, 0.456 mmol, 65.7% yield) as a beige solid. MS (ESI) m/z 199.2 [M+1] ⁺ .

2-((3-Bromo-4-hydroxyphenyl)amino)-2-methylpropanenitrile.

To a solution of 4-amino-2-bromophenol (5.00 g, 26.6 mmol) in DCM (177 ml) and acetone (89 ml) was added trimethylsilyl cyanide (4.66 ml, 37.2 mmol) and trimethylsilyl trifluoromethylsulfonate (0.241 ml , 1.33 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated to remove the solvent. The crude material was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give 2-((3-bromo-4-hydroxyphenyl)amino)-2methylpropanenitrile (4.56 g, 17.87 mmol, 67.2% yield ) as a brown solid. MS (ESI) m/z 256.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.55-9.66 (m, 1H), 7.05 (d, J=2.69 Hz, 1H), 6.83-6.87 (m, 1H), 6.776.81 (m, 1H) , 5.51 (s, 1H), 1.55 (s, 6H).

- 76 044376

4-(3-(3-Bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

2-((3-Bromo-4-hydroxyphenyl)amino)-2-methylpropanenitrile (1.00 g, 3.92 mmol) and 4-isothiocyanato2-(trifluoromethyl)benzonitrile (0.894 g, 3.92 mmol) were combined in DMA (13.07 ml) and stirred at room temperature overnight. MeOH (5 ml) and 3.0 N aqueous HCl solution (5 ml) were added and the reaction mixture was heated at 70°C. After 2 hours, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc before the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give 4-(3-(3bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile (1.23 g, 2.423 mmol, 62.0% yield) as a white solid. MS (ESI) m/z 484.0 [M+1]+.

2-Bromo-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)phenylacetate.

4-(3-(3-bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile solution (0.75 g, 1.55 mmol ) in DCM (7.74 ml), treated with DIPEA (0.541 ml, 3.10 mmol) and acetyl chloride (0.132 ml, 1.86 mmol), stirred at room temperature. After 12 h, the reaction mixture was diluted with EtOAc (100 ml) and the organic layer was washed with saturated aqueous sodium bicarbonate (2x100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated to give a colorless oil, which was purified by silica gel column chromatography (20-50% EtOAc in hexanes) to give the title compound (0.766 g, 1.455 mmol, 94% yield). MS (ESI) m/z 526.0 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.97 (s, 1H), 7.94 (s, 1H), 7.82 (dd, J=2.1, 8.2 Hz, 1H), 7.58 (d, J=2.3 Hz , 1H), 7.36-7.27 (m, 2H), 2.40 (s, 3H), 1.61 (s, 6H).

4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenylacetate.

To a mixture of 2-bromo-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)phenylacetate (2 g, 3.80 mmol) , [(2-dicyclohexylphosphino-2',6'-bis(K, N-dimethylαmuno)-1,1'biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(P) methanesulfonate (0.311 g, 0.380 mmol) and 2-(2dicyclohexylphosphanylphenyl)-K ¹ ,K ¹ ,N,N-tetramethyl-benzene-1,3-diamine (0.166 g, 0.38 mmol), combined in a Schlenk flask and purged with argon , toluene (15.20 ml) was added. The reaction mixture was placed in an ice bath for 5 min, then treated with 0.5 M ethylzinc(II) bromide in THF (6.08 mL, 3.04 mmol, 0.8 eq.). After 30 min, an additional 0.5 equivalent of ethylzinc(II) bromide solution (3.80 mL, 1.90 mmol) was used at 0°C for 30 min and the reaction was quenched by adding 2.0 M aqueous HCl (2.470 mL, 4 .94 mmol), and the mixture was diluted with EtOAc (350 ml). The organic layer was washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid. The crude material was purified by silica gel column chromatography (0-45% EtOAc in hexanes) to give 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine- 1-yl)-2ethylphenylacetate (0.986 g, 2.07 mmol, 55.0% yield). MS(ESI) m/z 476 [M+1] ⁺ .

4-(3-(-3-Ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

A suspension of 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2-ethylphenylacetate (0.876 g, 1.84 mmol) and carbonate potassium (0.255 g, 1.84 mmol) in MeOH (20 ml) was stirred at ambient temperature. After 40 min, the solution was diluted with EtOAc (200 ml) and partitioned with water (50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.766 g, 1.76 mmol, 96.0% yield). MS (ESI) m/z 434 [M+1] ⁺ .

4-(3-(4-(2-Bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

1,2-Dibromoethane (2.99 mL, 34.6 mmol, 20.0 eq.), cesium carbonate (1.97 g, 6.06 mmol, 3.5 eq.) and 4-(3(3- ethyl 4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.750 g, 1.73 mmol, 1 eq.) was dissolved in DMF (20, 36 ml, 0.085 M) in a preheated flask, and the reaction was stirred at 60°C for 18 hours under a nitrogen atmosphere. The reaction was quenched with water and the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-100% EtOAc in hexanes). Fractions were concentrated to a residue which was triturated with DCM and hexane to give 4-(3-(4-(2bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 (trifluoromethyl)benzonitrile (0.296 g, 0.548 mmol, 31.7% yield) as a beige solid. MS (ESI) m/z 540.0 [M] ⁺ .

Ethyl 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1

- 77 044376 yl)-2-ethylphenoxy)ethyl)piperazin-1 -yl)cyclopropanecarboxylate.

4-(3-(4-(2- bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.296 g, 0.547 mmol, 1.2 eq.) and DIPEA (0.279 ml, 1.596 mmol, 3.5 eq.) The vessel was sealed and the mixture was heated to 60°C with stirring for 18 hours. The reaction mixture was concentrated at and purified by silica gel column chromatography (0-10% MeOH in DCM) to give ethyl 1 -(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl) piperazin-1yl)cyclopropanecarboxylate (0.090 g, 0.137 mmol, 30.0% yield) as an orange oily liquid. MS (ESI) m/z 658.2 [M+1]+.

(S)-2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-ethylphenoxy)ethyl)piperidin-1-yl)propanoic acid tetrahydrochloride.

K ethyl 1 -(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2-ethylphenoxy) ethyl)piperazin-1-yl)cyclopropanecarboxylate (0.090 g, 0.137 mmol) was added with 6 M aqueous HCl (1.140 mL, 6.84 mmol) slowly at 0°C. The reaction mixture was gradually heated to 100°C and stirred for 18 hours. The reaction mixture was concentrated to obtain 1-(4(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl 4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)piperazin-1-yl)cyclopropanecarboxylic acid trihydrochloride (0.108 g, 0.139 mmol, 102% yield) as a pale yellow solid. MS (ESI) m/z 630.2 [M+1] ⁺ .

-(4-(2-(4-(3 -(4-Cyano-3 -(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2ethylphenoxy)ethyl)piperazine -1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)cyclopropanecarboxamide hydrochloride.

1-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl) piperazin-1-yl)cyclopropanecarboxylic acid tetrahydrochloride (0.108 g, 0.139 mmol, 1 eq.) was combined with 3-((3-aminophenyl)amino)piperidine-2,6-dione trifluoroacetate salt (0.046 g, 0.139 mmol, 1 eq. .), HATU (0.058 g, 0.153 mmol, 1.1 eq.), DIPEA (0.170 ml, 0.975 mmol, 7 eq.) in DMF (0.696 ml, 0.2 mol), and the reaction mixture was stirred at 25°C within 15 min. The reaction was quenched with water and the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were concentrated. The crude material was purified by standard methods to give 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl) -2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)cyclopropanecarboxamide hydrochloride (0.027 g, 0.032 mmol, 22.7% yield). MS (ESI) m/z 831.6 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 10.49 (us s, 1H), 9.48 (s, 1H), 8.39 (d, 1H, J=8.3 Hz), 8.29 (d, 1H, J=1.7 Hz), 8.07 (dd, 1H, J=1.7, 8.3 Hz), 7.1-7.2 (m, 4H), 7.02 (t, 1H , J=8.0 Hz), 6.79 (dd, 1H, J=1.0, 8.1 Hz), 6.43 (dd, 1H, J=1.7, 8.1 Hz), 4 .49 (t, 2H, J=4.4 Hz), 4.30 (dd, 1H, J=4.8, 11.3 Hz), 3.58 (ush s, 2H), 3.44 (t , 4H, J=10.6 Hz), 2.97 (ush d, 2H, J=12.2 Hz), 2.7-2.9 (m, 3H), 2.66 (k, 2H, J =7.4 Hz), 2.59 (td, 1H, J=4.3, 17.2 Hz), 2.1-2.1 (m, 1H), 1.89 (dk, 1H, J= 4.5, 12.2 Hz), 1.50 (s 6H), 1.17 (t, 3H, J=7.5 Hz), 1.1-1.2 (m, 2H), 1.0-1 ,1 (m, 2H).

Example 11: N-(3-Chloro-5-((2,6-d ioxopiperidin-3-yl)amino)phenyl)-1-(4-(2-(4-(3-(6-cyano-5 (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)piperazin-1-yl)cyclopropan-1-carboxamide hydrochloride

5-(3-(4-(2-Bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

1,2-Dibromoethane (2.39 mL, 27.6 mmol, 20 eq.), cesium carbonate (1.57 g, 4.83 mmol, 3.5 eq.) and 5-[3-(3ethyl-4 -Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-3-(trifluoromethyl)pyridine-2carbonitrile (0.600 g, 1.38 mmol, 1 eq.) was dissolved in DMF (16.2 ml, 0.085 mol) in a preheated flask, and the reaction mixture was stirred at 60°C for 18 hours under a nitrogen atmosphere. The reaction was quenched with water and diluted with EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc in hexanes). The fractions were concentrated and the residue triturated in DCM and hexanes to give 5-[3[4-(2-bromoethoxy)-3-ethylphenyl]-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1 -yl] -3(trifluoromethyl)pyridine-2-carbonitrile (0.324 g, 0.60 mmol, 43.3% yield) as a pale pink solid. MS (ESI) m/z 539.8 [M] ⁺ .

Ethyl 1-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2

- 78 044376 thioxoimidazolidin-1 -yl)-2-ethylphenoxy)ethyl)piperazin-1 -yl)cyclopropan-1-carboxylate.

To a solution of ethyl 1-piperazin-1-ylcyclopropanecarboxylate hydrochloride (0.181 g, 0.69 mmol, 1.15 eq.) in DMF (6.00 ml, 0.100 mol) was added 5-[3-[4-(2-bromoethoxy )-3-ethylphenyl]-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile (0.324 g, 0.60 mmol, 1 eq.) and DIPEA ( 0.36 ml, 2.09 mmol, 3.5 eq.). The reaction vessel was sealed and heated to 60°C with stirring for 18 hours. The solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give ethyl 1-[4-[2- [4[3-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2ethylphenoxy]ethyl]piperazin-1-yl] cyclopropane carboxylate (0.036 g, 0.05 mmol, 9.1% yield) as a light yellow semi-solid. MS (ESI) m/z 496.0 [M+1]+.

-(4-(2-(4-(3 -(6-Cyano-5-(trifluoromethyl)pyridin-3 -yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1 -yl)-2-ethylphenoxy )ethyl)piperazin-1-yl)cyclopropane-1-carboxylic acid trihydrochloride.

To ethyl-1-[4-[2-[4-[3-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl]- 2-ethylphenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxylate (0.036 g, 0.05 mmol, 1 eq.) was slowly added with 6.0 N aqueous HCl (0.46 mL, 2.73 mmol, 50 eq.) at 0°C. The reaction mixture was gradually heated to 100°C and stirred for 18 hours, then concentrated to give 1-[4-[2-[4-[3-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5 ,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl]-2-ethylphenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxylic acid trihydrochloride (0.040 g, 0.05 mmol, 99.9% yield) as pale yellow solid. MS (ESI) m/z 629.8 [M+1] ⁺ .

N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-1-(4-(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridine -3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)piperazin-1-yl)cyclopropan-1-carboxamide hydrochloride.

1-[4-[2-[4-[3-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1yl]-2 -ethyl-phenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxylic acid trihydrochloride (0.040 g, 0.050 mmol, 1 eq.) was combined with 3-(3-amino-5-chloro-anilino)piperidine-2,6-dione ( 13.8 mg, 0.050 mmol, 1 eq.), HATU (22.8 mg, 0.060 mmol, 1.1 eq.), DIPEA (0.05 ml, 0.270 mmol, 5 eq.) and DMF (0.273 ml, 0.200 M), and the reaction was stirred at 25°C for 18 hours. The reaction was quenched with water and diluted with EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic layers were concentrated and purified by standard methods to give N-[3-chloro-5-[(2,6-dioxo-3-piperidyl)amino]phenyl]1-[4-[2-[4-[3-[ 6-cyano-5-(trifluoromethyl)-3-pyridyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2ethylphenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxamide hydrochloride (0.005 g, 5.8x10 ^-2 mmol, yield 10.6%). MS (ESI) m/z 866.7 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-de) δ ppm 10.81 (s, 1H), 10.53 (s, 1H), 10.45 (us s, 1H), 9.22 (d, 1H, J=1.8 Hz), 8.76 (d, 1H, J=2.1 Hz), 7.2-7.3 (m, 3H), 7.02 (s, 1H), 6.98 (s, 1H), 6.57 (t, 1H, J =1.8 Hz), 6.36 (ush s, 1H), 4.4-4.5 (m, 2H), 4.34 (ush dd, 1H, J=4.8, 11.9 Hz) , 3.69 (USD, 2H, J=10.8 Hz), 3.58 (USD, 2H, J=4.4, 7.7 Hz), 3.22 (K, 2H, J=9 ,8 Hz), 2.5-2.8 (m, 7H), 2.4-2.5 (m, 2H), 2.0-2.1 (m, 1H), 1.8-2, 0 (m, 6H), 1.5-1.6 (m, 1H), 1.18 (t, 3H, J=7.5 Hz).

Example 12: 2-(4-(2-(2-Chloro-4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7diazaspiro[3,4] octan-5-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl) amino)phenyl)acetamide hydrochloride

(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)carbamate.

To a solution of tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (10.00 g, 48.02 mmol, 1 eq.) and 3-bromopiperidin-2,6-dione (9.22 g, 48.02 mmol, 1 eq.) to DMF (100 ml) was added sodium bicarbonate (4.03 g, 48.02 mmol, 1 eq.). The reaction mixture was stirred at 50°C for 10 hours, then filtered. The filtrate was purified by preparative reverse phase HPLC (25-55% acetonitrile in water + 0.225% formic acid, 30 min) to give tert-butyl (3-((2,6-dioxopiperidin-3yl)amino)phenyl)carbamate (6, 04 g, 18.91 mmol, 39.4% yield) as a green solid.

1H NMR (400 MHz, DMSO-de) δ ppm 10.76 (s, 1H), 9.02 (s, 1H), 6.92 (t, J=8.0 Hz, 1H), 6.85 (s, 1H), 6.65 (d, J =8.4 Hz, 1H), 6.29 (d, J=7.6 Hz, 1H), 5.78 (d, J=7.2 Hz, 1H), 2.76-2.59 (m , 2H), 2.11-2.07 (m, 1H), 1.92-1.82 (m, 1H).

3-((3-Aminophenyl)amino)piperidine-2,6-dione.

To a solution of tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (6.04 g, 18.91 mmol, 1 eq.) in DCM (50 ml) was added 4.0 M solution of HCl in dioxane (28.37 ml, 6 eq.), and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated to dryness. 3-((3- 79 044376

Aminophenyl)amino)piperidine-2,6-dione hydrochloride (4.50 g, 17.60 mmol, 93.1% yield) was isolated as a light green solid and used in the next step without purification.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 10.12 (s, 3H), 7.16 (t, J=8.0 Hz, 1H), 6.70-6.68 (m,

1H), 6.64-6.63 (m, 1H), 6.55-6.53 (m, 1H), 4.36-4.32 (m, 1H), 2.79-2.70 ( m, 1H), 2.67-2.56 (m, 1H), 2.11-2.05 (m, 1H), 1.95-1.86 (m, 1H).

tert-Butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazine-1carboxylate.

To a solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (1.05 g, 4.30 mmol, 1.1 eq.), HATU (1.78 g, 4.69 mmol, 1.2 eq.) and DIPEA (1.26 g, 9.78 mmol, 2.5 eq.) in DMF (10 ml) was added 3-(3-aminoanilino)piperidine-2,6-dione hydrochloride (1, 00 g, 3.91 mmol, 1 eq.) at 0°C. The mixture was stirred at 15°C for 10 hours.

Water (60 ml) was added to the mixture and the resulting suspension was extracted with EtOAc (40 ml x 2 ). The combined organic extracts were washed with brine (50 mlx5), dried, filtered and concentrated to give tert-butyl-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2oxoethyl )piperazine-1-carboxylate (1.37 g, 3.08 mmol, 78.6% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.78 (s, 1H), 9.84 (ush, 1H), 7.01 (t, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.82 (d, J=7 .6 Hz, 1H), 6.42 (d, J=8.0 Hz, 1H), 5.92 (d, J=7.2 Hz, 1H), 4.28-4.22 (m, 1H ), 3.63-3.33 (m, 10H), 2.72-2.70 (m, 1H), 2.62-2.56 (m, 1H), 2.13-2.07 (m , 1H), 1.95-1.84 (m, 1H), 1.40 (s, 9H).

K-(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)-2-(piperazin-1-yl)acetamide.

To a solution of tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2oxoethyl)piperazine-1-carboxylate (1.35 g, 3.03 mmol , 1 eq.) in DCM (10 ml) was added a 4.0 M solution of HCl in dioxane (3.79 ml, 5 eq.). The reaction mixture was stirred at 15°C for 12 hours. EtOAc (20 ml) was added to the suspension and the resulting suspension was filtered. The filter cake was washed with EtOAc (20 ml) and dried under reduced pressure to give K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)-2-(piperazin-1-yl)acetamide hydrochloride (1, 26 g, crude) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.82 (s, 1H), 10.67 (s, 1H), 10.01 (ush, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.01 (s, 1H ), 6.89 (d, J=7.6 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 4.29-4.26 (m, 3H), 3.73 -3.57 (m, 4H), 3.44-3.35 (m, 4H), 2.77-2.69 (m, 1H), 2.61-2.57 (m, 1H), 2 .11-2.09 (m, 1H), 1.98-1.89 (m, 1H).

1-((3-Chloro-4-hydroxyphenyl)amino)cyclobutanecarbonitrile.

Trimethylsilylformonitrile (0.249 g, 2.51 mmol, 1.20 eq.) was added dropwise to a mixture of 4-amino2-chlorophenol (0.300 g, 2.09 mmol, 1 eq.) and cyclobutanone (0.293 g, 4.18 mmol, 2 eq.) in DCM (3 ml). The mixture was stirred at 25°C for 10 hours. At the end of the dropwise addition of saturated aqueous sodium bicarbonate solution (0.5 ml), the mixture was concentrated to a residue, which was purified by column chromatography (0-50% EtOAc in petroleum ether) to give 1- ((3-chloro-4hydroxyphenyl)amino)cyclobutanecarbonitrile (0.320 g, 1.44 mmol, 68.8% yield) as a red solid. MS (ESI) m/z 223.2 [M+1]+.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (s, 1H), 6.84 (d, J=8.7 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 6.476.40 (m, 1H), 6.27 ( s, 1H), 2.72-2.61 (m, 2H), 2.29 (br. d, J=10.5 Hz, 2H), 2.12-2.00 (m, 2H).

4-(5-(3-Chloro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2(trifluoromethyl)benzonitrile.

Thiocarbonyl dichloride (0.108 g, 0.943 mmol, 1 eq.) was added dropwise to a mixture of 1-((3-chloro-4hydroxyphenyl)amino)cyclobutanecarbonitrile (0.210 g, 0.943 mmol, 1 eq.) and 4-amino-2(trifluoromethyl) benzonitrile (0.176 g, 0.943 mmol, 1 eq.) in DMA (3 ml). The mixture was stirred at 60°C for 12 hours, then diluted with MeOH (0.6 ml) and aqueous HCl (2M, 0.4 ml) and stirred at 15°C for 2 hours. The mixture was poured into water (10 ml ), and the aqueous phase was extracted with EtOAc (15 mlx3). The combined organic phases were washed with brine (10 mlx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The material was purified by preparative TLC followed by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to give 4-(5-(3-chloro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3,4]octan-7yl)-2-(trifluoromethyl)benzonitrile (0.208 g, 0.460 mmol, 48.8% yield) as a brown solid. MS (ESI) m/z 451.9 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (s, 1H), 8.37 (d, J=8.3 Hz, 1H), 8.22 (d, J=1.8 Hz, 1H), 8.097.97 (m, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.23-7.18 (m, 1H), 7.15 (s, 1H), 2.64-2.55 (m, 2H) , 2.47-2.37 (m, 2H), 1.951.89 (m, 1H), 1.60-1.49 (m, 1H).

4-(5-(4-(2-Bromoethoxy)-3-chlorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2(trifluoromethyl)benzonitrile.

To a mixture of 4-(5-(3-chloro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2(trifluoromethyl)benzonitrile (0.200 g, 0 .44 mmol, 1 eq.) in acetonitrile (7 ml), potassium carbonate (0.245 g, 1.77 mmol, 4 eq.) and 1,2-dibromoethane (0.416 g, 2.21 mmol, 5 eq.) were added. The mixture was stirred at 80°C for 12 hours, then concentrated and poured into water (10 ml). The aqueous phase was extracted

- 80 044376

EtOAc (15 mlx3). The combined organic phases were washed with brine (10 mlx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The material was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give 4-(5-(4-(2-bromoethoxy)-3-chlorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro [3.4]octan-7-yl)-2(trifluoromethyl)benzonitrile (0.170 g, 0.285 mmol, 64.4% yield) as a light yellow oil. MS (IERT) m/z 558.1 559.1 [M+1, M+2] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.01-7.95 (m, 2H), 7.84 (dd, J=1.9, 8.2 Hz, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.21 (dd , J=2.5, 8.7 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 4.44 (t, J=6.3 Hz, 2H), 3.75 (t, J=6.3 Hz, 2H), 2.74-2.64 (m, 2H), 2.61-2.50 (m, 2H), 2.33-2.17 (m, 1H ), 1.74-1.67 (m, 1H).

2-(4-(2-(2-Chloro-4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5yl )phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

To a solution of 4-(5-(4-(2-bromoethoxy)-3-chlorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2(trifluoromethyl)benzonitrile ( 0.161 g, 0.288 mmol, 1.1 eq.) and N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)-2-(piperazin-1-yl)acetamide hydrochloride (0.100 g, 0.262 mmol , 1.00 eq.) DIPEA (0.169 g, 1.310 mmol, 5 eq.) was added to DMF (1 ml). The mixture was stirred at 60°C for 12 hours, then treated with potassium iodide (0.087 g, 0.524 mmol, 2 eq.) and stirred at 80°C for 8 hours. The material was purified by standard methods to obtain 2-(4-(2 -(2-chloro-4-(7-(4-cyano-3(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)ethyl)piperazine -1-yl)-N(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.046 g, 0.052 mmol, 20.0% yield). MS (ESI) m/z 823.4 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 10.46-10.03 (m, 1H), 8.39 (d, J=8.3 Hz, 1H), 8.22 (d, J=1.5 Hz , 1H), 8.10-7.97 (m, 1H), 7.60 (s, 1H), 7.43 (s, 2H), 7.03 (s, 1H), 6.97 (s, 1H), 6.84 (br. d, J=7.9 Hz, 1H), 6.50-6.38 (m, 1H), 4.60 (br. s, 2H), 4.31-4.22 (m, 1H), 3.93 (br s, 13H), 2.82-2.68 (m, 1H), 2.62 (br s, 2H), 2.43 (br s, J=10, 3 Hz, 3H), 2.15-2.05 (m, 1H), 2.02-1.83 (m, 2H), 1.61-1.50 (m, 1H).

Example 13: 2-(4-(2-(4-(3 -(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)-2-cyclopropylphenoxy )ethyl)piperazin-1 -yl)-N-(3 -((2,6-dioxopiperidin-3 yl)amino)phenyl)acetamide hydrochloride

tert-Butyl 4-(2-(2-bromo-4-nitrophenoxy)ethyl)piperazine-1-carboxylate.

To a mixture of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (5.71 g, 22.94 mmol, 1 eq.) and 2-bromo4-nitrophenol (5.00 g, 22.94 mmol, 1 eq.) in acetonitrile (50 ml) was added potassium carbonate (15.85 g, 114.68 mmol, 5 eq.). The mixture was stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 ml) and water (20 ml). The aqueous phase was extracted with EtOAc (15 mlx1). The combined organic phases were washed with water (20 mlx3) and brine (10 mlx1), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo, tert-Butyl 4(2-(2-bromo-4-nitrophenoxy)ethyl)piperazine-1-carboxylate (8.22 g, 19.10 mmol, 83.3% yield) was obtained as a yellow solid and used without further purification. MS (ESI) m/z 432.0 [M+3] ⁺ .

tert-Butyl 4-(2-(4-amino-2-bromophenoxy)ethyl)piperazine-1-carboxylate.

Zinc ( 4.56 g, 69.72 mmol, 5 eq.) and ammonium chloride (14.92 g, 278.88 mmol, 20 eq.). The mixture was stirred at 50°C for 48 hours, then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by semipreparative reverse phase HPLC (5-35% acetonitrile + 0.225% formic acid in water). The collected fractions were concentrated to remove most of the acetonitrile and treated with saturated aqueous sodium bicarbonate to adjust the pH to 7. The aqueous phase was extracted with EtOAc (200 ml x 3 ). The combined organic phase was washed with brine (100 mlx1), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. tert-Butyl 4-(2-(4-amino-2-bromophenoxy)ethyl)piperazine-1-carboxylate (3.02 g, 7.55 mmol, 54.2% yield) was obtained as a yellow solid. MS (ESI) m/z 400.1 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-de) δ ppm 6.83 (d, J=8.8 Hz, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.51 (dd, J=2.4, 8.8 Hz, 1H ), 4.90 (US s, 2H), 3.97 (t, J=5.6 Hz, 2H), 3.29 (US s, 4H), 2.67 (t, J=5.6 Hz , 2H), 2.47-2.41 (m, 4H), 1.39 (s, 9H).

tert-Butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine- 81 044376

1-carboxylate.

Methyl 2- bromo-2-methylpropanoate (2.24 g, 12.39 mmol, 3 eq.). The mixture was stirred at 120°C for 12 hours. The mixture was concentrated under reduced pressure and diluted with water (20 ml). The aqueous phase was extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (10 mlx1), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30-60% EtOAc in petroleum ether), tert-Butyl-4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino )phenoxy)ethyl)piperazine-1-carboxylate (1.90 g, 3.80 mmol, 92.0% yield) was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (d, J=8.8 Hz, 1H), 6.75-6.66 (m, 1H), 6.36 (dd, J=2.8, 8.8 Hz, 1H), 5 ,83-5.78 (m, 1H), 5.81 (s, 1H), 3.99 (t, J=5.6 Hz, 2H), 3.59 (s, 3H), 3.29 ( ush s, 4H), 2.72-2.65 (m, 2H), 2.46-2.39 (m, 4H), 1.41-1.37 (m, 15H).

tert-Butyl 4-(2-(2-cyclopropyl-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate.

To a mixture of tert-butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.300 g, 0.599 mmol , 1 eq.) and 2-cyclopropyl-4,4,5,5tetramethyl-1,3,2-dioxaborolane (0.201 g, 1.200 mmol, 2 eq.) in dioxane (5 ml) and water (0.5 ml) add potassium phosphate (0.636 g, 3.000 mmol, 5 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.088 g, 0.120 mmol, 0.2 eq.) under nitrogen. The mixture was stirred at 120°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc in petroleum ether) followed by semipreparative reverse phase HPLC (10-40% acetonitrile + 0.225% formic acid in water, 10 min).

The collected fractions were then concentrated to remove most of the acetonitrile and lyophilized. tert-Butyl 4-(2-(2-cyclopropyl-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.108 g, 0.234 mmol, yield 39.0%) was obtained as a yellow oil. MS (IER) m/z 462.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.15 (s, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.16 (dd, J=2.8, 8.6 Hz, 1H), 5.95 (d , J=2.8 Hz, 1H), 5.37 (us s, 1H), 3.96 (t, J=5.6 Hz, 2H), 3.57 (s, 3H), 3.38 ( ush s, 4H), 2.69 (t, J=5.6 Hz, 2H), 2.47-2.40 (m, 4H), 2.12-2.00 (m, 1H), 1, 45-1.31 (m, 15H), 0.90-0.75 (m, 1H), 0.79 (s, 1H), 0.50-0.36 (m, 1H), 0.50 ( s, 1H).

tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl) piperazine-1-carboxylate.

To a mixture of tert-butyl 4-(2-(2-cyclopropyl-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.108 g, 0.234 mmol , 1 eq.) and 4-isothiocyanato-2(trifluoromethyl)benzonitrile (0.160 g, 0.702 mmol, 3 eq.) in EtOAc (1 ml) was added TEA (0.118 g, 1.170 mmol, 5 eq.). The mixture was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (66.7% EtOAc in petroleum ether). tert-Butyl 4-(2(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2cyclopropylphenoxy)ethyl)piperazine -1-carboxylate (0.090 g, 0.137 mmol, 58.5% yield) was obtained as a yellow solid. MS (ESI) m/z 658.1 [M+1] ⁺ .

4-(3-(3 -Cyclopropyl-4-(2-(piperazin-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride

To a solution of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-cyclopropylphenoxy) ethyl)piperazine-1-carboxylate (0.09 g, 0.1374 mmol, 1 eq.) in EtOAc (2 ml) was added to a solution of HCl in dioxane (4 M, 5 ml). The mixture was stirred at 25°C for 30 minutes. The mixture was concentrated under reduced pressure. 4-(3-(3-Cyclopropyl-4-(2(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile hydrochloride (0.10 g, crude) was obtained as a yellow oil and used without further purification. MS (ESI) m/z 558.1 [M+1] ⁺ .

2-Chloro-K-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

To a mixture of 2-chloroacetic acid (1.39 g, 14.66 mmol, 1.1 eq.), HATU (5.57 g, 14.66 mmol, 1.1 eq.) and DMF (40 ml), stirring at 15°C for 2 hours, add 3-((3aminophenyl)amino)piperidine-2,6-dione hydrobromide (4.00 g, 13.33 mmol, 1 eq.) and DIPEA (5.17 g, 39 .98 mmol, 6.96 ml, 3 eq.). The reaction mixture was stirred at 15°C for 1 hour, diluted with brine (150 ml) and EtOAc (150 ml), and the layers were separated. The aqueous layer was extracted with EtOAc (100 mlx2). The combined organic extracts were concentrated and the resulting suspension was filtered. The filtrate was purified by reverse phase semipreparative HPLC (10-40% acetonitrile in water + 0.05% HCl, 26 min) to give 2-chloro-K-(3-((2,6-dioxopiperidin-3-yl) amino)phenyl)acetamide (2.60 g, 8.79 mmol, 66.0% yield) as a gray solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 10.17 (s, 1H), 7.06-7.02 (m, 2H), 6.86 (d, J=8.0 Hz,

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1H), 6.48 (dd, J=8.0, 1.6 Hz, 1H), 4.36-4.26 (m, 1H), 4.22 (s, 2H), 2.77-2 .68 (m, 1H), 2.59 (dt, J=17.6, 4.0 Hz,

1H), 2.12-2.05 (m, 1H), 1.91 (cd, J=12.4, 4.8 Hz, 1H).

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2cyclopropylphenoxy)ethyl) piperazin-1-yl)-H-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

To a mixture of 4-(3-(3-cyclopropyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl )benzonitrile hydrochloride (0.100 g, 0.168 mmol, 1 eq.) and 2-chloro-I-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.060 g, 0.202 mmol, 1 eq. 2 eq.) in DMF (2 ml) was added DIPEA (0.109 g, 0.842 mmol, 5 eq.). The mixture was stirred at 50°C for 10 hours. The mixture was filtered and the filtrate was purified by standard methods to give 2-(4-(2-(4-(3-(4-cyano3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2cyclopropylphenoxy)ethyl)piperazin-1-yl)-H-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride ( 0.079 g, 0.095 mmol, yield 56.5%). MS (ESI) m/z 817.2 [M+1]+.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm. 10.80 (s, 1H), 10.38 (us s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H) , 8.06 (dd, J=1.6, 8.2 Hz, 1H), 7.19-7.11 (m, 2H), 7.07-7.00 (m, 1H), 6.97 (s, 1H), 6.86 (ush s, 2H), 6.46 (ush d, J=8.0 Hz, 1H), 4.53 (ush s, 2H), 4.25 (ush d dd , J=4.8, 11.2 Hz, 1H), 4.09 (br s, 4H), 3.83 (br s, 8H), 2.79-2.68 (m, 1H), 2.64- 2.51 (m, 2H), 2.29-2.17 (m, 1H), 2.10 (td, J=4.4, 8.5 Hz, 1H), 1.91 (dk, J= 4.8, 12.4 Hz, 1H), 1.47 (s, 6H), 1.00-0.88 (m, 2H), 0.66-0.54 (m, 2H).

Example 14: 2-(4-(2-(4-(3 -(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy )ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride

2-(4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl) piperazin-1-yl)-H-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

To a mixture of 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl )benzonitrile hydrochloride (0.150 g, 0.258 mmol, 1 eq.) and 2-chloro-I-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.091 g, 0.309 mmol, 1 eq. 2 eq.) in DMF (2 mL) (prepared as described herein), DIPEA (0.167 g, 1.29 mmol, 5 eq.) was added. The mixture was stirred at 50°C for 10 hours, then filtered. The filtrate was purified by standard methods to obtain 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-ethylphenoxy)ethyl)piperazin-1-yl)-X-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride (0.106 g, 0.131 mmol, 50.8% yield). MS (ESI) m/z805.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 10.80 (s, 1H), 10.48 (us s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=1.2 Hz, 1H) , 8.08 (d, J=8.4 Hz, 1H), 7.24-7.11 (m, 3H), 7.09-7.01 (m, 1H), 7.09-7.01 (m, 1H), 6.98 (s, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.47 (bd, J=7.6 Hz, 1H), 4, 52 (US s, 2H), 4.26 (US dd, J=4.8, 11.4 Hz, 1H), 4.16 (US s, 4H), 3.70 (US s, 8H), 2 ,80-2.66 (m, 3H), 2.66-2.52 (m, 2H), 2.10 (td, J=4.0, 8.8 Hz, 1H), 1.91 (dk , J=4.0, 12.0 Hz, 1H), 1.53-1.47 (m, 1H), 1.50 (s, 5H), 1.17 (t, J=7.6 Hz, 3H).

Example 15: (2R)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine- 1-yl)phenoxy)ethyl)piperazin-1-yl)-X-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)propanamide hydrochloride

2-(3-Chloro-4-hydroxyanilino)-2-methylpropanenitrile.

To a solution of 4-amino-2-chlorophenol (45 g, 0.31 mol) in DCM (450 ml) and acetone (225 ml) was added trimethylsilyltrifluoromethanesulfonate (3.48 g, 16 mmol) and trimethylsilylformonitrile (43.5 g, 440 mol) at 10°C. After addition, the reaction mixture was stirred at 25°C for 16 hours, then concentrated to a residue, which was purified by silica gel column chromatography (petroleum ether and EtOAc, 15:1 ~ 7:1), to give 2-(3-chloro- 4-hydroxy-anilino)-2-methylpropanenitrile (41.5 g, 62.8% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 9.52 (s, 1H), 6.89-6.84 (m, 2H), 6.76-6.73 (m, 1H), 5.52 (s, 1H),

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1.54 (s, 6H).

4-[3-(3-Chloro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2(trifluoromethyl)benzonitrile.

To a solution of 2-(3-chloro-4-hydroxyanilino)-2-methylpropanenitrile (14.6 g, 69 mmol) in DMA (150 ml) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (19, 0 g, 83 mmol) at 20°C. After stirring at 20°C for 2 hours, the reaction mixture was diluted with MeOH (150 ml) and aqueous HCl (2 M, 150 ml) at 20°C and stirred at 70°C for 5 hours. The reaction mixture was cooled to 10°C and filtered. The filter residue was washed with water (200 ml) and dried to give 4-[3-(3-chloro-4hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2 -(trifluoromethyl)benzonitrile (20.0 g, 65.6% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.72 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.07 (dd, J=1 .6 Hz, 8.0 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.15-7.10 (m, 2H), 1.49 (s, 6H).

tert-Butyl 4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy)ethyl )piperazine-1-carboxylate.

tert-Butyl 4-(2-chloroethyl)piperazine-1-carboxylate (0.424 g, 1.705 mmol, 1.5 eq.) was dissolved in DMF (8.42 ml, 0.135 mol). Cesium carbonate (0.556 g, 1.705 mmol, 1.5 eq) and 4-(3-(3-chloro-4hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 were added -(trifluoromethyl)benzonitrile (0.500 g, 1.137 mmol, 1 eq.) and the reaction mixture was heated to 60°C for 18 hours. The reaction was quenched with water, diluted with EtOAc, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-10% MeOH in DCM) and the pure fractions were combined and concentrated to give tert-butyl-4-(2-(2-chloro-4-(3-(4-cyano-3-( trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)phenoxy)ethyl)piperazine-1-carboxylate (0.792 g, 1.075 mmol, 95.0% yield) as a yellow oil. MS (ESI) m/z 652.2 [M] ⁺ .

4-(3-(3-Chloro-4-(2-(piperazin-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1 -yl)2-(trifluoromethyl) benzonitrile hydrochloride.

tert-Butyl 4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy)ethyl )piperazine-1-carboxylate (0.701 g, 1.075 mmol, 1 eq.) was suspended in DCM (4.75 mL, 0.226 M) and treated with a solution of HCl in dioxane (4.03 mL, 16.13 mmol, 15 eq.) . The reaction mixture was stirred at room temperature for 3 hours and then concentrated to give 4-(3-(3-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5- oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.633 g, 1.076 mmol, 100% yield) as a white solid. MS (ESI) m/z 552.2 [M] ⁺ .

(R)-Methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)phenoxy)ethyl)piperazin-1-yl)propanoate.

(S)-Methyl 2-chloropropanoate (0.044 mL, 0.408 mmol, 1.2 eq.) was added to the stirred mixture of 4(3-(3-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl) -4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile hydrochloride (0.200 g, 0.340 mmol, 1 eq.), THF (2.90 ml, 0.117 M) and TEA (0.189 ml, 1.359 mmol, 4 eq.). The reaction mixture was stirred for 60 hours at 80°C. The reaction mixture was concentrated and purified by silica gel column chromatography (20-40% EtOAc in hexanes) to give (R)-methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo2-thioxoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoate (0.105 g, 0.165 mmol, 48.4% yield) as a yellow solid substances. MS (ESI) m/z 638.2 [M] ⁺ .

(R)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )phenoxy)ethyl)piperazin-1-yl)propanoic acid.

(R)-Methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)phenoxy)ethyl)piperazin-1-yl)propanoate (0.105 g, 0.165 mmol, 1 eq.) was suspended in a 3:1 mixture of THF (1.592 ml) and water (0.531 ml) (0.078 mol), treated with lithium hydroxide ( 0.041 g, 1.715 mmol, 10.42 eq) and stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and water, and the pH was adjusted to ~3 with 6 M aqueous HCl. The aqueous layer was extracted with EtOAc and the extracts were dried over sodium sulfate, filtered and concentrated to give (R)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoic acid (0.120 g, 0.133 mmol, 81.0% yield) as a beige solid. MS (ESI) m/z 624.2 [M] ⁺ .

(2R)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )phenoxy)ethyl)piperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)propanamide hydrochloride.

(R)-2-(4-(2-(2-Chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )phenoxy)ethyl)piperazin-1-yl)propanoic acid (0.103 g, 0.165 mmol, 1 eq.) was combined with 3-((3-aminophenyl)amino)piperidine-2,6-dione trifluoroacetate salt (0.055 g, 0.165 mmol, 1 eq), HATU (0.069 g, 0.182 mmol, 1.1 eq), DIPEA (0.115 mL, 0.660 mmol, 4 eq), and DMF (0.825 mL, 0.2 mol). The reaction mixture was stirred at 25°C for 2 and quenched with water and diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and the residue was purified by standard methods to give (2R)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)propanamide hydrochloride (0.041 g , 0.049 mmol, yield

29.9%). MS (ESI) m/z 825.2 [M] ⁺ ;

1H NMR (400 MHz, DMSO-06) δ ppm 10.79 (s, 1H), 9.97 (s, 1H), 8.40 (d, J=8.31 Hz, 1H), 8.27 (d, J=1.71 Hz, 1H), 8.06 (dd, J=1.59, 8.31 Hz, 1H), 7.55 (t, J=1.16 Hz, 1H), 7.37 (d, J=0.98 Hz, 2H ), 6.99-7.05 (m, 2H), 6.84 (br.d, J=7.95 Hz, 1H), 6.43 (dd, J=1.28, 8.13 Hz, 1H), 4.51 (US s, 2H), 4.26 (US dd, J=4.71, 11.55 Hz, 1H), 3.40 (US s, 4H), 3.14-3, 34 (m, 8H), 2.74 (ush ddd, J=5.62, 11.98, 17.85 Hz, 1H), 2.55-2.63 (m, 1H), 2.082.13 (m , 1H), 1.90 (ush dk, J=4.65, 12.19 Hz, 1H), 1.51 (s, 6H), 1.35 (ush s, 3H).

Example 16: 2-((S)4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)- 2-ethylphenoxy)ethyl)-3-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3 yl)amino)phenyl)acetamide

tert-Butyl (S)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- ethylphenoxy)ethyl)-3-methylpiperazine-1-carboxylate.

4-(3-(4-(2-Bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.09 g, 0.167 mmol) (prepared as described herein), (3)tert-butyl 3-methylpiperazine-1-carboxylate (0.040 g, 0.200 mmol) and DIPEA (0.073 mL, 0.416 mmol) were combined in DMF (1.25 mL) and the mixture was heated to 70°C in a sealed vessel. After 16 h, the solution was concentrated under reduced pressure to obtain an orange residue. The residue was purified by column chromatography (0-90% EtOAc in hexanes) to give tert-butyl (S)-4-(2-(4-(3-(4Cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl 4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)3-methylpiperazine-1-carboxylate (0.084 g, 0.127 mmol, 69.0% yield). MS (ESI) m/z 660 [M+1] ⁺ .

(S)-4-(3-(3-Ethyl-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile dihydrochloride.

(S)-tert-butyl 4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- ethylphenoxy)ethyl)-3-methylpiperazine-1-carboxylate (0.084 g, 0.13 mmol) was dissolved in DCM (0.5 ml). A 4.0 M solution of HCl in dioxane (0.637 mL, 2.55 mmol) was added to the solution. The mixture was stirred at ambient temperature in a sealed vessel. After 45 min, the solution was concentrated under reduced pressure to give (S)-4-(3-(3-ethyl-4-(2-(2-methylpiperazin-1yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo -2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile dihydrochloride as a white solid (0.085 g, 0.13 mmol, 106% yield). MS (ESI) m/z 560 [M+1] ⁺ .

2-((S)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-3-methylniperazin-1-yl)-N-(3-((2,6-dioxopineridin-3yl)amino)phenyl)acetamide.

To a mixture of (S)-4-(3-(3-ethyl-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl )-2-(trifluoromethyl)benzonitrile dihydrochloride (0.086 g, 0.136 mmol) and 2chloro-H-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.040 g, 0.136 mmol) in DMF ( 0.340 ml) DIPEA (0.071 ml, 0.408 mmol) was added. The reaction solution was heated to 45°C. After 3 h, the solution was diluted with DMSO and purified by standard methods to give the title compound (0.073 g, 0.076 mmol, 56.0% yield). MS (ESI) m/z 819.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-a ₆ ) δ ppm 10.77 (s, 1H), 9.37 (s, 1H), 8.38 (d, J=8.19 Hz, 1H), 8.29 (s, 1H), 8.15 (s, 1H ), 8.07 (dd, J=8.25, 1.65 Hz, 1H), 7.08-7.18 (m, 3H), 6.96-7.03 (m, 2H), 6, 80 (br.d., J=7.95 Hz, 1H), 6.36-6.42 (m, 1H), 5.88 (d., J=7.82 Hz, 1H), 4.26 ( br.s, 1H), 4.12 (br.t, J=5.14 Hz, 2H), 3.33 (br.dd., J=2.45, 1.59 Hz, 4H), 3, 00-3.22 (m, 4H), 2.92 (br. d, J=11.62 Hz, 1H), 2.53-2.78 (m, 10 N), 2.25-2.46 ( m, 1H), 1.99-2.14 (m, 2H), 1.89 (td, J=12.07, 7.64 Hz, 1H), 1.49 (s, 6H), 1.24 (ush s, 2H), 1.16 (t, J=7.46 Hz, 3H), 1.06 (d, J=6.11 Hz, 3H), 0.95 (d, J=6.60 Hz, 1H), 0.80-0.90 (m, 2H).

Example 17: 2-((R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-2-methylpinerazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride

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(R)-tert-Butyl-4-(2-(2-bromo-4-nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

To a solution of 2-bromo-1-(2-bromoethoxy)-4-nitrobenzene (9.00 g, 27.70 mmol, 1 eq.) (prepared as described herein) and (R)-tert-butyl 2 -methylpiperazine-1-carboxylate (5.55 g, 27.70 mmol, 1 eq.) in DMF (70 ml) was added DIPEA (7.16 g, 55.39 mmol, 2 eq.). The reaction mixture was stirred at 60°C for 12 hours, then diluted with water (300 ml) and EtOAc (200 ml), and the layers were separated. The aqueous layer was extracted with EtOAc (10 ml). The combined organic extracts were washed with brine (100 mlx4), dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0-30% EtOAc in petroleum ether) to give (R)-tert-butyl-4-(2-(2-bromo-4nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate (10 .97 g, 24.69 mmol, 89.1% yield) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=2.8 Hz, 1H), 8.20 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=9.2 Hz, 1H ), 4.27-4.21 (m, 3H), 3.82 (d, J=13.2 Hz, 1H), 3.08 (td, J=12.4, 3.2 Hz, 1H) , 2.91-2.85 (m, 3H), 2.75 (d, J=11.2 Hz, 1H), 2.39 (dd, J=10.8, 3.6 Hz, 1H), 2.20 (td, J=12.0, 3.6 Hz, 1H), 1.46 (s, 9H), 1.22 (d, J=6.4Hz, 3H).

(R)-tert-Butyl-2-methyl-4-(2-(4-nitro-2-vinylphenoxy)ethyl)piperazine-1-carboxylate.

Mixture of (R)-tert-butyl-4-(2-(2-bromo-4-nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate (10.96 g, 24.67 mmol, 1 eq.), 4 ,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.60 g, 49.33 mmol, 2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium ( II) (0.90 g, 1.23 mmol, 0.05 eq.), potassium phosphate (15.71 g, 74.00 mmol, 3 eq.), dioxane (100 ml) and water (50 ml) were stirred at 90°C in a nitrogen atmosphere for 12 hours.

Brine (100 ml) was added to the mixture and the layers were separated. The aqueous layer was extracted with EtOAc (50 ml). The combined organic extracts were washed with brine (100 ml), dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give (R)-tert-butyl 2-methyl-4-(2-(4-nitro-2vinylphenoxy)ethyl)piperazine-1-carboxylate ( 9.62 g, 24.57 mmol, 99.6% yield) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.36 (d, J=2.8 Hz, 1H), 8.14 (dd, J=9.2, 2.8 Hz, 1H), 7.01-6.92 (m, 2H), 5 .91 (dd, J=17.6, 0.8 Hz, 1H), 5.43 (dd, J=11.2, 0.8 Hz, 1H), 4.23-4.20 (m, 3H ), 3.82 (d, J=13.2 Hz, 1H), 3.09 (td, J=12.8, 3.6 Hz, 1H), 2.85-2.81 (m, 3H) , 2.69 (d, J=11.2 Hz, 1H), 2.35 (dd, J=11.2, 4.0 Hz, 1H), 2.16 (td, J=11.6, 3 .6 Hz, 1H), 1.46 (s, 9H), 1.22 (d, J=6.8 Hz, 3H).

(R)-tert-Butyl-4-(2-(4-amino-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

A mixture of (R)-tert-butyl-2-methyl-4-(2-(4-nitro-2-vinylphenoxy)ethyl)piperazine-1-carboxylate (11.60 g, 29.63 mmol, 1 eq.), palladium on activated carbon (1.00 g, purity 10%) and MeOH (120 ml) were stirred at 30° C. under a hydrogen atmosphere (50 psi) for 12 hours. The suspension was filtered and the filtrate was concentrated. The crude product (R)-tert-butyl 4-(2-(4-amino-2-ethylphenoxy)ethyl)-2methylpiperazine-1-carboxylate (10.75 g, 29.57 mmol, 99.8% yield) was isolated in as a brown oil and used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 6.68 (d, J=8.4 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.4, 2.8 Hz, 1H ), 4.21-4.20 (m, 1H), 4.01 (t, J=5.6 Hz, 1H), 3.81 (d, J=13.2 Hz 1H), 3.10 (td, J=12.8, 3.2 Hz, 1H), 2.87 (d, J=11.2 Hz, 1H), 2.79-2.68 (m, 3H), 2.57 (k, J =7.6 Hz, 1H), 2.31 (dd, J=11.2, 3.6 Hz, 1H), 2.12 (td, J=12.0, 3.2 Hz, 1H), 1 .46 (s, 9H), 1.23 (s, 3H), 1.17 (t, J=7.6 Hz, 1H).

(R)-tert-Butyl-4-(2-(4-((2-cyanopron-2-yl)amino)-2-ethylphenoxy)ethyl)-2-methylpiperazine-1carboxylate.

Mixture of (R)-tert-butyl 4-(2-(4-amino-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (5.00 g, 13.76 mmol, 1 eq.), magnesium sulfate (4.140 g, 34.39 mmol, 2.5 eq.) and 2-hydroxy-2-methylpropanenitrile (13.98 g, 164.27 mmol, 15.00 ml, 11.94 eq.) were stirred at 60°C within 12 hours

Water (60 ml) and EtOAc (40 ml) were added to the mixture and the layers were separated. The aqueous layer was extracted with EtOAc (30 ml). The combined organic extracts were washed with brine (50 ml x 4), dried, filtered and concentrated. Crude product (R)-tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (5.92 g, crude), isolated as a yellow oil, was used in the next step without further purification. MS (ESI) m/z 431.3 [M+1]+.

(R)-4-(3-(3-Ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile.

Mixture of (R)-tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)-2-ethylphenoxy)ethyl)-2-methylpiperazine 1-carboxylate (5.92 g, 13.75 mmol, 1 eq.), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (3.14 g, 13.75 mmol, 1 eq.) and DMF (50 ml) were stirred at 20°C for 1 h.

A solution of HCl in MeOH (4 M, 17.19 mL, 5 eq.) was added to the mixture and the reaction mixture was stirred at 80° C. for 1 hour. The solvent was removed under reduced pressure. The remaining solution was purified

- 86 044376 semipreparative reverse-phase HPLC (10-45% acetonitrile in water + 0.05% HCl, 29 min). The collected fractions were concentrated to remove most of the organic volatiles. Sodium bicarbonate was added to the aqueous solution to adjust the pH to 8. The aqueous layer was extracted with EtOAc (200 mlx2). The combined organic extracts were washed with brine (200 ml), dried, filtered and concentrated to give (R)-4-(3-(3-ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)- 4,4dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.71 g, 6.560 mmol, 47.7% yield) as a light yellow solid. MS (ESI) m/z 560.1 [M+1] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.99-7.96 (m, 2H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.09-7.05 (m, 2H), 6.93 ( d, J=8.4 Hz, 1H), 4.16 (t, J=5.6 Hz, 2H), 3.07-3.03 (m, 1H), 2.98-2.90 (m , 3H), 2.87 (t, J=5.6 Hz, 2H), 2.68 (k, J=7.6 Hz, 1H), 2.32-2.28 (m, 1H), 1.96 (t, J=10.8 Hz, 1H), 1.57 (s, 6H), 1.22 (t, J=7.6 Hz, 3H), 1.12 (d, J=6.4 Hz , 3H).

2-((R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

Mixture of (R)-4-(3-(3-ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl) -2-(trifluoromethyl)benzonitrile (3.50 g, 6.25 mmol, 1 eq.), 2-chloro-H-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide (2, 07 g, 7.00 mmol, 1.12 eq.), DIPEA (2.02 g, 15.63 mmol, 2.72 ml, 2.5 eq.) and DMF (15 ml) were stirred at 60°C in for 8 hours. The solution was filtered and the filtrate was purified by standard methods to give 2-((R)-(4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl -4-oxo)-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl) acetamide hydrochloride (2.61 g, 3.03 mmol, 48.5% yield). MS (ESI) m/z 819.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 10.78 (s, 1H), 10.37 (ush, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.29 (d, J=1.6 Hz, 1H), 8.08-8.06 (m, 1H), 7.22-7.13 (m, 3H), 7.05-7.00 (m, 2H), 6.86 (d, J=7.6 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 4.50 (ush, 2H), 4.27 (dd, J=11.2, 5.6 Hz, 1H), 4.14-3.84 (m, 5H), 3.49-3.20 (m, 6H), 2.75-2.57 (m, 4H), 2.12-2.06 (m, 1H ), 1.90 (cd, J=12.4, 4.8 Hz, 1H), 1.49 (s, 6H), 1.32 (ush, 3H), 1.17 (t, J=7, 2 Hz, 3H).

Example 18: 2-((S)4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2otylphenoxy)ethyl)-2-methylpiperazin-1-yl)-H-(3-((2,6-dioxopiperidin-3yl) amino)phenyl)acetamide

tert-Butyl (S)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

4-(3-(4-(2-Bomethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.100 g, 0.185 mmol) , (S)-tert-butyl 2-methylpiperazine-1-carboxylate (0.044 g, 0.222 mmol) and DIPEA (0.081 ml, 0.463 mmol) were combined in DMF (1.5 ml) and the mixture was heated to 70°C under scintillation container with a screw cap. After 16 h, the solution was concentrated under reduced pressure to obtain an orange residue. The residue was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give the title compound (0.087 g, 0.132 mmol, 71% yield). MS (ESI) m/z 660[M+1] ⁺ .

(8)-4-(3-(3-Ethyl-4-(2-(3-ethylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile dihydrochloride.

(3)-tert-butyl 4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (0.087 g, 0.132 mmol) was dissolved in DCM (0.5 ml). A 4.0 M solution of HCl in dioxane (0.659 mL, 2.64 mmol) was added to the solution. The mixture was stirred at ambient temperature in a scintillation vessel with a screw cap. After 45 min, the solution was concentrated under reduced pressure to give the title compound (0.085 g, 0.134 mmol, 102% yield). MS (ESI) m/z 560 [M+1] ⁺ .

2-((8)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide.

Into a 1 dram bottle containing (S)-4-(3-(3-ethyl-4-(2-(3-methylpiperazin-1yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile dihydrochloride (0.085 g, 0.134 mmol) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.040 g, 0.134 mmol) DMF (0.336 mL) was added followed by DIPEA (0.070 mL, 0.403 mmol). The reaction solution was heated to 45°C, then, after 45 minutes, to 60°C. After 16 h, the solution was diluted with DMSO and purified by standard methods to give the title compound (0.084 g, 0.088 mmol, 65.0% yield). MS (ESI) m/z 819.2 [M+1] ⁺ .

- 87 044376

1H NMR (400 MHz, DMSOC) δ ppm 10.77 (s, 1H), 9.36 (s, 1H), 8.38 (d, J=8.19 Hz, 1H), 8.27-8.31 (m, 1H), 8.16 (s, 1H), 8.07 (d, J=7.74 Hz, 1H), 7.06-7.20 (m, 3H), 6.97-7.03 (m, 2H), 6, 80 (d, J=8.31 Hz, 1H), 6.39 (d, J=8.52 Hz, 1H), 5.88 (d, J=7.70 Hz, 1H), 4.27 (ush s, 1H), 4.16 (ush t, J=5.26 Hz, 2H), 3.16-3.30 (m, 2H), 3.00 (ush d, J=16.02 Hz , 2H), 2.67-2.88 (m, 6 N), 2.53-2.66 (m, 5 N), 2.27-2.46 (m, 1H), 1.99-2 .19 (m, 2H), 1.90 (ush s, 1H), 1.49 (s, 6 H), 1.24 (ush s, 1H), 1.16 (t, J=7.46 Hz , 3H), 0.93-1.06 (m, 3H), 0.85 (ush d, J=10.76 Hz, 1H); MS(ESI) m/z 819 [M+1]+.

Example 19: 2-((R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-3-(hydroxymethyl)piperazin-1-yl)-N-(3-((2,6dioxopiperidin-3 -yl)amino)phenyl)acetamide formate

tert-Butyl (R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- ethylphenoxy)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate.

4-(3-(4-(2-Bomethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.095 g, 0.176 mmol) ,(R)-tert-butyl (hydroxymethyl)piperazine-1carboxylate (0.046 g, 0.211 mmol) and DIPEA (0.077 ml, 0.439 mmol) were combined in DMF (1.25 ml) and the mixture was heated to 70°C in a scintillation vessel with screw cap. After 16 hours, the solution was concentrated under reduced pressure to give a yellow oil. The oil was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give the title compound (0.063 g, 0.093 mmol, 53.0% yield). MS (ESI) m/z 676[M+1] ⁺ .

(R)-4-(3-(3-Ethyl-4-(2-(2-(hydroxymethyl)piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrile dihydrochloride.

(R)-tert-butyl 4-(2-(4-(3-(4-Cyano-3 -(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- ethylphenoxy)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (0.063 g, 0.093 mmol) was dissolved in DCM (0.5 mL) and a 4.0 M solution of HCl in dioxane (0.466 mL, 1.865 mmol) was added to the solution. . The solution was stirred at ambient temperature. After 90 min, the solution was concentrated under reduced pressure to give the title compound as the hydrochloride salt (0.065 g, 0.095 mmol, quantitative yield). MS (ESI) m/z 576 [M+1] ⁺ .

2-((R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-3-(hydroxymethyl)piperazin-1-yl)-X-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide formate.

(R)-4-(3-(3-Ethyl-4-(2-(2-(hydroxymethyl)piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrile dihydrochloride (0.068 g, 0.105 mmol) and DIPEA (0.092 mL, 0.524 mmol) were combined in DMF (0.262 mL). 2-Chloro-Al3((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.031 g, 0.105 mmol) was then added to the solution and the mixture was heated to 45°C in a screw cap scintillation vial. After 3 h, the solution was diluted with DMSO (1 mL) and purified by standard methods to give the title compound (0.033 g, 0.034 mmol, 32.3% yield). MS (ESI) m/z 835.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 9.36 (s, 1H), 8.38 (d, J=8.19 Hz, 1H), 8.29 (d, J=1.71 Hz, 1H), 8.07 (dd, J=8.25, 1.65 Hz, 1H), 7.07-7.17 (m, 3H), 6.96-7.03 (m, 2H), 6.81 ( d, J=7.95 Hz, 1H), 6.39 (dd, J=8.13, 1.53 Hz, 1H), 5.87 (d, J=7.82 Hz, 1H), 4.43- 4.63 (t, 1H), 4.20-4.30 (t, 1H), 4.12 (ush t, J=5.38 Hz, 2H), 3.68 (ush dd, J=10.64, 3.91 Hz, 1H), 3.39-3.54 (m, 2H), 3.11-3.26 (m, 2H), 3.06 (s, 2H), 2.94 (us dd, J=11.19, 4, 10 Hz, 1H), 2.56-2.84 (m, 9 N), 2.30-2.47 (m, 2H), 2.21 (ut, J=9.41 Hz, 1H), 2.02-2.15 (m, 1H), 1.88 (ush dd, J=12.29, 4.34 Hz, 1H), 1.49 (s, 6 N), 1.24 (ush s , 1H), 1.16 (t, J=7.52 Hz, 3H), 0.95 (d, J=6.60 Hz, 1H), 0.810.89 (m, 1H).

Example 20: 2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-isopropylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride

2-((3-Bromo-4-hydroxyphenyl)amino)-2-methylpropanenitrile.

To a solution of 4-amino-2-bromophenol (5.00 g, 26.6 mmol) in DCM (177 ml) and acetone (89 ml) was added trimethylsilyl cyanide (4.66 ml, 37.2 mmol) and trimethylsilyl trifluoromethylsulfonate (0.241 ml , 1.33 mmol). The reaction mixture was stirred at room temperature for 1 h and concentrated

- 88 044376 for solvent removal. The crude material was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give 2-((3-bromo-4-hydroxyphenyl)amino)-2-methylpropanenitrile (4.56 g, 17.9 mmol, yield 67, 2%) as a brown solid. MS (ESI) m/z 256.2 [M+1]+.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.55-9.66 (m, 1H), 7.05 (d, J=2.69 Hz, 1H), 6.83-6.87 (m, 1H), 6.776.81 (m, 1H) , 5.51 (s, 1H), 1.55 (s, 6H).

5-(3-(3-Bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

2-((3-Bromo-4-hydroxyphenyl)amino)-2-methylpropanenitrile (1 g, 3.92 mmol) and 5-isothiocyanato-3(trifluoromethyl)picolinonitrile (0.898 g, 3.92 mmol) were combined in DMA ( 13.07 ml) and stirred at room temperature overnight. MeOH (5 ml) and 3.0 N aqueous HCl were added and the reaction mixture was heated at 70°C for 4 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give 5-(3-(3-bromo-4-hydroxyphenyl)-4,4dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)- 3-(trifluoromethyl)picolinonitrile (1.2 g, 2.40 mmol, 61.4% yield) as a white solid. MS (ESI) m/z 484.0 [M+1] ⁺ .

tert-Butyl 4-(2-(2-bromo-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )phenoxy)ethyl)piperazine-1-carboxylate.

5-(3-(3-Bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile (1.20 g, 2.47 mmol) , tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (0.725 g, 2.47 mmol), sodium iodide (0.371 g, 2.47 mmol) and cesium carbonate (1.611 g, 4.95 mmol) were combined in DMF (12.36 ml) and heated at 50°C for 3 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine (3x) and the combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The crude material was purified by silica gel column chromatography (0-15% MeOH in DCM) to give tert-butyl 4-(2-(2-bromo 4-(3(6-cyano-5-(trifluoromethyl)pyridin-3-yl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)phenoxy)ethyl)piperazine-1-carboxylate (1.31 g, 1.60 mmol, 64.6% yield) as a yellow powder. MS (ESI) m/z 697.8 [M+1] ⁺ .

tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- isopropylphenoxy)ethyl)piperazine-1-carboxylate.

A mixture of tert-butyl 4-(2-(2-bromo-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1- yl)phenoxy)ethyl)piperazine-1-carboxylate (0.250 g, 0.358 mmol), [(2dicyclohexylphosphino-2',6'-bis(K,K-dimethylamino)-1,1'-biphenyl)-2-(2 '-amino-1,1'biphenyl)]palladium(P) methanesulfonate (0.088 g, 0.108 mmol) and 2-(2-dicyclohexylphosphanylphenyl)K ¹ ,K ¹ ,Ni,Ni-tetramethyl-benzene-1,3-diamine (0.047 g, 0.108 mmol) was purged with nitrogen, suspended in toluene (1.434 ml) and purged with argon. The reaction mixture was cooled in an ice bath for 10 min, after which a solution of isopropylzinc(II) bromide in THF (1.075 mL, 0.538 mmol) was added dropwise. The reaction solution was stirred at 0°C for 20 min, then warmed to room temperature. After 2 hours, an additional 1.5 equiv was added. isopropylzinc bromide and the reaction mixture was stirred at room temperature, resulting in complete conversion after 5 hours. 1.0 M aqueous HCl (1 ml) was added, followed by EtOAc (60 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (2x50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated to give a dark amber oil, which was purified by silica gel column chromatography (0.7-1.5% MeOH in DCM with 0.2% triethylamine) to give tert-butyl-4-(2 -(4(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2isopropylphenoxy)ethyl)piperazine-1- carboxylate (0.190 g, 0.224 mmol, 62.6% yield), contaminated with some ligand oxidized 2-(2-dicyclohexylphosphanylphenyl)-K ¹ , K ¹ , K ³ , K ³ tetramethyl-benzene-1,3-diamine. MS (ESI) m/z 661.2 [M+1] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.14-9.04 (m, 1H), 8.37 (s, 1H), 7.09-7.04 (m, 2H), 6.88-6.79 (m, 1H), 4. 19-4.15 (m, 2H), 3.49-3.44 (m, 4H), 3.38-3.28 (m, 1H), 2.89 (t, J=5.6 Hz, 2H), 2.57 (s, 4H), 1.59 (s, 6H), 1.47 (s, 9H), 1.24 (d, J=7.0 Hz, 6H).

5-(3-(3-Isopropyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin1-yl)-3-(trifluoromethyl)picolinonitrile .

To a solution of tert-butyl-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-isopropylphenoxy)ethyl)piperazine-1-carboxylate (0.12 g, 0.18 mmol) in DCM (0.908 ml) was added TFA (0.420 ml, 5.45 mmol). After stirring at room temperature for 90 min, the reaction mixture was diluted with EtOAc (50 ml) and the organic layer was washed with saturated aqueous sodium bicarbonate (2x50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated to give 5-(3-(3-isopropyl-4-(2-(piperazin-1yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1 -yl)-3-(trifluoromethyl)picolinonitrile (0.094 g, 0.17 mmol, 92.0% yield) as a yellow oil. The material was further used without additional purification. MS (ESI) m/z 561.2 [M+1]+.

2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- nsopropylphenoxy)ethyl)piperazin-1-yl)-X-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

Mixture of 5-(3-(3-isopropyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-3-(trifluoromethyl) picolinonitrile (0.098 g, 0.175 mmol) and 2-chloro-I-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide (0.052 g, 0.175 mmol) in DMF (0.438 ml) were treated with DIPEA (0.122 ml, 0.700 mmol) and heated to 45°C. After 18 h, the reaction solution was diluted with DMSO to a total volume of 2 ml, filtered and purified by standard methods to give 2-(4-(2-(4-(3-(6cyano-5-(trifluoromethyl)pyridin-3-yl)-5 ,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2isopropylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl) acetαmide hydrochloride (0.057 g, 0.069 mmol, 40.0%). MS (ESI) m/z 820.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 10.37-10.18 (m, 1H), 9.26 (d, J=2.1 Hz, 1H), 8.83 (d, J=2.1 Hz , 1H), 7.24-7.14 (m, 3H), 7.08-7.02 (m, 1H), 7.00-6.96 (m, 1H), 6.88-6.82 (m, 1H), 6.46 (dd, J=1.9, 8.1 Hz, 1H), 4.55-4.45 (m, 3H), 4.31-4.22 (m, 3H ), 4.06-3.55 (m, 10H), 3.40-3.31 (m, 1H), 2.79-2.60 (m, 2H), 2.162.03 (m, 1H), 1.99-1.84 (m, 1H), 1.52 (s, 6H), 1.20 (d, J=6.8 Hz, 6H).

Example 21: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-(4-(3-(6-cyano-5( trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(2fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetamide hydrochloride

2-(2-(Benzyloxy)-5-nitrophenyl)ethan-1-ol.

1-(Benzyloxy)-4-nitro-2-vinylbenzene (3.12 g, 12.22 mmol) was dissolved in THF (61.1 ml), placed under nitrogen and cooled to 0°C before adding 9-borobicyclo[ 3.3.1])nonane (26.9 ml, 13.44 mmol). After stirring at room temperature overnight, the reaction mixture was cooled to 0°C before adding NaOH (2.69 ml, 13.44 mmol) and hydrogen peroxide (1.37 ml, 13.44 mmol). The ice bath was being removed. After 1 hour, the reaction mixture was partitioned between EtOAc and 1.0 N aqueous HCl. The organic layer was washed with brine and the combined organic extracts were dried over magnesium sulfate, filtered and condensed. The crude material was purified by silica gel column chromatography (0-80% EtOAc in hexanes) to give 2-(2-(benzyloxy)-5nitrophenyl)ethan-1-ol (1.33 g, 4.87 mmol, yield 39.8 %). In the form of yellow oil. MS (ESI) m/z 274.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-Y6) δ ppm 8.10-8.16 (m, 2H) 7.47-7.52 (m, 2H) 7.40-7.45 (m, 2H) 7.33-7.39 (m, 1H) 7, 27 (d, J=8.93 Hz, 1H) 5.30 (s, 2H) 4.69 (t, J=5.26 Hz, 1H) 3.61-3.70 (m, 2H) 2, 84 (t, J=6.60 Hz, 2H).

1-(Benzyloxy)-2-(2-fluoroethyl)-4-nitrobenzene.

2-(2-(Benzyloxy)-5-nitrophenyl) EtOH (1.16 g, 4.24 mmol) was dissolved in DCM (21.22 ml), placed under nitrogen and cooled to 0°C before adding dropwise 1 .0 M solution of diethylaminosulfur trifluoride (DAST, 8.49 ml, 8.49 mmol) in DCM. After 30 min, the reaction mixture was poured into ice water, stirred for 2 min, and the phases were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (030% EtOAc in hexanes) to give 1-(benzyloxy)-2-(2-fluoroethyl)-4-nitrobenzene (0.560 g, 2.03 mmol, 47.9% yield) as white solid.

1H NMR (400 MHz, CDCl3) δ ppm 8.11-8.19 (m, 2H) 7.36-7.46 (m, 5 N) 6.96-7.02 (m, 1H) 5.20 (s, 2H) 4.58-4 .75 (m, 2H) 3.06-3.21 (m, 2H).

4-Amino-2-(2-fluoroethyl)phenol.

1-(Benzyloxy)-2-(2-fluoroethyl)-4-nitrobenzene (0.560 g, 2.04 mmol) was dissolved in MeOH (20.3 ml), treated with a catalytic amount of 10% Pd/C. The reaction vessel was sealed and purged with hydrogen. The hydrogen atmosphere was maintained using a balloon during the reaction. After 2 hours, the reaction mixture was degassed with nitrogen and the catalyst was removed by filtration through a celite pad. The filtrate was concentrated under reduced pressure to give 4-amino-2-(2-fluoroethyl)phenol (0.316 g, 2.04 mmol, 100% yield) as a light purple solid. MS (ESI) m/z 156.2 [M+1] ⁺ .

2-((3-(2-Fluoroethyl)-4-hydroxyphenyl)amino)-2-methylpropanenitrile.

4-Amino-2-(2-fluoroethyl)phenol (0.316 g, 2.04 mmol) was dissolved in DCM (10.20 ml) and acetone (10.20 ml) and treated with trimethylsilyl cyanide (0.357 ml, 2.85 mmol) and trimethylsilyltrifluoromethylsulfonate (0.018 ml, 0.10 mmol). Stirring was continued for 1 hour at room temperature. The reaction mixture was concentrated to an oil under reduced pressure and the crude material was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give 2-((3(2-fluoroethyl)-4-hydroxyphenyl)amino)-2-methylpropanenitrile ( 0.209 g, 0.94 mmol, 46.2% yield) as a brown solid. MS (ESI) m/z 241.2 [M+1]+.

5-(3-(3-(2-Fluoroethyl)-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

2-((3-(2-Fluoroethyl)-4-hydroxyphenyl)amino)-2-methylpropanenitrile (0.209 g, 0.940 mmol) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (0.216 g, 0.94 mmol) were combined in DMA (3.13 ml) and stirred at room temperature. After 1 hour, a 3.0 N aqueous solution of HCl (0.628 ml, 1.88 mmol) and MeOH (0.6 ml) was added and the solution was heated to 70°C. After 2 hours, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with DCM and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give 5-(3-(3-(2-fluoroethyl)-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine -1-yl)-3(trifluoromethyl)picolinonitrile (0.193 g, 0.427 mmol, 45.3% yield) as an off-white solid. MS (ESI) m/z 453.2 [M+1] ⁺ .

tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- (2-fluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate.

5-(3-(3-(2-Fluoroethyl)-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile (0.180 g, 0.398 mmol) , tert-butyl 4-(2-bromoethyl)piperazine-1carboxylate (0.117 g, 0.398 mmol) and cesium carbonate (0.156 g, 0.477 mmol) were combined in DMF (2.65 ml) and heated at 70°C. After 90 min, an additional 0.1 equiv was used. tert-butyl 4-(2bromoethyl)piperazine-1-carboxylate. After 30 min, the reaction mixture was partitioned between EtOAc and brine. The organic layer was washed with brine and the combined organic extracts were dried over magnesium sulfate, filtered and condensed. The crude material was purified by silica gel column chromatography (0-10% EtOAc in hexanes) to give tert-butyl-4-(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5 ,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(2fluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.100 g, 0.150 mmol, 37.8% yield) as an off-white solid . MS (ESI) m/z 665.3 [M+1] ⁺ .

5-(3-(3-(2-Fluoroethyl)-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-3- (trifluoromethyl)picolinonitrile hydrochloride.

tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- (2-fluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.100 g, 0.150 mmol) was dissolved in DCM (3 ml) and treated with 4.0 M aqueous HCl (0.752 ml) in dioxane. After stirring at room temperature for 90 min, the solvents were evaporated to give 5-(3(3-(2-fluoroethyl)-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5 -oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile dihydrochloride (0.096 g, 0.151 mmol, 100% yield) as a white solid. MS (ESI) m/z 565.2 [M+1] ⁺ .

tert-Butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-(2-fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate.

Solution of 5-(3-(3-(2-fluoroethyl)-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-3 -(trifluoromethyl)picolinonitrile dihydrochloride (0.096 g, 0.151 mmol) in THF (1.5 ml) was treated with tert-butyl-2-bromoacetate (0.025 ml, 0.166 mmol) and DIPEA (0.105 ml, 0.602 mmol). After stirring at room temperature for 90 min, the reaction was partitioned between EtOAc and water. The organic layer was washed with brine and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give crude tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3- yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-(2-fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate (0.101 g, 0.149 mmol, 99.0% yield ) as an off-white solid. MS (ESI) m/z 679.3 [M+1] ⁺ .

2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- (2-fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid.

To a solution of tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1- yl)-2-(2-fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate (0.101 g, 0.149 mmol) in THF (0.992 ml) was added a 4.0 M solution of HCl in dioxane (0.744 ml, 2.98 mmol). After stirring at 50°C overnight, the solvents were removed under reduced pressure to obtain a colorless oil. Diethyl ether was added to form a white precipitate. After trituration, the solvents were removed and 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1- yl)-2-(2-fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid dihydrochloride (0.104 g, 0.150 mmol, 100% yield) was isolated as a colorless oil. MS (ESI) m/z 623.2 [M+1] ⁺ .

K-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridine -3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(2fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetamide hydrochloride.

- 91 044376

2-(4-(2-(4-(3 -(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- (2-fluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid dihydrochloride (0.050 g, 0.072 mmol), 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione hydrochloride (0.023 g, 0.079 mmol), HATU (0.041 g, 0.108 mmol) and DIPEA (0.046 g, 0.359 mmol) were combined in DMF (1 ml) and stirred at room temperature. After 90 min, the reaction mixture was diluted with DMSO (1 ml), filtered and purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3yl)amino)phenyl)-2-(4-(2 -(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)2-(2-fluoroethyl)phenoxy)ethyl )piperazin-1-yl)acetamide hydrochloride (0.020 g, 0.021 mmol, 29.9% yield). MS (ESI) m/z 858.6 [M+1]+.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm. 10.81 (s, 1H) 9.20-9.31 (m, 1H) 8.83 (d, J=1.96 Hz, 1H) 7.15-7.33 (m, 3H) 6.97 (s, 1H) 6.89 (us s, 1H) 6.48 (s, 1H) 4.54-4.78 (m, 4H) 4.26-4.39 (m, 2H) 3.65- 3.83 (m, 6 N) 3.423.53 (m, 4H) 3.00-3.15 (m, 3H) 2.62-2.82 (m, 2H) 2.02-2.14 (m , 1H) 1.84-1.96 (m, 1H) 1.52 (s, 6H).

Example 22: N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-((R)-4-(2-(4-(3-(6-cyano-5 (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)acetamide hydrochloride

(R)-tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)-2methylpiperazine-1-carboxylate.

To a solution of (R)-tert-butyl 4-(2-(4-amino-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (5.00 g, 13.76 mmol, 1.00 eq.) (prepared as described herein) and methyl 2-bromo-2methylpropanoate (5.04 g, 27.84 mmol, 3.6 mL, 2.02 eq.) was added DIPEA (17.81 g, 137.79 mmol , 24 ml, 10.02 eq.) per serving. The mixture was stirred at 127°C under nitrogen for 12 hours, then diluted with water (800 ml) and extracted with EtOAc (200 ml x 3). The combined organic layers were washed with brine (300 mlx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (10-25% EtOAc in petroleum ether). Compound (R)-tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate (6.40 g, 13.80 mmol, 50.2% yield) was obtained as a dark brown oil. MS (ESI) m/z 464.3 [M+1] ⁺ .

5-Isothiocyanato-3-(trifluoromethyl)picolinonitrile.

To a solution of 5-amino-3-(trifluoromethyl)picolinonitrile (10.00 g, 53.44 mmol, 1.00 eq.) in toluene (100 ml) was added thiophosgene (9.22 g, 80.16 mmol, 6 ml , 1.50 eq.) in one portion under nitrogen atmosphere. The mixture was stirred at 110°C for 2 hours, concentrated under reduced pressure at 60°C to obtain a residue, which was purified by silica gel column chromatography (0-5% EtOAc in petroleum ether). The compound 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (14.00 g, 61.09 mmol, 57.2% yield) was obtained as a colorless oil.

(R)-tert-butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

To a solution of (R)-tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)-2-methylpiperazine-1- carboxylate (8.00 g, 17.26 mmol, 1.00 eq.) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (7.91 g, 34.51 mmol, 2.00 eq.) in EtOAc (20 mL) add TEA (10.91 g, 107.77 mmol, 15 mL, 6.25 eq.) in one portion under nitrogen. The mixture was stirred at 80°C for 12 hours, diluted with water (800 ml) and extracted with EtOAc (300 mlx4). The combined organic extracts were washed with brine (300 mlx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel (15-20% EtOAc in petroleum ether). Compound (R)-tert-butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- 1-yl)-2ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (9.500 g, 12.39 mmol, 71.8% yield, 86.2% purity) was obtained as a dark brown oil. MS (ESI) m/z 661.3 [M+1] ⁺ .

(R)-5-(3-(3-Ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 3-(trifluoromethyl)picolinonitrile.

To a solution of (R)-tert-butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo2-thioxoimidazolidin-1 -yl)-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (9.50 g, 14.38 mmol, 1.00 eq.) in DCM (10 ml) was added in one portion with 4.0 M HCl solution in dioxane (95 ml, 26.43 eq.). The mixture was stirred at 20°C for 2 hours, then treated with saturated sodium bicarbonate (250 ml) and sodium bicarbonate solid added to adjust the pH to 7. The mixture was then extracted with DCM (50 ml x 5). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

- 92 044376 pressure to obtain a residue. The residue was purified by column chromatography on silica gel (0-10%

MeOH in DCM). Compound (R)-5-(3-(3-Ethyl-4-(2-(3-methylninerasin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5oxo-2-thioxoimidazolidin-1-yl) -3-(trifluoromethyl)picolinonitrile (7.100 g, 11.70 mmol, 81.4% yield, 92.4% purity) was obtained as a dark red solid. MS (ESI) m/z 561.1 [M+1]+.

N-(3-Chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-((R)-4-(2-(4-(3-(6-cyano-5(trifluoromethyl) pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)acetamide.

To a solution of (R)-5-(3-(3-ethyl-4-(2-(3-methylninerasin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl )-3-(trifluoromethyl)picolinonitrile (3.00 g, 5.35 mmol, 1.00 eq.) and 2-χλορ-Ν(3-chloro-5-((2,6-dioxopiperidin-3-yl) amino)phenyl)acetamide (1.86 g, 5.62 mmol, 1.05 eq.) in DMF (30 ml) was added DIPEA (2.07 g, 16.05 mmol, 2.80 ml, 3.00 eq. .) one serving. The mixture was stirred at 50°C under a nitrogen atmosphere for 12 hours and then cooled to 20°C. Water (200 ml) was added to the mixture. The resulting suspension was filtered and the filter cake was dried under reduced pressure and purified by standard methods to give N-(3-chloro-5-(2,6-dioxoniperidin-3-ylamino)phenyl)-2-((R)-4( 2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)-2 -methylpiperazin-1-yl)acetamide hydrochloride (2.73 g, 3.05 mmol, 57.0% yield). MS (ESI) m/z 854.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-a ₆ ) δ ppm 10.80 (s, 1H), 10.42 (us s, 1H), 9.24 (d, J=1.6 Hz, 1H), 8.82 (d, J=1.7 Hz, 1H) , 7.23-7.19 (m, 1H), 7.18-7.13 (m, 2H), 6.98 (s, 1H), 6.89 (s, 1H), 6.49 (s , 1H), 4.50 (br s, 2H), 4.33 (dd, J=4.8, 11.5 Hz, 1H), 4.03 (br s, 10H), 2.80-2, 66 (m, 3H), 2.65-2.52 (m, 2H), 2.10-2.03 (m, 1H), 1.91 (dk, J=4.7, 12.5 Hz, 1H), 1.52 (s, 6H), 1.27 (br s, 3H), 1.17 (t, J=7.5 Hz, 3H).

Example 23: 2-((R)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin- 1-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-^(3-((2,6-dioxopiperidin-3yl)amino)-5-fluorophenyl)acetamide hydrochloride

5-Fluorobenzene-1, 3-diamine.

To a solution of 3-fluoro-5-nitroaniline (10.00 g, 64.06 mmol, 1 eq.) in MeOH (200 ml) was added Pd/C (10%, 1.00 g) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen atmosphere (50 psi) at 25°C for 12 hours, filtered and concentrated under reduced pressure to give 5-fluorobenzene-1,3-diamine (6.50 g, 51.53 mmol, yield 80.4%) in the form of a brown oil.

1H NMR (400 MHz, CDCl ₃ ) δ 5.59 (d, J=2.0 Hz, 1H), 5.53-5.50 (m, 2H), 4.96 (m, 4H).

3-(3-Amino-5-fluoroanilino)piperidine-2,6-dione.

To a solution of 5-fluorobenzene-1,3-diamine (0.10 g, 0.793 mmol, 1 eq.) in DMF (2 ml) was added 3-bromopiperidine-2,6-dione (0.137 g, 0.713 mmol, 0.9 eq. ). The mixture was stirred at 70°C for 3 hours, then poured into ice water (20 ml). The aqueous phase was extracted with EtOAc (20 mlx3). The combined organic extracts were washed with brine (20 mlx3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (50% EtOAc in petroleum ether) to give 3-(3-amino-5-fluoroanilino)piperidine-2,6-dione (0.067 g, 0.282 mmol, 35.6% yield) as a white solid. . MS (ESI) m/z 238.1 [M+1] ⁺ .

2-Χλορ-Ν-(3-((2,6-dioxopiperidin-3 -yl)amino)-5-fluorophenyl)acetamide.

To a solution of 3-((3-amino-5-fluorophenyl)amino)piperidine-2,6-dione (18.00 g, 75.88 mmol, 1 eq.) and 2-chloroacetic acid (7.17 g, 75.88 mmol, 1 eq.) HATU (57.70 g, 151.75 mmol, 2 eq.) and DIPEA (49.03 g, 379.4 mmol, 5 eq.) were added to DMF (200 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice water (500 ml). The aqueous phase was extracted with EtOAc (500 mlx3). The combined organic extracts were washed with brine (500 mlx3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (33-50% EtOAc in petroleum ether) to give 2-chloro-N-(3-((2,6-dioxopiperidin-3yl)amino)-5-fluorophenyl)acetamide (12.00 g , 38.25 mmol, yield 50.4%) as a white solid.

1H NMR (400 MHz, DMSO-de) δ ppm 10.81 (s, 1H), 10.20 (s, 1H), 6.77-6.66 (m, 2H), 6.33 (d, J=7.96 Hz, 1H), 6.29 -6.21 (m, 1H), 4.39-4.26 (m, 1H), 4.22 (s, 2H), 2.78 (d, J=5.36 Hz, 1H), 2, 65-2.55 (m, 1H), 2.18-2.04 (m, 1H), 1.97-1.82 (m, 1H).

2-((R)-4-(2-(4-(3-(6-Cyαno-5-(trifluoromethyl)niridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2otylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)-5-fluorophenyl)acetamide hydrochloride.

To a solution of (R)-5-(3-(3-ethyl-4-(2-(3-methylninerasin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2- 93 044376 thioxoimidazolidine DIPEA (2.07 g, 16.05 mmol, 2.80 ml, 3 eq.) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide (2.52 g, 5.62 mmol, 1.05 eq.). The mixture was stirred at 50°C for 12 hours, then purified by standard methods to obtain 2((R)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-ul )Amino)-5fluorophenyl)acetamide hydrochloride (1.53 g, 1.82 mmol, 34.0% yield). MS (ESI) m/z 838.2 [M+1]+.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 10.52 (s, 1H), 9.25 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 7.22-7.14 (m, 3H), 6.79-6.74 (m, 2H), 6.29 (d, J=12.4 Hz, 1H), 4.31 (d, J= 11.6 Hz, 4.8 Hz, 1H), 3.563.52 (m, PN), 2.74-2.60 (m, 6H), 2.07-2.06 (m, 1H), 1, 93-1.91 (m, 1H), 1.52 (s, 6H), 1.27 (s, 3H), 1.18 (d, J=7.2 Hz, 3H).

Example 24: 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-K-(3-((2,6dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide hydrochoride

2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3-yl)amino)-5fluorophenyl)acetamide hydrochloride.

To a solution of 5-(3-(4-(2-(3,3-Dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-3 -(trifluoromethyl)picolinonitrile hydrochloride (3.60 g, 5.89 mmol, 1.0 eq.) (prepared as described herein) and 2-chloro-K-(3-((2,6-dioxopiperidine- 3-yl)amino)5-fluorophenyl)acetamide (4.62 g, 14.73 mmol, 2.5 eq.), (prepared as described herein), in DMF (30 ml) was added DIPEA (3, 81 g, 29.45 mmol, 5.13 ml, 5.0 eq.) under nitrogen. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was diluted with water (150 ml) and extracted with EtOAc (200 ml x 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by standard methods to give 2-(4-(2-(4-(3-(6Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3-yl)amino) -5fluorophenyl)acetamide hydrochloride (2.63 g, 2.92 mmol, 49.5% yield). MS (ESI) m/z 852.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-b ₆ ) δ ppm. 10.79 (s, 1H), 10.67-9.66 (m, 1H), 9.24 (d, J=1.6 Hz, 1H), 8.82 (d, J=1.6 Hz , 1H), 7.31-7.04 (m, 3H), 6.89-6.63 (m, 2H), 6.27 (br.d, J=12.0 Hz, 1H), 4.48 (US s, 2H), 4.34-4.30 (US dd, J=4.8, 11.6 Hz, 1H), 4.01 (US s, 2H), 3.40-3.33 ( m, 7H), 2.82-2.54 (m, 5H), 2.14-2.03 (m, 1H), 1.90 (m, 1H), 1.52 (s, 6H), 1 .39 (ush s, 6H), 1.18 (t, J=7.6 Hz, 3H).

Example 25: 2-((K)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin- 1-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride

2-((R)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)niridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide.

Mixture of (C)-5-(3-(3-ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl) -3-(trifluoromethyl)picolinonitrile (3.00 g, 5.35 mmol, 1 eq.), 2-chloro-X-(3((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride ( 1.78 g, 5.35 mmol, 1 eq.), (prepared as described herein), DIPEA (1.73 g, 13.38 mmol, 2.33 mL, 2.5 eq.) and DMF (15 ml) was stirred at 60°C for 8 hours. The solution was filtered. The filtrate was purified by standard methods to obtain 2-((R)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo -2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride (2.97 g , 3.44 mmol, yield 64.3%). MS (ESI) m/z 820.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6) 5 ppm 10.80 (s, 1H), 10.66 (br, 1H), 9.24 (d, J=2.0 Hz, 1H), 8 .82 (d, J=2.0 Hz, 1H), 7.22-7.14 (m, 3H), 7.08-7.03 (m, 2H), 6.90 (d, J=8 .0 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 4.53 (ush,

- 94 044376

2H), 4.38-4.25 (m, 5H), 3.69-3.51 (m, 7H), 2.78-2.65 (m, 3H), 2.61-2.56 ( m, 1H), 2.11-2.07 (m, 1H), 1.91 (cd,

J=12.4, 4.8 Hz, 1H), 1.51 (s, 6H), 1.39 (d, J=5.2 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H).

Example 26: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(4-(3-(4- cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)acetamide hydrochloride

(R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)-2- ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

4-(3-(4-(2-bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile solution (3.50 g, 6.48 mmol, 1 eq.), (prepared as described herein), (R)-tert-butyl 2-methylpiperazine-1-carboxylate (1.43 g, 7.12 mmol, 1.1 eq. ) and DIPEA (2.51 g, 19.43 mmol, 3.38 ml, 3 eq.) in DMF (10 ml) were stirred at 60°C for 12 hours. The mixture was diluted with water (50 ml) and extracted with EtOAc ( 50 mlx2). The combined organic phases were washed with water (30 mlx3) and brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (10-16% EtOAc in petroleum ether) to give (R)tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (3.20 g, 4.85 mmol, 74.9% yield), which was prepared in as a white solid. MS (H3PI) m/z [M+1]+.

1H NMR (400 MHz, CDCl3) δ ppm 8.03-7.94 (m, 2H), 7.85 (dd, J=1.7, 8.2 Hz, 1H), 7.12-7.03 (m, 2H), 6.95 ( d, J=8.6 Hz, 1H), 4.24 (br s, 2H), 3.84 (br s, J=12.2 Hz, 1H), 3.12 (br s, 1H), 3 .01-2.71 (m, 4H), 2.68 (k, J=7.5 Hz, 2H), 2.49-2.09 (m, 2H), 1.58 (s, 6H), 1.52-1.42 (m, 9H), 1.27-1.18 (m, 6H).

(R)-4-(3-(3-Ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile.

To a solution of (R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (3.20 g, 4.85 mmol, 1 eq.) in DCM (10 ml) was added 4.0 M solution of HCl in dioxane (10 ml, 8. 25 eq.), and the resulting solution was stirred at 20°C for 2 hours. The mixture was concentrated to give (R)-4-(3-(3-ethyl-4-(2-(3methylpiperazin-1-yl)ethoxy) phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile hydrochloride (3.50 g, crude) as a white solid, which was used in the next step without purification. MS (ESI) m/z 560.2 [M+1]+.

N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(4-(3-(4-cyano-3 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)acetamide hydrochloride.

To a solution of (R)-4-(3-(3-ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl )-2-(trifluoromethyl)benzonitrile hydrochloride (3.50 g, 5.87 mmol, 1 eq.) and 2chloro-N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino) phenyl)acetamide (1.94 g, 5.87 mmol, 1 eq.) in DMF (20 ml) was added DIPEA (3.79 g, 29.36 mmol, 5.11 ml, 5 eq.) and the resulting solution stirred at 60°C for 12 hours. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (50 mlx2), and the combined organic phases were washed with water (30 mlx3) and brine (50 ml), dried over anhydrous sodium sulfate and concentrated . The residue was purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(4-(3- (4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)acetamide hydrochloride (2.16 g, 2.39 mmol, yield 40.7%). MS (ESI) m/z 853.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6+D2O) δ ppm 10.77 (s, 1H), 10.41 (us s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H) , 8.05 (dd, J=1.7, 8.3 Hz, 1H), 7.25-7.06 (m, 3H), 6.97 (t, J=1.6 Hz, 1H), 6.85 (s, 1H), 6.49 (t, J=1.8 Hz, 1H), 4.46 (ush s, 2H), 4.31 (dd, J=5.0, 11.7 Hz, 1H), 4.05 (br. d, J=15.9 Hz, 1H), 3.83 (br. d, J=15.8 Hz, 1H), 3.75-3.68 (m, 4H ), 3.59-3.42 (m, 4H), 3.32 (ush t, J=11.1 Hz, 1H), 2.79-2.55 (m, 4H), 2.12-2 .04 (m, 1H), 1.90 (dk, J=4.6, 12.3 Hz, 1H), 1.48 (s, 6H), 1.26 (ush d, J=6.0 Hz , 3H), 1.16 (t, J=7.5 Hz, 3H).

Example 27: 2-(4-(3 -(4-(3 -(4-cyano-3 -(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenyl )propyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)-5-fluorophenyl)acetamide hydrochloride

- 95 044376

4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenyl trifluoromethanesulfonate.

4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile solution (0.45 g, 1.04 mmol ) (prepared as described herein) in DCM (10.4 ml) was treated with DIPEA (0.91 ml, 5.19 mmol), then cooled to 0°C before adding trifluoromethanesulfonic anhydride (0.193 ml, 1.14 mmol ). After 2 hours, the reaction mixture was diluted with EtOAc (75 ml) and the organic layer was washed with saturated aqueous sodium bicarbonate (2x100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated to give an amber glassy oil, which was purified by silica gel column chromatography (15-30% EtOAc in hexanes) to give 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4- dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.45 g, 1.04 mmol) as a pale yellow solid. MS (ESI) m/z 566.0 [M+1]+.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.99 (d, J=8.3 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.83 (dd, J=2.1, 8.3 Hz, 1H ), 7.44 (d, J=8.7 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.23 (dd, J=2.6, 8.7 Hz , 1H), 2.82 (k, J=7.5 Hz, 2H), 1.61 (s, 6H), 1.31 (t, J=7.5 Hz, 3H).

4-(3-(3-Ethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl) -2-(trifluoromethyl)benzonitrile.

A mixture of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenyl trifluoromethanesulfonate (0.400 g, 0.707 mmol), [( 2-dicyclohexylphosphino-2',6'-bis(N,Ndimethylamino)-1,G-biphenyl)-2-(2'-amino-1,G-biphenyl)]palladium(P) methanesulfonate (0.077 g, 0.177 mmol ), and [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-diphenyl)-2-(2'-amino-1,1'diphenyl)]palladium(P ) methanesulfonate (0.143 g, 0.177 mmol) was suspended in toluene (2.021 ml), purged with argon and cooled to 0°C before adding 0.5 M solution of (3-((tetrahydro-2H-pyran-2yl)oxy)propyl)zinc (P) bromide in THF (2.122 ml, 1.061 mmol). After 1.5 h, 0.5 equivalents of 3((tetrahydro-2H-pyran-2-yl)oxy)propyl)zinc(II) bromide in THF (0.353 mmol, 0.707 ml) was added and the reaction was warmed to room temperature for 3 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (1 ml), then diluted with EtOAc (50 ml), and the organic layer was washed with saturated aqueous sodium bicarbonate (2x50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated to give a brown oil, which was purified by silica gel column chromatography (10-30% EtOAc in hexanes) to give 4-(3-(3-ethyl-4-(3((tetrahydro-2H- pyran-2-yl)oxy)propyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.36 g, 0.64 mmol, yield 91 .0%). MS (ESI) m/z 582.2 [M+Na] ⁺ .

1H NMR (400 MHz, CDCl3) δ ppm 8.01-7.95 (m, 2H), 7.85 (dd, J=2.0, 8.3 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7 ,11-7.02 (m, 2H), 4.62 (dd, J=2.7, 4.4 Hz, 1H), 3.94-3.80 (m, 2H), 3.57-3 .45 (m, 2H), 2.83-2.76 (m, 2H), 2.72 (k, J=7.7 Hz, 3H), 1.99-1.69 (m, 5H), 1.64-1.59 (m, 2H), 1.58 (s, 6H), 1.26 (t, J=7.5 Hz, 3H).

4-(3-(3-Ethyl-4-(3-hydroxypropyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

To a solution of 4-(3-(3-ethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)phenyl)-4,4-dimethyl-5-oxo2-thioxoimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrile (0.400 g, 0.715 mmol) in DCM (3.57 ml) and EtOH (3.57 ml) was added p-toluenesulfonic acid (0.014 g, 0.071 mmol). The reaction solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 ml) and the organic layer was washed with saturated aqueous sodium bicarbonate (2x100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated to give a light yellow oil, which was used without further purification. MS (ESI) m/z 476.2 [M+1] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.02-7.93 (m, 2H), 7.85 (dd, J=2.0, 8.4 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7 ,11-7.03 (m, 2H), 3.76 (ush t, J=6.2 Hz, 2H), 2.82-2.67 (m, 4H), 1.96-1.85 ( m, 2H), 1.58 (s, 6H), 1.42 (br. d, J=1.3 Hz, 1H), 1.26 (t, J=7.6 Hz, 3H).

tert-Butyl 4-(3 -(4-(3 -(4-cyano-3 -(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenyl)propyl) piperazine-1-carboxylate.

A solution of 4-(3-(3- ethyl 4-(3-hydroxypropyl)phenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.180 g, 0.379 mmol) in DCM (3.79 ml) . After 1 hour at 0°C, sodium triacetoxyborohydride (0.241 g, 1.136 mmol) was added, followed by a solution of tert-butylpiperazine-1-carboxylate (0.210 g, 0.326 mmol) in MeOH (2 ml), and the reaction mixture was transferred

- 96 044376 stirred at room temperature. After 1 hour, the reaction mixture was diluted with EtOAc (50 ml) and the organic layer was washed with saturated aqueous sodium bicarbonate (2x50 ml) and brine (50 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (1-3% MeOH in DCM with 0.2% triethylamine) to give tert-butyl 4-(3-(4-(3 -(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenyl)propyl)piperazine-1-carboxylate (0.210 g, 0.326 mmol, yield 86.0%). MS (ESI) m/z 643.8 [M+1]+.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.00-7.92 (m, 2H), 7.88-7.80 (m, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.10-7.00 ( m, 2H), 3.49-3.39 (m, 4H), 2.75-2.65 (m, 4H), 2.50-2.37 (m, 6H), 1.89-1, 78 (m, 2H), 1.58 (s, 6H), 1.46 (s, 9H), 1.25 (t, J=7.6 Hz, 3H).

4-(3-(3-Ethyl-4-(3-(piperazin-1-yl)propyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1yl)-2-(trifluoromethyl)benzonitrile hydrochloride

To a solution of tert-butyl 4-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenyl) propyl)piperazine-1-carboxylate (0.210 g, 0.326 mmol) in DCM (3.26 ml) was added TFA (0.754 ml, 9.79 mmol). The reaction solution was stirred at room temperature for 3 hours, then diluted with EtOAc (50 ml), and the organic layer was washed with saturated aqueous sodium bicarbonate (2x100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated to give 4-(3-(3-ethyl-4-(3-(piperazin-1yl)propyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1 -yl)-2-(trifluoromethyl)benzonitrile (0.167 g, 0.307 mmol, 94.0% yield) as an amber oil, which was used further without further purification. MS (ESI) m/z 544.0 [M+1] ⁺ .

2-(4-(3-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenyl)propyl) piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide hydrochloride.

To a mixture of 4-(3-(3-ethyl-4-(3-(piperazin-1-yl)propyl)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl )benzonitrile (0.080 g, 0.147 mmol) and 2-χλορ-N-(3-((2,6dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide (0.046 g, 0.147 mmol) in DMF (0.368 ml) DIPEA (0.129 mL, 0.736 mmol) was added. The reaction solution was stirred at 45°C for 18 hours, then diluted with DMSO to a total volume of 2 ml, filtered and purified by standard methods to give 2-(4-(3-(4-(3-(4-cyano-3-( trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)2-ethylphenyl)propyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3 -yl)amino)-5-fluorophenyl)acetamide hydrochloride (0.039 g, 0.047 mmol, 32.0%). MS (ESI) m/z 821.4 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 10.36-10.19 (m, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.09 (dd, J=1.9, 8.3 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.19 (s, 2H), 6.77 (dd, J=2.1, 11.0 Hz, 1H), 6.72 (s, 1H), 6.346.19 (m, 1H), 4.62-4.38 (m, 3H), 4.35-4.25 (m, 3H), 4.18 -3.62 (m, 6H), 3.48-3.12 (m, 6H), 2.71 (b.d., J=7.3 Hz, 4H), 2.64-2.54 (m, 1H), 2.14-2.00 (m, 3H), 1.91 (dk, J=4.8, 12.3 Hz, 1H), 1.51 (s, 5H), 1.21 (t , J=7.5 Hz, 3H).

Example 28: N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-((R)-4-(2-(4-(7-(4-cyano-3 (trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)acetamide hydrochloride

(R)-tert-butyl 4-(2-(4-((1-cyanocyclobutyl)amino)-2-ethylphenoxy)ethyl)-2-methylpiperazine-1carboxylate.

To a solution of (R)-tert-butyl 4-(2-(4-amino-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (6.00 g, 16.51 mmol, 1.00 eq.) , (prepared as described herein) and cyclobutanone (4.69 g, 66.91 mmol, 5 mL, 4.05 eq.) in DCM (60 mL) was added dropwise in one portion of trimethylsilyl cyanide (4.76 g, 47.96 mmol, 6 ml, 2.91 equiv.) at 0°C under nitrogen. The mixture was stirred at 20°C for 48 hours, then diluted with water (150 ml) and extracted with DCM (60 ml x 3). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (10-23% EtOAc in petroleum ether). Compound (R)-tert-butyl 4-(2-(4-((1cyanocyclobutyl)amino)-2-ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (5.70 g, 12.54 mmol, yield 76 .0%) was obtained as a light yellow oil. MS (ESI) m/z 443.4 [M+1] ⁺ .

(R)-4-(5-(3-Ethyl-4-(2-(3-methylniperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane-7 -yl)-2-(trifluoromethyl)benzonitrile.

Solution of (R)-tert-butyl 4-(2-(4-(( 1 -cyanocyclobutyl)amino)-2-ethylphenoxy)ethyl)-2methylpiperazine-1-carboxylate (2.50 g, 5.65 mmol, 1. 00 eq.) and 4-isothiocyanato-2(trifluoromethyl)benzonitrile (1.93 g, 8.47 mmol, 1.50 eq.) in DMF (20 ml) was stirred at 20°C in

- 97 044376 nitrogen atmosphere for 1 hour, then treated with a 4.0 M solution of HCl in MeOH (15.0 ml, 10.62 eq.) and MeOH (10 ml) at 70°C for 12 hours. The reaction mixture was diluted water (200 ml) and extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 mlx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to give (R)-4-(5-(3-ethyl-4-(2-(3methylpiperazin-1-yl)ethoxy)phenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2(trifluoromethyl)benzonitrile (2.75 g, 4.77 mmol, 84.4% yield), isolated as light yellow solid matter. MS (ESI) m/z 572.1 [M+1]+.

N-(3-Chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-((R)-4-(2-(4-(7-(4-cyano-3(trifluoromethyl) phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1-yl)acetamide hydrochloride.

To a solution of (R)-4-(5-(3-ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane -7-yl)-2-(trifluoromethyl)benzonitrile (0.100 g, 0.175 mmol, 1.00 eq.) and 2-χλορ-Ν(3-chloro-5-((2,6-dioxopiperidin-3-yl) amino)phenyl)acetamide (0.064 g, 0.192 mmol, 1.10 eq.) in DMF (3 ml) was added DIPEA (0.074 g, 0.574 mmol, 0.100 ml, 3.28 eq.) in one portion. The mixture was stirred at 50°C under nitrogen for 12 hours, then diluted with water (100 ml) and extracted with DCM (40 mlx4). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by standard methods to give N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)2-((R)-4-(2-(4-(7-(4-cyano -3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)acetamide hydrochloride (0.128 g , 0.142 mmol, yield 81.0%). MS (ESI) m/z 865.4 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 10.24 (ush s, 1H), 8.37 (d, J=8.3 Hz, 1H), 8.26-8.24 (m, 1H), 8, 05 (d, J=8.2 Hz, 1H), 7.27-7.23 (m, 1H), 7.22-7.16 (m, 2H), 6.97 (s, 1H), 6 .91 (ush s, 1H), 6.48 (s, 1H), 4.50 (ush s, 2H), 4.33 (ush dd, J=4.8, 11.7 Hz, 1H), 3 ,18 (ush s, 10H), 2.81-2.65 (m, 4H), 2.63-2.55 (m, 3H), 2.45-2.37 (m, 2H), 2, 11-2.03 (m, 1H), 2.00-1.87 (m, 2H), 1.58-1.47 (m, 1H), 1.27-1.16 (m, 6H).

Example 29: 2-((R)-4-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[ 3.4]octan-5-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl) amino) phenyl)acetamide hydrochloride

(R)-5-(5-(3-Ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane-7 -yl)-3-(trifluoromethyl)picolinonitrile.

Mixture of (R)-tert-butyl-4-(2-(4-(( 1 -cyanocyclobutyl)amino)-2-ethylphenoxy)ethyl)-2-methylpiperazine 1-carboxylate (3.00 g, 6.78 mmol, 1 eq.), intermediate prepared as described herein, and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (2.33 g, 10.17 mmol, 1.5 eq.) in DMF (15 ml) were stirred at 20°C under nitrogen for 2 hours, then treated with MeOH (5 ml) and 4.0 M aqueous HCl in MeOH (20 ml, 11.80 eq.). The reaction mixture was stirred at 70°C for 11 hours, then concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate, then diluted with water (50 ml) and extracted with EtOAc (40 mlx3). The combined organic extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether, then 0-20% MeOH in DCM). (R)-5-(5-(3-Ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octane7 -yl)-3-(trifluoromethyl)picolinonitrile (3.90 g, 6.69 mmol, 98.7% yield) was obtained as a white solid after concentration of the fractions. MS (ESI) m/z573.3 [M+1] ⁺ .

2-((R)-4-(2-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane -5-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

A mixture of (R)-5-(5 -(3 -ethyl-4-(2-(3 -methylpiperazin-1 -yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane- 7-yl)-3-(trifluoromethyl)picolinonitrile (0.070 g, 0.122 mmol, 1 eq.) and 2-χλορ-Ν(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.038 g, 0.128 mmol, 1.05 eq.) in DMF (2 ml) was treated with DIPEA (0.047 g, 0.367 mmol, 0.064 ml, 3 eq.) and stirred at 50°C for 8 hours. The reaction mixture was then filtered, the filtrate purified by standard methods to give 2((R)-4-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7 -diazaspiro[3.4]octan-5-yl)2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.076 g, 0.086 mmol, 70.6% yield). MS (ESI) m/z 832.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 10.79 (s, 1H), 10.26 (us s, 1H), 9.23 (d, J=1.8 Hz, 1H), 8.77 (d,

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J=1.8 Hz, 1H), 7.27-7.24 (m, 1H), 7.22-7.19 (m, 2H), 7.07-7.02 (m, 1H), 7 .00 (s, 1H), 6.86 (ush d, J=7.8 Hz, 1H),

6.46 (USD, J=8.3 Hz, 1H), 4.52 (USD, 2H), 4.27 (USD, J=4.9, 11.2 Hz, 1H), 3, 73 (ush s, 3H), 3.62 (ush s, 4H),

3.30 (br s, 1H), 2.79-2.73 (m, 1H), 2.71 (d, J=7.3 Hz, 2H), 2.68 (br s, 1H), 2 .65-2.56 (m, 3H), 2.55-2.52 (m,

2H), 2.46 (USD, J=9.9 Hz, 2H), 2.11 (USD, J=4.8, 12.8 Hz, 1H), 2.02-1.89 (m , 2H), 1.58-1.51 (m, 1H), 1.30 (ush s, 3H), 1.20 (t, J=7.5 Hz, 3H).

Example 30: N-(3 -chloro-5 -((2,6-dioxopiperidin-3 -yl)amino)phenyl)-2-(( 1 S,4S)-5-(2-(4-(3 - (6-cyano-5(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)2,5-diazabicyclo[2.2.1 ]heptan-2-yl)acetamide hydrochloride

(1S,4S)-tert-butyl 5-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.

To a solution of 5-(3-(4-(2-bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1 -yl)3-(trifluoromethyl)picolinonitrile (0.300 g, 0.554 mmol, 1 eq.) (prepared as described herein) in acetonitrile (5 ml) was added (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2carboxylate (0.110 g, 0.554 mmol , 1 eq.) and potassium carbonate (0.230 g, 1.660 mmol, 3 eq.). The reaction mixture was stirred at 80°C for 12 hours, then filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-4% MeOH in DCM) to give (1S,4S)-tert-butyl 5-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3 -yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.320 g, 0.486 mmol, yield 87.7%) as a brown oil. MS (ESI) m/z 659.4 [M+1]+.

5-(3-(4-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5- oxo-2thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.

A solution of (1S,4S)-tert-butyl 5-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo2-thioxoimidazolidin- 1-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.320 g, 0.486 mmol, 1 eq.) in dioxane (10 ml) was treated with 4.0 HCl solution in dioxane (20.0 ml, 165 eq.) and stirred at 20°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by semipreparative reverse phase HPLC (17-37% acetonitrile + 0.05% HCl in water, 9 min). The isolated fraction was concentrated to remove most of the acetonitrile, and the resulting suspension was lyophilized to give 5-(3-(4-(2-((lS,4S)-2,5diazabicyclo[2.2.1]heptan-2-yl)ethoxy)- 3-Ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)3-(trifluoromethyl)picolinonitrile dihydrochloride (0.227 g, 0.376 mmol, 77.4% yield), as a white solid. MS (IER) m/z=559.l [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.79-11.87 (m, 1H), 10.55-9.53 (m, 2H), 9.26 (d, J=1.8 Hz, 1H), 8.84 (d, J= 2.0 Hz, 1H), 7.26-7.13 (m, 3H), 4.73-4.44 (m, 4H), 3.93-3.66 (m, 4H), 3.39 (s, 2H), 2.67 (k, J=7.3 Hz, 2H), 2.38 (d, J=7.8 Hz, 1H), 2.16 (d, J=11.9 Hz , 1H), 1.53 (s, 6H), 1.19 (t, J=7.5 Hz, 3H).

N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((1S,4S)-5-(2-(4-(3-(6-cyano -5(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)2,5-diazabicyclo[2.2.1]heptan-2 -yl)acetamide hydrochloride.

To a solution of 2-chloro-N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.111 g, 0.336 mmol, 1 eq.) in DMF (2 ml) was added 5-(3-(4-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-3ethylphenyl)-4,4-dimethyl-5-oxo- 2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.200 g, 0.336 mmol, 1 eq., HCl) and DIPEA (0.130 g, 1.010 mmol, 175.62 µl, 3 eq.). The reaction mixture was stirred at 60°C for 12 hours. The reaction pH was then adjusted to pH 6 by adding formic acid (0.3 ml). The mixture was purified by standard methods to give N-(3-chloro-5-((2,6-dioxopineridin3-yl)amino)phenyl)-2-((1S,4S)-5-(2-(4-(3- (6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)acetamide hydrochloride (0.163 g, 0.173 mmol, 51.5% yield). MS (ESI) m/z 852.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-de) δ ppm 13.19-11.24 (m, 1H), 10.80 (s, 2H), 9.25 (d, J=1.8 Hz, 1H), 8.83 (d, J=1.8 Hz , 1H), 7.29-7.11 (m, 3H), 7.09-6.75 (m, 2H), 6.50 (s, 1H), 4.56 (s, 6H), 4, 32 (dd, J=4.9, 11.7 Hz, 1H), 4.21 (s, 2H), 3.83 (s, 4H), 3.39 (s, 2H), 2.82-2 .70 (m, 1H), 2.70-2.64 (m, 2H), 2.62-2.57 (m, 1H), 2.08 (td, J=4.0, 8.4 Hz , 1H), 1.91 (dk, J=4.7, 12.3 Hz, 1H), 1.52 (s, 6H), 1.19 (t, J=7.5 Hz, 3H).

Example 31: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((2R,5R)-4-(2-(4-(3-( 4-cyano3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,5dimethylpiperazin-1-yl)acetamide trifluoroacetate

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tert-Butyl (2R,5R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-ethylphenoxy)ethyl)-2,5-dimethylpiperazine-1-carboxylate.

4-(3-(4-(2-Bomethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.200 g, 0.370 mmol) (prepared as described herein), (2R,5R)-tert-butyl-2,5-dimethylpiperazine-1-carboxylate (0.095 g, 0.444 mmol) and DIPEA (0.162 mL, 0.925 mmol) were combined in DMF (1 .5 ml), and the mixture was heated to 70°C in a vessel with a screw cap. After 16 h, the solution was concentrated under reduced pressure to give an orange residue, which was purified by silica gel column chromatography (0-80% EtOAc in hexanes) to give the title compound (0.204 g, 0.299 mmol, 81.0% yield). MS (ESI) m/z 674 [M+1]+.

4-(3-(4-(2-((2R,5R)-2,5-Dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrile dihydrochloride.

(2R,5R)-tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-ethylphenoxy)ethyl)-2,5-dimethylpiperazine-1-carboxylate (0.204 g, 0.303 mmol) was dissolved in DCM (1.5 ml). A 4.0 M solution of HCl in dioxane (1.89 mL, 7.57 mmol) was added to the solution, and the mixture was stirred at ambient temperature. After 45 min, the solution was concentrated under reduced pressure to give the title compound (0.200 g, 0.309 mmol, quantitative yield). MS (ESI) m/z 574 [M+1] ⁺ .

N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((2R,5R)-4-(2-(4-(3-(4-cyano -3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,5dimethylpiperazin-1-yl)acetamide trifluoroacetate.

4-(3-(4-(2-((2R,5R)-2,5-Dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrile dihydrochloride (0.110 g, 0.170 mmol), 2-chloroN-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.067 g, 0.204 mmol), sodium iodide (0.026 g, 0.170 mmol) and DIPEA (0.149 ml, 0.851 mmol) were combined in DMF (0.5 ml) and the mixture was stirred at 60°C in a scintillation vial with a screw cap. After 2 h, the solution was diluted with DMSO (1 ml) and purified by standard methods to give N-(3-Chloro-5-((2,6-dioxopiperidin-3yl)αmino)phenyl)-2-((2R,5R)-4 -(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,5 -dimethylpiperazin-1-yl)acetamide trifluoroacetate (0.058 g, 0.060 mmol, 40.2% yield). MS (IER) m/z 867 [M] ⁺ 869 [M+2] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.78-10.82 (m, 1H), 9.80-10.09 (m, 1H), 9.53-9.74 (m, 1H), 8.39 (d, J=8.31 Hz, 1H), 8.29 (d, J=1.71 Hz, 1H), 8.07 (dd, J=8.31, 1.71 Hz, 1H), 7.12-7.24 (m , 3H), 6.95 (ush d, J=4.89 Hz, 1H), 6.89 (ush s, 1H), 6.47 (ush s, 1H), 6.12-6.42 (m , 1H), 4.40 (ush s, 2H), 4.32 (ush dd, J=11.43, 4.34 Hz, 2H), 3.26-3.42 (m, 3H), 3, 00-3.26 (m, 4H), 2.55-2.78 (m, 4H), 2.02-2.11 (m, 1H), 1.92 (us s, 1H), 1.50 (s, 8 N), 1.40 (ush s, 1H), 1.07-1.29 (m, 8 N), 0.95 (d, J=6.60 Hz, 1H), 0.81 -0.89 (m, 1H).

Example 32: 2-((2R,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide trifluoacetate

tert-Butyl (2R,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-ethylphenoxy)ethyl)-2,6-dimethylpiperazine-1-carboxylate.

4-(3-(4-(2-Bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.210 g, 0.389 mmol) (prepared as described herein), (2R,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (0.100 g, 0.466 mmol) and DIPEA (0.170 mL, 0.972 mmol) were combined in DMF (3 mL ), and the mixture was heated to 70°C in a vessel with a screw cap. After 90 min, the solution was condensed under reduced pressure to give an orange residue, which was purified by silica gel column chromatography (0-70% EtOAc in hexanes) to give the title compound (0.206 g, 0.306 mmol, 79.0% yield). MS (ESI) m/z 674 [M+1] ⁺ .

4-(3-(4-(2-((3R,5R)-3,5-Dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrile dihydrochloride.

(2R,6R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-ethylphenoxy)ethyl)-2,6-dimethylpiperazine-1-carboxylate (0.206 g, 0.306 mmol) was dissolved in DCM (1.5 ml). A 4.0 M solution of HCl in dioxane (1.91 mL, 7.64 mmol) was added to the solution, and the mixture was stirred at ambient temperature. After 45 minutes, the solution was concentrated under reduced pressure to give the title compound (0.210 g, 0.325 mmol, quantitative yield). MS (ESI) m/z 574 [M+1]+.

N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((2R,6R)-4-(2-(4-(3-(4-cyano -3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,6dimethylpiperazin-1-yl)acetamide trifluoroacetate.

4-(3-(4-(2-((3R,5R)-3,5-Dimethylπpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrile dihydrochloride (0.105 g, 0.162 mmol), 2-chlorochloro-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.053 g, 0.179 mmol), Sodium iodide (0.024 g, 0.162 mmol) and DIPEA (0.142 ml, 0.812 mmol) were combined in DMF (0.5 ml) and the mixture was stirred at 60°C in a screw cap vial. After 48 h, the solution was diluted with DMSO (1 ml) and purified by standard methods to give X-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2((2R,6R)- 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)2-ethylphenoxy)ethyl)-2 ,6-dimethylpiperazin-1-yl)acetamide trifluoroacetate (0.033 g, 0.035 mmol, 22.0% yield). MS (ESI) m/z 833 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.79 (s, 1H), 10.23-10.43 (m, 1H), 9.59-9.81 (m, 1H), 9.22-9.48 (m, 1H), 8. 39 (d, J=8.19 Hz, 1H), 8.29 (d, J=1.71 Hz, 1H), 8.07 (dd, J=8.13, 1.77 Hz, 1H), 7.11-7.22 (m, 3H), 6.897.11 (m, 2H), 6.39-6.49 (m, 1H), 4.07-4.29 (m, 4H), 3, 74-4.00 (m, 6N), 3.58-3.70 (m, 3H), 3.44-3.52 (m, 2H), 3.06-3.35 (m, 2H) , 2.83 (ush d, J=3.18 Hz, 2H), 2.57-2.79 (m, 5 N), 2.37-2.44 (m, 1H), 2.33 (dt , J=3.67, 1.83 Hz, 2H), 2.03-2.16 (m, 2H), 1.82-1.98 (m, 1H), 1.50 (s, 7 N) , 1.40 (s, 1H), 1.22-1.36 (m, 7 H), 1.17 (t, J=7.46 Hz, 4H), 0.98-1.09 (m, 2H), 0.81-0.88 (m, 3H), 0.01-0.01 (m, 1H), -0.03 - -0.01 (m, 2H).

Example 3 3: 2-(4-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane -5-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-K-(3-((2,6dioxopiperidin-3 -yl)amino)phenyl)acetamide hydrochloride

1-((3-Ethyl-4-hydroxyphenyl)amino)cyclobutanecarbonitrile.

Trimethylsilyl cyanide (0.607 g, 6.12 mmol, 0.766 mL, 1.2 eq.), and the solution was stirred at 20°C for 6 hours. Tetrabutylammonium fluoride (1.02 mL, 0.2 eq.) was added and the solution was stirred for 30 min. The reaction mixture was concentrated and diluted with EtOAc (200 ml), washed with brine (100 ml), dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to give 1-((3-ethyl-4-hydroxyphenyl)amino)cyclobutanecarbonitrile (0.778 g, 3.60 mmol, 70.4% yield) in as a brown solid. MS (ESI) m/z 217.1 [M+1] ⁺ .

5-(5-(3-ethyl-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3 (trifluoromethyl)picolinonitrile.

Thiophosgene (0.239 g, 2.08 mmol, 0.159 mL, 1 eq.) was added dropwise to a mixture of 1-(3-ethyl-4hydroxyanilino)cyclobutanecarbonitrile (0.450 g, 2.08 mmol, 1 eq.) and 5-amino- 3(trifluoromethyl)pyridine-2-carbonitrile (0.389 g, 2.08 mmol, 1 eq.) in DMA (18 ml). The mixture was stirred at 60°C for 12 hours, then MeOH (2.7 ml) and 2.0 M aqueous HCl (1.8 ml, 1.73 eq.) were added. After 2 h at 15°C, the reaction mixture was diluted with EtOAc (200 ml), washed with brine (100 ml x 3), dried, filtered and concentrated under reduced pressure. 5-(5-(3-Ethyl-4-hydroxyphenyl)-8oxo-6-thioxo-5,7-diazaspiro[3,4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (1.160 g, crude) was obtained as a brown solid and used in the next step without further purification. MS (ESI) m/z 447.0 [M+1] ⁺ .

5-(5-(4-(2-Bromoethoxy)-3-ethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3(trifluoromethyl)picolinonitrile.

To a solution of 5-(5-(3-ethyl-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-7-yl)-3 (trifluoromethyl)picolinonitrile (0.400 g , 0.896 mmol, 1 eq.) in acetonitrile (10 ml) was added potassium carbonate (0.371 g, 2.69 mmol, 3 eq.) and 1,2-dibromoethane (3.370 g, 17.92 mmol, 1.35 ml, 20 eq.). The mixture was stirred at 80°C for 12 hours, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (20-33% EtOAc in petroleum ether). Compound 5-(5-(4-(2bromoethoxy)-3-ethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3(trifluoromethyl)picolinonitrile (0.400 g, 0.723 mmol, 80.7% yield) was obtained as a yellow solid. MS (ESI) m/z 553.0 [M+1] ⁺ .

tert-Butyl 4-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-5-yl )-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate.

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To a solution of 5-(5-(4-(2-bromoethoxy)-3-ethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-7-yl)-3(trifluoromethyl) picolinonitrile (0.400 g, 0.723 mmol, 1 eq.) in DMF (8 ml) was added DIPEA (0.280 g, 2.17 mmol, 3 eq.) and tert-butyl-2,2-dimethylpiperazine-1-carboxylate (0.232 g , 1.08 mmol, 1.5 eq.). The mixture was stirred at 60°C for 12 hours. The mixture was purified by preparative HPLC (36-66% acetonitrile + 0.05% formic acid in water, 10 min). Compound tert-butyl 4-(2-(4-(7-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octane-5- yl)-2-ethylphenoxy)ethyl)-2,2dimethylpiperazine-1-carboxylate (0.400 g, 0.582 mmol, 80.6% yield) was obtained as a white solid. MS (ESI) m/z 687.3 [M+1] ⁺ .

5-(5-(4-(2-(3,3-Dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-7-yl) -3-(trifluoromethyl)picolinonitrile.

To a solution of tert-butyl 4-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane-5 -yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate (0.350 g, 0.509 mmol, 1 eq.) in EtOAc (3 ml) was added 4.0 M HCl in EtOAc (3.75 ml, 29.4 eq.). The mixture was stirred at 25°C for 12 hours, then concentrated under reduced pressure at 40°C. Compound 5-(5-(4-(2-(3,3-dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-7-yl )-3-(trifluoromethyl)picolinonitrile hydrochloride (0.300 g, 0.481 mmol, 94.4% yield) was obtained as a white solid. MS (ESI) m/z 587.2 [M+1] ⁺ .

2-(4-(2-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5yl )-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

To a solution of 5-(5-(4-(2-(3,3-dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane-7- yl)-3-(trifluoromethyl)picolinonitrile hydrochloride (0.300 g, 0.481 mmol, 1 eq.) in DMF (5 ml) was added DIPEA (0.311 g, 2.41 mmol, 5 eq.) and 2-chloro-N-( 3-((2,6-dioxonineridin3-yl)amino)phenyl)acetamide (0.157 g, 0.529 mmol, 1.1 eq.). The mixture was stirred at 50°C for 12 hours, then purified by standard methods to obtain 2-(4-(2-(4-(7-(6-cyano5(trifluoromethyl)pyridin-3-yl)-8-oxo-6 -thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-ethylphenoxy)ethyl)2,2-dimethylπpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide hydrochloride (0.120 g, 0.134 mmol, 27.8% yield). MS (ESI) m/z 846.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm. 10.81 (s, 1H), 10.27 (s, 1H), 9.22 (d, J=1.60 Hz, 1H), 8.77 (s, 1H), 7.26-7.19 (m, 3H), 7.05-7.01 (m, 2H), 6.87 (d, J=8.40 Hz, 1H), 6.47 (d, J=8.40 Hz, 1H) , 4.49 (s, 2H), 4.28 (dd, J=11.6 Hz, 4.8 Hz, 1H), 2.70-2.61 (m, 6H), 2.50-2, 49 (m, 10H), 2.48-2.46 (m, 2H), 2.11-2.08 (m, 1H), 1.96-1.88 (m, 2H), 1.53- 1.39 (m, 7H), 1.20 (t, J=7.60 Hz, 3H).

Example 34: 2-((2R,6S)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3 -yl)amino)phenyl)acetamide hydrochloride

(2R,6S)-tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-ethylphenoxy)ethyl)-2,6-dimethylpiperazine-1-carboxylate.

A mixture of cesium carbonate (0.395 g, 1.211 mmol), 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ( 0.350 g, 0.807 mmol) (prepared as described herein), and (2R,6S)-tert-butyl 4-(2-bromoethyl)-2,6-dimethylpiperazine-1-carboxylate (0.311 g, 0.969 mmol) in DMF (4.04 ml) was stirred at 60°C for 12 hours. The reaction mixture was diluted with EtOAc (75 ml) and the organic layer was washed with saturated aqueous sodium bicarbonate (2x100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated to give a brown oil, which was purified by column chromatography (20-40% EtOAc in hexanes) to give (2R,6S)-tert-butyl 4-(2-(4-(3-(4 -cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazine-1-carboxylate (0.366, 0.543 mmol, yield 67.3%). MS (ESI) m/z 674.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.00-7.94 (m, 2H), 7.89-7.78 (m, 1H), 7.12-7.04 (m, 2H), 6.95 (d, J=8.6 Hz, 1H), 4.17-4.08 (m, 4H), 2.82 (t, J=5.6 Hz, 2H), 2.76-2.64 (m, 4H), 2.32 (dd, J=4.5, 11.3 Hz, 2H), 1.58 (s, 6H), 1.47 (s, 9H), 1.29 (d, J=6.7 Hz, 6H) , 1.23 (t, J=7.5 Hz, 3H).

4-(3-(4-(2-((3R,5S)-3,5-Dimethylpiperazin-1-ul)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidine-1- yl)-2-(trifluoromethyl)benzonitrile.

Solution of (2R,6S)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-2,6-dimethylpiperazine-1-carboxylate (0.366 g, 0.543 mmol) in DCM (2.72 mL) was treated with TFA (1.255 mL, 16.30 mmol). The reaction solution was stirred at room temperature overnight, then diluted with EtOAc (75 ml), and the organic layer

- 102 044376 washed with saturated aqueous sodium bicarbonate solution (2x100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated to give 4-(3-(4-(2-((3R,5S)-3,5dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl- 5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile as a glassy solid, which was subsequently used without further purification. MS (ESI) m/z 574.2 [M+1]+.

2-((2R,6S)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-mioxoimidazolidin1-yl)- 2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

Mixture of 4-(3-(4-(2-((3R,5S)-3,5-dimethylniperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1 -yl)-2-(trifluoromethyl)benzonitrile (0.100 g, 0.174 mmol) and 2-chloro-K-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide (0.052 g, 0.174 mmol) in DMF (0.349 ml) was treated with DIPEA (0.122 ml, 0.697 mmol). The reaction solution was stirred at 45°C. After 16 hours, a 30% conversion was observed. Sodium iodide (0.013 g, 0.087 mmol) was added and the temperature was raised to 60°C. After 36 h, the reaction solution was diluted with DMSO to a total volume of 2 ml, filtered and purified by standard methods to give 2-((2R,6S)-4-(2-(4-(3-(4-Cyano-3-(mriformethyl) phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3 -yl)amino)phenyl)acetamide hydrochloride (0.012 g, 0.014 mmol, 8.0%). MS (IES) m/z 833.0 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.79 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.118.02 (m, 1H), 7.26-7.12 (m, 3H), 7.07-6.96 (m, 2H), 6.84-6.78 (m, 1H), 6.47-6.40 (m, 1H ), 4.49-4.38 (m, 2H), 4.30-4.24 (m, 1H), 3.54-3.49 (m, 9H), 2.73-2.62 (m , 3H), 2.13-2.05 (m, 1H), 1.97-1.85 (m, 1H), 1.50 (s, 6H), 1.24-1.10 (m, 9H ).

Example 35: N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-((R)-4-(2-(4-(3-(4-cyano-3 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(2,2difluoroethyl)phenoxy)ethyl)-2-methylpiperazin-1-yl)acetamide hydrochloride

2-(2-Bromoethoxy)-5-nitrobenzaldehyde.

A mixture of 2-hydroxy-5-nitrobenzaldehyde (10.00 g, 59.84 mmol, 1.00 eq.), 1,2-dibromoethane (112.41 g, 598.38 mmol, 45.15 ml, 10 eq. ), potassium carbonate (24.81 g, 179.51 mmol, 3 eq.) and 18-crown-6 (1.580 g, 5.980 mmol, 0.10 eq.) in acetonitrile (100 ml) were heated until condensation appeared 85° C for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain an oily residue, which was washed with petroleum ether (300 mlx2). The crude product was purified by silica gel column chromatography (0-15% EtOAc in petroleum ether) to give 2-(2-bromoethoxy)-5-nitrobenzaldehyde (10.32 g, 37.65 mmol, 62.9% yield) as white solid matter. MS (ESI) m/z 558.1.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 10.52 (s, 1H), 8.73 (d, J=2.9 Hz, 1H), 8.44 (dd, J=2.9, 9.2 Hz, 1H), 7.11 (d , J=9.2 Hz, 1H), 4.56 (t, J=5.9 Hz, 2H), 3.77 (t, J=5.9 Hz, 2H).

(R)-tert-Butyl-4-(2-(2-formyl-4-nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

Mixture of 2-(2-bromoethoxy)-5-nitrobenzaldehyde (9.00 g, 32.84 mmol, 1 eq.), tert-butyl (R)-tert-butyl 2-methylpiperazine-1-carboxylate (7.89 g, 39 .41 mmol, 1.20 eq.) and sodium bicarbonate (8.28 g, 98.52 mmol, 3 eq.) in acetonitrile (45 ml) were stirred at 85°C for 12 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10-20% EtOAc in petroleum ether). Contaminated fractions were purified by preparative reverse-phase HPLC (15-45% acetonitrile in water + 0.225% formic acid, for 25 min). The pure fraction was concentrated under reduced pressure to remove most of the acetonitrile, and the pH was adjusted to pH 8 with saturated aqueous sodium bicarbonate and extracted with EtOAc (50 ml x 3 ). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. (R)-tert-Butyl-4-(2-(2-formyl-4-nitrophenoxy)ethyl)-2methylpiperazine-1-carboxylate (2.10 g, 5.34 mmol, 16.3% yield) was obtained as a light yellow oil, then purified by silica gel column chromatography followed by preparative reverse phase HPLC purification to obtain a light yellow oil. MS (ESI) m/z 394.2 [M+1] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 10.46 (s, 1H), 8.71 (d, J=2.8 Hz, 1H), 8.43 (dd, J=2.9, 9.2 Hz, 1H), 7.14 (d , J=9.3 Hz, 1H), 4.34 (t, J=5.6 Hz, 2H), 4.23 (br s, 1H), 3.83 (br q, J=13.2 Hz , 1H), 3.08 (dt, J=3.3, 12.8 Hz, 1H), 2.96-2.79 (m, 3H), 2.68 (br. d, J=11.0 Hz , 1H), 2.37 (dd, J=3.9, 11.1 Hz, 1H), 2.17 (dt, J=3.5, 11.6 Hz, 1H), 1.46 (s, 9H), 1.21 (d, J=6.8 Hz, 3H).

(R)-tert-butyl 4-(2-(2-(2,2-difluorovinyl)-4-nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

- 103 044376

Mixture of (R)-tert-butyl-4-(2-(2-formyl-4-nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate (11.00 g, 27.96 mmol, 1.00 eq.) , sodium 2-chloro-2,2-difluoroacetate (6.39 g, 41.94 mmol, 1.50 eq.) and PPh ₃ (11.00 g, 41.94 mmol, 1.50 eq.) in DMF (50 ml) was stirred at 120°C for 6 hours. The reaction mixture was diluted with EtOAc (200 ml) and washed with water (500 ml x 4). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by preparative reverse phase HPLC purification (20-50% acetonitrile in water + 0.1% TFA, for 33 min). The isolated fraction was concentrated under reduced pressure and the pH was adjusted to 8 with sodium bicarbonate (aq., saturated) and extracted with EtOAc (100 mlx5). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (R)-tert-butyl 4-(2-(2-(2,2-difluorovinyl)-4-nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate (7.62 g, 17.65 mmol, yield 63 .1%) was obtained as a yellow semi-solid. MS (ESI) m/z 428.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.37 (d, J=2.7 Hz, 1H), 8.13 (dd, J=2.7, 9.0 Hz, 1H), 6.95 (d, J=9.0 Hz, W ), 5.76-5.53 (m, 1H), 4.21 (t, J=5.7 Hz, 3H), 3.83 (br. d, J=13.2 Hz, 1H), 3, 09 (dt, J=3.3, 12.7 Hz, 1H), 2.91-2.75 (m, 3H), 2.67 (wd, J=11.1 Hz, 1H), 2, 35 (dd, J=3.9, 11.1 Hz, 1H), 2.15 (dt, J=3.4, 11.6 Hz, 1H), 1.46 (s, 9H), 1.22 (d, J=6.8 Hz, 3H).

(R)-tert-Butyl-4-(2-(4-amino-2-(2,2-difluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

To a solution of (R)-tert-butyl 4-(2-(2-(2,2-difluorovinyl)-4-nitrophenoxy)ethyl)-2-methylpiperazine-1carboxylate (6.00 g, 14.04 mmol, 1. 00 eq.) in MeOH (60 ml) and TFA (1 ml) was added Pd/C (0.60 g, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 25°C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give (R)-tert-butyl 4-(2(4-amino-2 -(2,2-difluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate (8.40 g, crude, trifluoroacetate) as a light yellow solid. MS (ESI) m/z 400.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.01-6.83 (m, 3H), 4.34-4.15 (m, 3H), 3.89 (b.d., J=14.3 Hz, 1H), 3.27-3.05 (m, 8H), 2.57 (k, J=7.6 Hz, 1H), 1.41 (s, 9H), 1.23-1.18 (m, 3H).

(R)-tert-butyl 4-(2-(2-(2,2-difluoroethyl)-4-((1-ethoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)-2- methylpiperazine-1-carboxylate.

To a mixture of (R)-tert-butyl 4-(2-(4-amino-2-(2,2-difluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1carboxylate (8.00 g, 20.03 mmol, 1 eq.) and ethyl 2-bromo-2-methylpropanoate (7.81 g, 40.05 mmol, 5.87 mL, 2 eq.) were added to DIPEA (30 mL) in one portion under nitrogen atmosphere. The mixture was stirred at 127°C for 12 hours. The reaction mixture was diluted with water (600 ml) and extracted with EtOAc (200 ml x 3). The combined organic extracts were washed with brine (200 mlx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (0-25% EtOAc in petroleum ether). Compound (R)tert-butyl 4-(2-(2-(2,2-difluoroethyl)-4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)- 2Methylpiperazine-1-carboxylate (4.60 g, 6.78 mmol, 33.8% yield) was obtained as a light yellow oil. MS (ESI) m/z 514.3 [M+1] ⁺ .

(R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- (2,2-difluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

To a solution of (R)-tert-butyl 4-(2-(2-(2,2-difluoroethyl)-4-((1-ethoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)- 2-methylpiperazine-1-carboxylate (4.50 g, 8.76 mmol, 1 eq.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (2.20 g, 9.64 mmol, 1.1 eq.) in EtOAc (10 mL), TEA (7.27 g, 71.85 mmol, 10 mL, 8.2 eq.) was added in one portion under nitrogen. The mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (150 ml) and extracted with EtOAc (50 ml x 3). The combined organic extracts were washed with brine (50 mlx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (10-30% EtOAc in petroleum ether). Compound (R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2 -(2,2-difluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate (3.11 g, 4.42 mmol, 50.5% yield) was obtained as a light yellow solid. MS (ESI) m/z 696.3 [M+1] ⁺ .

(R)-4-(3-(3-(2,2-difluoroethyl)-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidine -1-yl)-2-(trifluoromethyl)benzonitrile.

To a solution of (R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)- 2-(2,2-difluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate (0.10 g, 0.14 mmol, eq.) in DCM (1 ml) was added in one portion of 4.0 M HCl solution in dioxane (5 ml, 139.15 eq.). The mixture was stirred at 25°C for 12 hours, then concentrated under reduced pressure at 60°C. The residue was purified by semipreparative reverse phase HPLC (17-47% acetonitrile + 0.225% formic acid in water for 12 min). The collected fraction was concentrated to remove most of the acetonitrile, then treated with 1.0 M aqueous HCl. After lyophilization, (R)-4-(3-(3-(2,2-difluoroethyl)-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo -2- 104 044376 thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.084 g, 0.133 mmol, yield

92.8%) was isolated as a white solid. MS (ESI) m/z 596.2 [M+1]+.

1H NMR (400 MHz, DMSOC) δ ppm 9.94 (ush s, 2H), 8.39 (d, J=8.3 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.08 (dd, J= 1.7, 8.3 Hz, 1H), 7.37-7.31 (w, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.22 (d, J=8 .8 Hz, 1H), 6.54-6.15 (m, 1H), 4.51 (us s, 2H), 3.94-3.58 (m, 6H), 3.34-3.22 (m, 4H), 1.49 (s, 6H), 1.32 (ush d, J=6.4 Hz, 3H).

N-(3-Chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-((R)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(2,2difluoroethyl)phenoxy)ethyl)-2-methylpiperazin-1-yl)acetamide hydrochloride.

To a solution of (K)-4-(3-(3-(2,2-difluoroethyl)-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5oxo-2 -thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.252 mmol, 1 eq.) and 2-chloroN-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino )phenyl)acetamide (0.089 g, 0.271 mmol, 1.07 eq.) in DMF (3 ml) was added DIPEA (0.098 g, 0.756 mmol, 0.131 ml, 3.00 eq.) in one portion under nitrogen atmosphere. The mixture was stirred at 50°C for 12 hours. The reaction mixture was diluted with water (80 ml) and extracted with DCM (40 mlx3). The combined organic extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard methods to give N-(3-Chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)2-((K)-4-(2-(4-(3-(4-cyano -3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2(2,2-difluoroethyl)phenoxy)ethyl)-2-methylpiperazin-1-yl)acetamide hydrochloride (0.092 g, 0.098 mmol, yield 38.8%). MS (ESI) m/z 889.0 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-Y6) δ ppm 10.79 (s, 1H), 10.74-10.51 (m, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.29 (s, 1H), 8.07 (dd, J=1.5, 8.3 Hz, 1H), 7.36-7.13 (m, 3H), 6.99 (s, 1H), 6.89 (s, 1H), 6, 54-6.49 (m, 1H), 6.48-6.17 (m, 1H), 4.53 (br s, 2H), 4.33 (br dd, J=4.9, 11.6 Hz, 1H), 4.19 (br s, 2H), 3.91 (br s, 5H), 3.39-3.23 (m, 5H), 3.16 (s, 1H), 2.80 -2.69 (m, 1H), 2.63-2.54 (m, 1H), 2.12-2.03 (m, 1H), 1.91 (dk, J=4.5, 12, 3 Hz, 1H), 1.49 (s, 6H), 1.32 (ush d, J=5.0 Hz, 3H).

Example 36: 2-((R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-cyano-5-((2,6dioxopiperidin-3 -yl)amino)phenyl)acetamide trifluoroacetate

2-((3H-[1,2,3]Triazol[4,5-b]pyridin-3-yl)oxy)-N-(3-cyano-5-((2,6-dioxopiperidin-3yl)amino )phenyl)acetamide.

3-Amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile (0.290 g, 1.19 mmol), 2-chloroacetic acid (0.112 g, 1.19 mmol) (prepared as described in herein), HATU (0.587 g, 1.54 mmol) and DIPEA (0.622 mL, 3.56 mmol) were combined in DMF (3 mL) and stirred at room temperature. After 45 minutes, the solution was concentrated under reduced pressure to give a dark oil. The oil was purified by silica gel column chromatography (0-90% EtOAc in hexanes). The resulting material was dissolved in 80% EtOAc in hexanes and the solution was washed with water and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (0.250 g, 0.56 mmol, 50% yield .0%). MS (ESI) m/z 421 [M+1] ⁺ .

2-((K)-4-(2-((6-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-4 -ethylpyridin-3-yl)oxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide trifluoroacetate.

(R)-5-(3-(3-Ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 3-(trifluoromethyl)picolinonitrile dihydrochloride (0.121 g, 0.190 mmol), 2((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-N-(3-cyano -5-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide (0.08 g, 0.190 mmol), sodium iodide (0.029 g, 0.190 mmol) and DIPEA (0.133 mL, 0.761 mmol) were combined in DMF ( 0.5 ml), and the mixture was stirred at 80°C in a vessel with a screw cap. After 16 h, the solution was diluted with DMSO (1 mL) and purified by standard methods to give the title compound (0.008 g, 0.009 mmol, 5.0% yield). MS (ESI) m/z 845 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-Y6) δ ppm 10.82 (s, 1H), 9.58-10.06 (m, 1H), 9.23-9.26 (m, 1H), 8.81-8.84 (m, 1H), 7. 24 (br s, 2H), 7.09-7.20 (m, 3H), 6.78 (br s, 1H), 6.53 (s, 2H), 4.39 (br s, 2H), 2.57-2.78 (m, 6 N), 2.02-2.14 (m, 1 H), 1.92 (cd, J = 12.19, 4.16 Hz, 1 H), 1.51 (s, 7 H), 1.24 (ush s, 1H), 1.17 (ush t, J=7.46 Hz, 4H), 0.95-1.10 (m, 3H).

Example 37: 2-((K)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin- 1-yl)-2-isopropylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

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(R)-tert-butyl 2-methyl-4-(2-(4-nitro-2-(prop-1-en-2-yl)phenoxy)ethyl)piperazine-1-carboxylate.

To a mixture of (R)-tert-butyl 4-(2-(2-bromo-4-nitrophenoxy)ethyl)-2-methylpiperazine-1-carboxylate (4.10 g, 9.23 mmol, 1 eq.) (prepared as described herein) and 4,4,5,5-tetramethyl-2-(prop-1-en2-yl)-1,3,2-dioxaborolane (0.98 g, 5.830 mmol, 0.63 equiv .) in dioxane (40 ml) and water (20 ml) were added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.338 g, 0.46 mmol, 0.050 eq.) and potassium phosphate (5, 88 g, 27.69 mmol, 3 eq.) in one portion at 25°C under nitrogen. The mixture was heated to 90°C and stirred for 12 hours, then cooled to 25°C and poured into ice water (60 ml). The aqueous phase was extracted with EtOAc (80 mlx3). The combined organic phases were washed with brine (60 mlx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (9% EtOAc in petroleum ether) to give (R)-tert-butyl 2-methyl-4(2-(4-nitro-2-(prop-1-en-2-yl)phenoxy) ethyl)piperazine-1-carboxylate (1.69 g, 4.17 mmol, 45.2% yield) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.16 (dd, J=8.8, 2.8 Hz, 1H), 8.11 (d, J=2.8 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H ), 5.23 (t, J=1.2 Hz, 1H), 5.17 (d, J=0.8 Hz, 1H), 4.19 (t, J=6.4 Hz, 3H), 3.81 (d, J=14.0 Hz, 1H), 3.11-3.04 (m, 1H), 2.84 (d, J=11.2 Hz, 1H), 2.79 (t , J=6.4 Hz, 2H), 2.69 (d, J=11.2 Hz, 1H), 2.32 (dd, J=11.2, 4.0 Hz, 1H), 2.14 -2.12 (m, 4H), 1.47 (s, 9H), 1.21 (d, J=6.8 Hz, 3H).

(R)-tert-butyl 4-(2-(4-amino-2-isopropylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

To a solution of (R)-tert-butyl 2-methyl-4-(2-(4-nitro-2-(prop-1-en-2-yl)phenoxy)ethyl)piperazine-1carboxylate (1.69 g, 4 .17 mmol, 1 eq.) in MeOH (15 ml) was added palladium on activated carbon (0.15 g, 10% purity) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 30°C for 12 hours, filtered, and the filtrate was concentrated. The residue was poured into ice water (50 ml). The aqueous phase was extracted with EtOAc (60 mlx2). The combined organic phases were washed with brine (40 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-60% EtOAc in petroleum ether). The compound (R)-tert-butyl 4-(2-(4-amino-2-isopropylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (1.33 g, 3.52 mmol, 84.5% yield) was isolated as brown butter.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.69 (d, J=8.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.4, 2.8 Hz, 1H ), 4.13 (k, J=7.2 Hz, 1H), 4.01 (t, J=4.8 Hz, 2H), 3.81 (d, J=12.8 Hz, 1H), 3.29-3.26 (m, 1H), 3.10 (m, 1H), 2.86 (d, J=11.6 Hz, 1H), 2.76-2.71 (m, 3H) , 2.30 (dd, J=11.2, 4.0 Hz, 1H), 2.11 (m, 1H), 1.47 (s, 9H), 1.24 (d, J=6.8 Hz, 3H), 1.19 (d, J=6.8 Hz, 6H) (R)-tert-Butyl-4-(2-(4-((2-cyanopropan-2-yl)amino)-2 -u-isopropylphenoxy)ethyl)-2-methylpiperαzine1-carboxylate.

To a mixture of (R)-tert-butyl 4-(2-(4-amino-2-isopropylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (1.33 g, 3.52 mmol, 1 eq.) in 2 -hydroxy-2-methylpropanenitrile (3.26 g, 38.33 mmol, 10.88 eq.), add magnesium sulfate (1.06 g, 8.81 mmol, 2.5 eq.) in one portion at 20°C to nitrogen atmosphere. The mixture was heated to 60°C and stirred for 2 hours, cooled to 25°C, then poured into ice water (60 ml). The aqueous phase was extracted with EtOAc (80 mlx2). The combined organic extracts were washed with brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give (R)-tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)- 2-isopropylphenoxy)ethyl)-2methylpiperazine-1-carboxylate (2.70 g, crude) as a brown oil. MS (ESI) m/z 445.3 [M+1]+.

(R)-4-(3 -(3 -Isopropyl-4-(2-(3-methylpiperazin-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile.

Mixture of (R)-tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)-2-isopropylphenoxy)ethyl)-2methylpiperazine-1-carboxylate (1.30 g, 2.34 mmol, 1 eq.) and 4-isothiocyanato-2(trifluoromethyl)benzonitrile (0.534 g, 2.34 mmol, 1 eq.) in DMF (10 ml) was stirred at 25°C for 1 h, then treated with 4.0 M solution of HCl in MeOH (2.92 ml, 5 eq.) and heated to 80°C for 17 hours. The mixture was cooled to 25°C, and poured into ice water (40 ml). The aqueous phase was extracted with EtOAc (50 mlx2). The combined organic extracts were washed with brine (40 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by semipreparative reverse phase HPLC (25-55% acetonitrile in water + 0.05% HCl, 25 min) to give (R)-4-(3-(3isopropyl-4-(2-(3-methylpiperazine-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.486 g, 0.797 mmol, 34.0% yield) as a yellow foam.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.95-8.01 (m, 2H) 7.87-7.84 (m, 1H), 7.08-7.06 (m, 2H), 6.94 (d, J=8.0

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Hz, 1H), 4.19-4.10 (m, 3H), 3.39-3.32 (m, 1H), 3.04-2.97 (m, 2H), 2.92-2, 82 (m, 4H), 2.25-2.22 (m, 1H), 1.92 (t,

J=10.4 Hz, 1H), 1.58 (s, 6H), 1.24 (d, J=6.8 Hz, 6H), 1.08 (d, J=6.4 Hz, 3H) .

2-((R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-tioxoumidazolinidin-1yl)-2- isopropylphenoxy)ethyl)-2-methylpiperazin-1-yl)-H-(3-((2,6-dioxopiperidin-3yl) amino) phenyl)acetamide hydrochloride.

To a mixture of (R)-4-(3-(3-isonponyl-4-(2-(3-methylniperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl )-2-(trifluoromethyl)benzonitrile hydrochloride (0.300 g, 0.491 mmol) and 2-chlorochloro-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.195 g, 0.586 mmol, 1 .19 eq.) in DMF (1.5 ml) was added DIPEA (0.170 g, 1.310 mmol, 2.7 eq.) in one portion at 25°C under nitrogen atmosphere. The mixture was heated to 60°C for 12 hours, then concentrated to dryness. The residue was purified by standard methods to give 2-((R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidine-1 -yl)-2-isopropylphenoxy)ethyl)-2-methylpiperazin-1 -yl)-I-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.174 g, 0.198 mmol, yield 40 .3%). MS (ESI) m/z 833.4 [M+1]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 10.51-10.26 (m, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.29 (d, J=1.6 Hz , 1H), 8.07 (dd, J=8.4, 1.6 Hz, 1H), 7.21-7.14 (m, 3H), 7.06-6.98 (m, 2H), 6.85 (d, J=7.6 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 4.50 (ush, 2H), 4.28-4.19 (m , 2H), 4.02-3.83 (m, 5H), 3.38-3.29 (m, 6H), 2.79-2.69 (m, 1H), 2.62-2.56 (m, 1H), 2.11-2.07 (m, 1H), 1.98-1.85 (m, 1H), 1.49 (s, 6H), 1.32 (br, 3H), 1.18 (d, J=6.8 Hz, 6H).

Example 38: 2-((R)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin- 1-yl)-2-isopropylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

(R)-5-(3 -(3 -Isopropyl-4-(2-(3 -methylpiperazin-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1 -yl)- 3-(trifluoromethyl)picolinonitrile.

To a mixture of (R)-tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)-2-isopropylphenoxy)ethyl)-2methylpiperazine-1-carboxylate (0.780 g, 1.40 mmol , 1 eq.) and 5-isothiocyanato-3(trifluoromethyl)picolinonitrile (0.322 g, 1.40 mmol, 1 eq.) (prepared as described herein) in DMF (3 ml) was added 4.0 M HCl solution in MeOH (4 M, 1.75 mL, 5 eq.). The mixture was stirred at 25°C for 1 hour, then heated to 80°C for 12 hours. The mixture was cooled to 30°C and concentrated under reduced pressure at 50°C. The residue was purified by semipreparative reverse phase HPLC (25-55% acetonitrile in water + 0.05% HCl, 40 min) to give (R)-5-(3-(3-isopropyl-4(2-(3-methylpiperazine-1- yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile hydrochloride (0.330 g, 0.540 mmol, 38.48% yield) as a light yellow solid . MS (ESI) m/z 575.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-b ₆ ) δ ppm. 10.04-9.56 (m, 2H), 9.25 (d, J=2 Hz, 1H), 8.82 (d, J=2 Hz, 1H), 7.21-7.14 (m , 3H), 4.47 (ush, 2H), 3.75-3.49 (m, 10H), 1.51 (s, 6H), 1.30 (ush, J=5.2 Hz, 3H) , 1.19 (dd, J=6.8, 1.6 Hz, 6H).

2-((R)-4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2-isopropylphenoxy)ethyl)-2-methylpiperazin-1-yl)-X-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

To a mixture of (R)-5-(3-(3-isononyl-4-(2-(3-methylninerasin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl )-3-(trifluoromethyl)picolinonitrile hydrochloride (0.150 g, 0.245 mmol, 1 eq.) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.091 mg , 0.275 mmol, 1.12 eq.) in DMF (1 ml) was added DIPEA (0.952 mg, 0.736 mmol, 3.00 eq.) and the mixture was heated to 60°C for 12 h and concentrated to dryness. The residue was purified by standard methods to give 2-((R)-4-(2-(4-(3(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)-2isopropylphenoxy)ethyl)-2-methylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride (0.131 mg, 0.148 mmol , yield 60.3%). MS (ESI) m/z 834.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.21 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H), 7.20-7.12 (m, 3H), 7.06-7 .02 (m, 1H), 6.92 (m, 1H), 6.82 (d, J=7.60 Hz, 1H), 6.44 (dd, J=8.0, 2.0 Hz, 1H), 4.41 (ush, 2H), 4.24 (dd, J=11.2, 4.8 Hz, 1H), 4.01-3.97 (m, 1H), 3.74-3 .23 (m, 11H), 2.76-2.67 (m, 1H), 2.61-2.57 (m, 1H), 2.10-2.05 (m, 1H), 1.94 -1.85 (m, 1H), 1.47 (s, 6H), 1.23 (d, J=6.4 Hz, 3H), 1.16 (d, J=6.8 Hz, 6H) .

Example 39: 2-((R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-(2-fluoroethyl)phenoxy)ethyl)-2-methylpiperazin-1-yl)-K-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

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4-(3-(3-(2-fluoroethyl)-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

To a solution of 2-((3-(2-fluoroethyl)-4-hydroxyphenyl)amino)-2-methylpropanenitrile (1.50 g, 6.75 mmol, 1 eq.) (prepared as described herein) in DMF (15 ml) 4-isothiocyanato-2(trifluoromethyl)benzonitrile (1.08 g, 4.72 mmol, 0.7 eq.) was added. The mixture was stirred at 20°C for 1 hour, then treated with 4.0 M HCl in MeOH (8.44 ml, 5 eq.) and stirred at 70°C for 12 hours under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was suspended in water (50 ml) and extracted with EtOAc (30 mlx5). The combined organic extracts were washed with brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-20% EtOAc in petroleum ether) to give 4-(3-(3-(2-fluoroethyl)-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidine-1 -yl)-2-(trifluoromethyl)benzonitrile (1.47 g, 3.26 mmol, 48.2% yield) as yellow gum. MS (ESI) m/z 452.1 [M+1]+.

Ή NMR (400 MHz, CH3OD) δ ppm 8.16-8.12 (m, 2H), 7.98 (br. d, J=2.0 Hz, 1H), 7.14 (d, J=2.6 Hz, 1H), 7.07 ( dd, J=2.6, 8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.68 (t, J=6.5 Hz, 1H), 4, 56 (t, J=6.5 Hz, 1H), 3.09-3.00 (m, 2H), 1.53 (s, 6H), 1.56-1.50 (m, 1H).

(R)-tert-butyl 4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate.

Solution of tert-butyl (211)-2-methylpiperazine-1-carboxylate (3.00 g, 14.98 mmol, 1 eq.), 2 bromoethanol (2.25 g, 17.98 mmol, 1.28 ml, 1. 2 eq.) and potassium carbonate (4.14 g, 29.96 mmol, 2 eq.) in acetonitrile (30 ml) were stirred at 90°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% EtOAc in petroleum ether). The organic layers were combined and concentrated under reduced pressure to give tert-butyl (2R)-4-(2-hydroxyethyl)-2-methyl-piperazine-1-carboxylate (1.50 g, 6.14 mmol, 40.9% yield ) as a yellow oil.

Ή NMR (400 MHz, CDCl ₃ ) δ ppm 4.21 (s, 1H), 3.81 (d, J=13.2 Hz, 1H), 3.59 (t, J=5.6 Hz, 2H), 3.06 (t, J=3 ,2, 12.8 Hz, 1H), 2.77 (dd, J=1.6, 11.2 Hz, 1H), 2.63 (d, J=11.2 Hz, 1H), 2.57 -2.39 (m, 3H), 2.23 (dd, J=4.0, 11.2 Hz, 1H), 2.12-1.99 (m, 1H), 1.43 (s, 9H ), 1.21 (d, J=6.8 Hz, 3H).

(R)-tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2- (2-fluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate.

Mixture of 4-(3-(3-(2-fluoroethyl)-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.200 g, 0.443 mmol , 1 eq.), tert-butyl (2R)-4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate (0.140 g, 0.575 mmol, 1.3 eq.) and PPh ₃ (0.174 g, 0.664 mmol , 1.5 eq.) in THF (2 ml) was cooled to 0°C. DIAD (0.134 g, 0.664 mmol, 0.129 mL, 1.5 eq.) was added to the solution and the solution was stirred at 50°C for 10 hours. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (100 mL x 3), organic The layers were combined and washed with brine (50 ml x 3), dried, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc in petroleum ether) to give (R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5dimethyl-4 -oxo-2-thioxoimidazolidin-1-yl)-2-(2-fluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1carboxylate (0.340 g, crude) as a brown oil. MS (ESI) m/z 678.1 [M+1]+.

(R)-4-(3 -(3 -(2-Fluoroethyl)-4-(2-(3 -methylpiperazin-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1 -yl)-2-(trifluoromethyl)benzonitrile.

Solution of (R)-tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2 -(2-fluoroethyl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate (0.300 g, 0.442 mmol, 1 eq.) in 4.0 M HCl in dioxane (2.77 ml, 25 eq.) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. (R)-4-(3-(3-(2-fluoroethyl)4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine residue -1-yl)-2(trifluoromethyl)benzonitrile (0.330 g, crude, hydrochloric acid) obtained as a light yellow solid was used directly in the next step. MS (ESI) m/z 578.1 [M+1]+.

2-((R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2- (2-fluoroethyl)phenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

A mixture of (R)-4-(3-(3-(2-fluoroethyl)-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin- 1-yl)-2-(trifluoromethyl)benzonitrile (0.200 g, 0.325 mmol, 1 equiv, hydrochloride), 2chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride ( 0.075 g, 0.227 mmol, 0.7 eq.) and DIPEA (0.147 g, 1.140 mmol, 0.198 mL, 3.5 eq.) in DMF (1 mL) were stirred at 50°C for

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h. The reaction mixture was filtered, the filtrate was purified by standard methods to obtain 2-((R)4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl)-2-(2fluoroethyl)phenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride (0.070 g, 0.080 mmol, yield 24.7%). MS (IER) m/z 837.3

[M+1]+.

1H NMR (400 MHz, DMSO-06) δ ppm 10.78 (s, 1H), 10.35 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.06 (dd, J=1.6, 8.4 Hz, 1H), 7.29-7.23 (m, 1H), 7.23-7.20 (m, 1H), 7.20- 7.14 (m, 1H), 7.06-6.99 (m, 1H), 6.97 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.44 (d, J=8.0 Hz, 1H), 4.71 (t, J=6.0 Hz, 1H), 4.59 (t, J=6.4 Hz, 1H), 4.49 (s , 2H), 4.25 (dd, J=4.8, 11.4 Hz, 1H), 4.17 (s, 6H), 3.35 (d, J=16.4 Hz, 6H), 3 .14-2.98 (m, 2H), 2.77-2.67 (m, 1H), 2.62-2.53 (m, 1H), 2.42 (dd, J=2.0, 4.0 Hz, 1H), 2.08 (td, J=4.6, 8.8 Hz, 1H), 1.96-1.82 (m, 1H), 1.47 (s, 6H), 1.34-1.18 (m, 3H).

Example 40: 2-((R)-4-(2-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-tioxoumidazolidin-1yl)-2- ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride

2-Chloro-4-isothiocyanatobenzonitrile.

To a mixture of 4-amino-2-chlorobenzonitrile (0.50 g, 3.28 mmol, 1 eq.) in water (5 ml) was added thiocarbonyl dichloride (0.754 g, 6.550 mmol, 0.502 ml, 2 eq.). The mixture was stirred at 25°C for 2 hours, then diluted with water (30 ml) and extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-1% EtOAc in petroleum ether) to give 2-chloro-4-isothiocyanatobenzonitrile (0.60 g, 3.08 mmol, 94.1% yield) as a white solid. MS (ESI) m/z 236.9 [M+1]+.

1H NMR (400 MHz, DMSO-66) δ ppm 7.61-7.67 (m, 1H), 7.91-7.96 (m, 1H), 8.02-8.06 (m, 1H).

(R)-tert-Butyl 4-(2-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)2-ethylphenoxy) ethyl)-2-methylpiperazine-1-carboxylate.

To a mixture of (R)-tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2yl)amino)phenoxy)ethyl)-2-methylpiperazine-1- carboxylate (0.450 g, 0.971 mmol, 1 eq.) and 2-chloro-4-isothiocyanatobenzonitrile (0.378 g, 1.940 mmol, 2 eq.) in EtOAc (3 mL) was added TEA (0.295 g, 2.910 mmol, 0.405 mL, 3 eq. ). The reaction mixture was stirred at 80°C for 8 hours, then diluted with water (80 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (33% EtOAc in petroleum ether) to give (R)-tert-butyl 4-(2-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl- 4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)ethyl)-2-methylpiperazine-1-carboxylate (0.600 g, 0.932 mmol, 96.0% yield) as a yellow oil. MS (ESI) m/z 626.3 [M+1]+.

(R)-2-Chloro-4-(3-(3-ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1 -yl)benzonitrile hydrochloride.

To a mixture of (R)-tert-butyl 4-(2-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy )ethyl)-2-methylpiperazine-1-carboxylate (0.200 g, 0.319 mmol, 1 equiv.) in DCM (2 ml) was added a 4.0 M solution of HCl in dioxane (0.08 ml, 1 equiv.). The reaction mixture was stirred at 25°C for 1.5 hours, then concentrated under reduced pressure to give (R)-2-chloro-4-(3-(3-ethyl-4-(2-(3-methylpiperazine-1 -yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)benzonitrile hydrochloride (0.168 g, crude), as a yellow solid. MS (ESI) m/z 526.0 [M+1]+.

2-((R)-4-(2-(4-(3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)2otulfenoxy)ethyl) -2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopipedin-3-yl)amino)phenyl)acetamide hydrochloride.

To a mixture of (R)-2-chloro-4-(3-(3-ethyl-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidine -1-yl)benzonitrile hydrochloride (0.168 g, 0.299 mmol, 1 eq.) and 2-chloro-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide (0.106 g, 0.358 mmol, 1.2 eq.) in DMF (1.5 ml) was added DIPEA (0.116 g, 0.896 mmol, 0.156 ml, 3 eq.). The mixture was stirred at 50°C for 8 hours, filtered, and the filtrate was purified by standard methods to give 2-((R)-4-(2-(4-(3-(3-chloro-4-cyanophenyl)5,5 -dimethyl-4-oxo-2-thioxoimidαzolidin-1-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3((2,6-dioxopiperidin-3-yl)amino) Phenyl)acetamide hydrochloride (0.095 g, 0.115 mmol, 38.5% yield). MS (ESI) m/z 785.1 [M+1]+.

1H NMR (400 MHz, DMSO-Y6) δ ppm 1.18 (t, J=7.46 Hz, 3H), 1.33 (ush s, 3H), 1.49 (s, 6 H), 1.86-1.96

- 109 044376 (m, 1H), 2.07-2.14 (m, 1H), 2.53-2.65 (m, 2H), 2.65-2.71 (m, 2H), 2, 71-2.81 (m, 1H), 3.74-3.82 (m, 4H), 3.864.07 (m, 4H), 4.27 (ush dd, J=11.31, 4.83 Hz , 2H), 4.51 (ush s, 2H), 6.47 (dd, J=8.25, 1.28 Hz, 1H), 6.87 (d,

J=8.44 Hz, 1H), 6.97-7.09 (m, 2H), 7.12-7.23 (m, 3H), 7.72 (dd, J=8.31, 1, 83 Hz, 1H), 8.03 (d, J=1.83 Hz, 1H),

8.18 (d, J=8.31 Hz, 1H), 10.21-10.57 (m, 1H), 10.80 (s, 1H).

Example 41: 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)-2-isopropylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3 -yl)amino)phenyl)acetamide hydrochloride

-(Benzyloxy)-4-nitro-2-(prop-1-en-2-yl)benzene.

To a mixture of 1-(benzyloxy)-2-bromo-4-nitrobenzene (10.00 g, 32.45 mmol, 1 eq.) (prepared as described herein) and 4,4,5,5-tetramethyl- 2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (10.91 g, 64.91 mmol, 2 eq.) in dioxane (100 ml), water (50 ml) added phosphate potassium (20.67 g, 97.36 mmol, 3 eq.) and diphenylphosphorus diferrocene palladium dichloride (1.190 g, 1.62 mmol, 0.05 eq.) in one portion at 25°C under a nitrogen atmosphere. The mixture was heated to 90°C and stirred for 12 hours, then concentrated under reduced pressure at 60°C and filtered. The residue was poured into ice water (300 ml). The aqueous phase was extracted with EtOAc (500 mlx3). The combined organic phases were washed with brine (200 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (9% EtOAc in petroleum ether) to give 1(benzyloxy)-4-nitro-2-(prop-1-en-2-yl)benzene (13.26 g, 49.20 mmol, yield 75.9%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.07-8.19 (m, 2H), 7.42-7.34 (m, 5H), 6.99-6.97 (m, 1H), 5.27-5.19 (m, 4H ), 2.15 (d, J=0.8 Hz, 3H).

4-Amino-2-isopropylphenol.

Palladium at activated carbon (3.00 g, purity 10%) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 30°C for 3 hours, then filtered, and the filtrate was concentrated. The crude product was purified by reverse phase silica gel column chromatography (0.1% FA condition) to give 4-amino-2-isopropylphenol (5.00 g, 33.07 mmol, 74.8% yield) as a brown solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 6.60-6.58 (m, 2H), 6.44 (dd, J=8.4, 2.8 Hz, 1H), 1.23 (d, J=7.2 Hz, 6H).

2-((4-Hydroxy-3-isopropylphenyl)amino)-2-methylpropanenitrile.

To a mixture of 4-amino-2-isopropylphenol (0.400 g, 2.65 mmol, 1 eq) in 2-hydroxy-2methylpropanenitrile (0.675 g, 7.94 mmol, 3 eq) was added magnesium sulfate (0.796 g, 6.61 mmol, 2.5 equiv.) at 25°C. The reaction mixture was heated to 60°C for 12 hours, then concentrated under reduced pressure at 40°C. The residue was poured into ice water (40 ml) and the aqueous phase was extracted with EtOAc (60 mlx2). The combined organic phases were washed with brine (40 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-((4-hydroxy-3-isopropylphenyl)amino)-2-methylpropanenitrile (0.730 g, crude) as a dark red solid substances. MS (ESI) m/z 192.1 [M-26] ⁺ .

4-(3-(4-Hydroxy-3-isopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

A mixture of 2-((4-hydroxy-3-isopropylphenyl)amino)-2-methylpropanenitrile (0.730 g, 3.34 mmol, 1 eq.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.530 g, 2.34 mmol, 0.7 eq.) in DMF (7.5 ml) was stirred at 25°C for 1 hour, then treated with a 4.0 M solution of HCl in MeOH (2 ml, 2.39 eq.). The solution was stirred at 70°C for 12 hours and concentrated under reduced pressure at 40°C. The residue was poured into ice water (50 ml) and the aqueous phase was extracted with EtOAc (60 mlx2). The combined organic phases were washed with brine (40 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (30-35% EtOAc in petroleum ether) to give 4-(3-(4-hydroxy-3-isopropylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile (1.110 g, 2.48 mmol, 74.2% yield) as a dark red oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.99-7.97 (m, 2H), 7.85 (dd, J=8.0, 1.2 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H), 7 .00-6.97 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.48-5.37 (m, 1H), 3.26 (m, 1H), 1.58 (s, 6H), 1.27-1.29 (d, J=7.4 Hz, 6H).

4-(3-(4-(2-Bromoethoxy)-3-isopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

- 110 044376

To a mixture of 4-(3-(4-hydroxy-3-isopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (1.11 g, 2.48 mmol, 1 eq.) and 1,2-dibromoethane (4.66 g, 24.80 mmol, 10 eq.) in acetonitrile (15 ml) was added potassium carbonate (1.03 g, 7.44 mmol, 3 eq. ) in one portion at 25°C. The mixture was heated to 90°C and stirred for 24 hours, then cooled and concentrated under reduced pressure at 40°C. The residue was poured into ice water (50 ml) and the aqueous phase was extracted with EtOAc (70 mlx2). The combined organic phases were washed with brine (60 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-45% EtOAc in petroleum ether) to give 4-(3-(4-(2-bromoethoxy)-3isopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1 -yl)-2-(trifluoromethyl)benzonitrile (0.66 g, 1.19 mmol, 48.0% yield) as a yellow oil.

¹ H NMR (400 MHz, CDC13) δ ppm 8.00-7.98 (m, 2H), 7.86 (dd, J=8.4, 1.6 Hz, 1H), 7.12-7.07 (m, 2H), 6.92 ( d, J=8.8 Hz, 1H), 4.37 (t, J=6.0 Hz, 2H), 3.72 (t, J=6.0 Hz, 2H), 3.44-3, 37 (m, 1H), 1.58 (s, 6H), 1.26-1.28 (d, J=6.8 Hz, 6H).

(3S,5R)-tert-Butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5dimethylpiperazine-1-carboxylate.

To a solution of 2-chloro-K-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.950 g, 3.21 mmol, 1.00 eq.) and (3S,5R)- tert-butyl 3,5-dimethylpiperazine-1-carboxylate (0.688 g, 3.21 mmol, 1.00 eq.) in DMF (10 ml) was added DIPEA (1.250 g, 9.64 mmol, 1.7 ml, 3 .00 eq.) and sodium iodide (0.144 g, 0.964 mmol, 0.30 eq.) in one portion under nitrogen. The mixture was stirred at 70°C for 12 hours, then filtered. The filtrate was concentrated under reduced pressure and purified by semipreparative reverse phase HPLC (10-40% acetonitrile + 0.225% formic acid in water, for 30 min). The collected fractions were extracted with EtOAc (100 mlx4). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (3S,5R)-tert-butyl 4-(2-((3-((2,6-dioxopiperidine- 3yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (1.20 g, 2.52 mmol, 78.4% yield) as a light yellow solid. MS (ESI) m/z 474.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.77 (s, 1H), 9.41 (s, 1H), 7.05-6.96 (m, 2H), 6.83-6.75 (m, 1H), 6.40 (dd, J=1.6, 8.1 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 4.33-4.22 (m, 1H), 3.74 (ush s, 2H), 3.27 (s, 2H), 2.80-2.53 (m, 6H), 2.15-2.04 (m, 1H), 1.89 (dk, J=4.8, 12.1 Hz, 1H), 1.40 (s, 9H), 1.00 (d, J=5.6 Hz, 6H).

2-((2S,6R)-2,6-Dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

To a solution of (3S,5R)-tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2oxoethyl)-3,5-dimethylpiperazin-1- carboxylate (1.70 g, 3.59 mmol, 1 eq.) in dioxane (10 mL) add hydrobromic acid (8.89 M, 10 mL, 24.8 eq.) in one portion. The mixture was stirred at 25°C for 1 hour, then diluted with water (150 ml) and lyophilized to give 2-((2S,6R)-2,6dimethylpiperazin-1-yl)-K-(3-((2,6 -dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (2.70 g, crude) as a red solid. MS (ESI) m/z 374.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 1 0.82-10.76 (m, 1H), 11.04-10.74 (m, 1H), 10.38-9.99 (m, 1H), 9.79-9.30 (m, 2H), 7.47-7.25 (m, 1H), 7.14 (s, 1H), 7.03-6.88 (m, 1H), 6.57 (dd, J=2.5, 8.9 Hz, 1H), 4.53-4.21 (m, 3H), 3.99 (ush s, 2H), 3.68-3.55 (m, 2H), 3.24 (ush s , 2H), 2.92-2.69 (m, 1H), 2.65-2.54 (m, 1H), 2.44-2.28 (m, 1H), 2.15-1.82 (m, 2H), 1.37 (ush s, 6H).

2-((2S,6R)4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2 -isopropylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

To a mixture of 4-(3-(4-(2-bromoethoxy)-3-isopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.271 mmol , 1 equiv.) and 2-((2S,6R)-2,6-dimethylpiperazin-1yl)-K-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (0.202 g , 0.445 mmol, 1.64 eq.) in DMF (1.5 ml), DIPEA (0.105 g, 0.817 mmol, 3 eq.), sodium iodide (0.020 g, 0.135 mmol, 0.5 eq.) was added in one portion at 25°C in a nitrogen atmosphere. The mixture was heated to 60°C and stirred for 12 hours, then cooled to 30°C and filtered. The filtered product was concentrated under reduced pressure and the residue was purified by standard methods to give 2-((2S,6R)-4-(2-(4-(3(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2isopropylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl) acetamide hydrochloride (0.072 g, 0.081 mmol, 29.8% yield). MS (ESI) m/z 847.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.79 (s, 1H), 10.65-9.98 (m, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=1.2 Hz , 1H), 8.08 (dd, J=8.4, 1.6 Hz, 1H), 7.23-7.18 (m, 2H), 7.17-7.11 (m, 1H), 7.07-6.96 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 6.45 (d, J=7.2 Hz, 1H), 4.48 (s , 2H), 4.26 (dd, J=11.2, 4.8 Hz, 1H), 4.18-3.90 (m, 6H), 3.75-3.64 (m, 5H), 2.80-2.69 (m, 1H), 2.64-2.56 (m, 1H), 2.13-2.05 (m, 1H), 1.97-1.85 (m, 1H ), 1.49 (s, 6H), 1.29 (s, 6H), 1.19 (d, J=6.8 Hz, 6H).

Example 42: 2-(3-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octane- 5-yl)-2-ethylphenoxy)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-M-(3-((2,6- 111 044376 dioxopiperidin-3 -yl)amino) phenyl)acetamide hydrochloride

5-[5-[4-(2-bromoethoxy)-3-ethylphenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-7-yl]-3 (trifluoromethyl)pyridin- 2-carbonitrile.

To a solution of 5-[5-(3-ethyl-4-hydroxy-phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl]-3 (trifluoromethyl)pyridin-2- carbonitrile (1.23 g, 2.75 mmol, 1 eq.) (prepared as described herein), in acetonitrile (30.8 ml, 0.09 M) was added potassium carbonate (1.16 g, 8. 28 mmol, 3 equiv.) and 1,2dibromoethane (4.77 ml, 55.1 mmol, 20 equiv.). The mixture was stirred at 80°C for 18 hours, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel column chromatography (0-33% EtOAc in hexanes) to give 5-[5-[4-(2-bromoethoxy)-3-ethylphenyl]-8-oxo-6-thioxo-5,7diazaspiro [3.4]octan-7-yl]-3-(trifluoromethyl)pyridin-2-carbonitrile (0.867 g, 1.56 mmol, 56.7% yield) as a light pink solid. MS (ESI) m/z 553.0 [M+1]+.

tert-Butyl 3-[2-[4-[7-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-5-yl] -2-ethyl-phenoxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

5-[ 5-[4-(2-bromoethoxy)-3-ethylphenyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile ( 0.125 g, 0.23 mmol, 1 eq.) and DIPEA (0.14 ml, 0.79 mmol, 3.5 eq.). The mixture was heated to 60°C with stirring for 18 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-100% hexane/EtOAc) to give tert-butyl 3-[2-[4-[7- [6-cyano-5-(trifluoromethyl)-3-pyridyl]-8oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-ethylphenoxy]ethyl] -3,8- diazabicyclo[3.2.1]octane-8carboxylate (0.129 g, 0.19 mmol, 83.4% yield) as an off-white solid. MS (ESI) m/z 685.2 [M+1] ⁺ .

5-[5-[4-[2-(3,8-Diazabicyclo[3.2.1]octan-3-yl)ethoxy]-3-ethyl-phenyl]-8-oxo-6-thioxo-5,7diazaspiro[ 3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile dihydrochloride.

tert-Butyl 3-[2-[4-[7-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-5-yl] -2-ethyl-phenoxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.129 g, 0.19 mmol, 1 eq.) was suspended in DCM (0.83 mL, 0.23 M), treated with 4.0 M HCl in dioxane (0.71 ml, 2.83 mmol, 15 eq.) and stirred at room temperature for 2 hours. The reaction was concentrated to give 5-[5-[4-[ 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)ethoxy]-3-ethyl-phenyl]-8oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl] - 3-(trifluoromethyl)pyridine-2-carbonitrile dihydrochloride (0.123 g, 0.19 mmol, 99.3% yield) as a beige solid. MS (ESI) m/z 585.2 [M+1] ⁺ .

2-(3-(2-(4-(7-(6-cyano-5 -(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octane-5 yl)-2-ethylphenoxy)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride.

2-Chloro-X-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetamide (0.083 g, 0.28 mmol, 1.5 eq.) was added to the stirred mixture of 5-[5- [4-[2-(3,8-diazabicyclo[3.2.1]octan-3-yl)ethoxy]-3-ethyl-phenyl]-8oxo-6-thioxo-5,7-diazaspiro[3.4]octane-7 -yl]-3-(trifluoromethyl)pyridin-2-carbonitrile dihydrochloride (0.123 g, 0.19 mmol, 1 eq.), sodium iodide (0.042 g, 0.28 mmol, 1.5 eq.), DMF (1 .55 ml, 1.2 mol) and DIPEA (0.16 ml, 0.94 mmol, 5 eq.). After stirring for 1 hour at 60°C, the solution was filtered and purified by standard methods to obtain 2-[3-[2-[4-[7-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-8oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-ethyl-phenoxy]ethyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]N-[3-[ (2,6-dioxo-3-piperidyl)αmino]phenyl]acetamide hydrochloride (0.106 g, 0.11 mmol, 61.5% yield). MS (ESI) m/z 844.4 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 10.48 (us s, 1H), 9.22 (d, 1H, J=1.7 Hz), 8.76 (d, 1H, J=2.0 Hz), 7 ,1-7.3 (m, 3H), 7.05 (t, 1H, J=8.0 Hz), 6.98 (s, 1H), 6.86 (d, 1H, J=8.9 Hz), 6.46 (dd, 1H, J=1.5, 8.1 Hz), 4.47 (ush s, 2H), 4.25 (ush dd, 1H, J=4.8, 11, 4 Hz), 4.20 (us s, 3H), 3.7-3.8 (m, 2H), 3.2-3.6 (m, 6H), 2.62.8 (m, 6H) , 2.3-2.5 (m, 4H), 2.22 (shir s, 2H), 2.1-2.1 (m, 1H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 1H), 1.20 (t, 3H, J=7.5 Hz).

Example 43: 2-((1S,4S)-5-(2-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5, 7diazaspiro[3.4]octan-5-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-((2,6dioxopiperidin-3-yl) amino)phenyl)acetamide hydrochloride

- 112 044376 tert-Butyl (1S,4S)-5-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5, 7diazaspiro[3.4]octan-5-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate.

To a solution of tert-butyl (lS,4S)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.057 g, 0.27 mmol, 1.2 eq.) in DMF (2.26 ml, 0.100 M) 5-[5-[4-(2-bromoethoxy)-3-ethyl-phenyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl) was added pyridine-2-carbonitrile (0.125 g, 0.23 mmol, 1 eq.), (prepared as described herein), and DIPEA (0.14 ml, 0.79 mmol, 3.5 eq.). The mixture was heated at 60°C with stirring for 18 hours. After concentration under reduced pressure, the reaction mixture was purified by silica gel column chromatography (0-100% hexane/EtOAc) to give tert-butyl (1S,4S)-5-(2- (4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]octan-5-yl)-2-ethylphenoxy)ethyl) -2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.130 g, 0.19 mmol, 84.0% yield) as a beige solid. MS (ESI) m/z 685.2 [M+1]+.

5-(5-(4-(2-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)ethoxy)-3-ethylphenyl)-8-oxo-6-thioxo- 5,7diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile dihydrochloride.

tert-Butyl (1S,4S)-5-(2-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4 ]octan-5-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.130 g, 0.19 mmol, 1 eq.) was suspended in DCM (0.84 mL, 0.226 mol) and treated with 4.0 M HCl in dioxane (0.71 mL, 2.85 mmol, 15 eq.). The reaction mixture was stirred at room temperature for 6 hours and concentrated to give 5-(5-(4-(2-((lS,4S)-2,5-diazabicyclo[2.2.2]octan-2yl)ethoxy)-3 -ethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3(trifluoromethyl)picolinonitrile dihydrochloride (0.124 g, 0.19 mmol, 99.3% yield) as beige solid. MS (ESI) m/z 585.2 [M+1] ⁺ .

2-((1S,4S)-5-(2-(4-(7-(6-Cyano-5-(trifluoromethyl)niridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4 ]octan-5-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl )acetamide hydrochloride.

2-Chloro-N-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetamide (0.084 g, 0.28 mmol, 1.5 eq.) was added to the stirred mixture of 5-(5- (4-(2-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)ethoxy)-3ethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 ]octan-7-yl)-3-(trifluoromethyl)picolinonitrile dihydrochloride (0.124 g, 0.19 mmol, 1 eq.), sodium iodide (0.043 g, 0.28 mmol, 1.5 eq.), DMF (1 .57 ml, 0.120 mol) and DIPEA (0.16 ml, 0.94 mmol, 5 eq.). The reaction mixture was stirred for 1 hour at 60°C, then the solution was filtered and purified by standard methods to obtain 2-((lS,4S)-5-(2-(4-(7-(6cyano-5-(trifluoromethyl)pyridine -3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octan-2-yl) -N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide hydrochloride (0.102 g, 0.11 mmol, 58.3% yield). MS (IER) m/z 844.4 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 10.54 (us s, 1H), 9.22 (d, 1H, J=1.8 Hz), 8.76 (d, 1H, J=2.0 Hz), 7 .2-7.3 (m, 3H), 7.05 (t, 1H, J=7.9 Hz), 6.99 (br s, 1H), 6.88 (b s, 1H, J=7 .9 Hz), 6.46 (USD, 1H, J=8.3 Hz), 4.57 (USD, 1H), 4.37 (USD, 2H), 4.26 (USD, 1H , J=4.8, 11.2 Hz), 4.04 (US s, 2H), 3.96 (US s, 2H), 3.86 (US s, 5H), 2.5-2.8 (m, 7H), 2.4-2.5 (m, 3H), 2.2-2.4 (m, 2H), 1.9-2.2 (m, 5H), 1.5-1 .6 (m, 1H), 1.20 (t, 3H, J=7.5 Hz).

Example 44: 2-((S)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)niridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin- 1-yl)-2-cyclopropylphenoxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide

1-(Benzyloxy)-2-cyclopropyl-4-nitrobenzene.

To a mixture of 1-benzyloxy-2-bromo-4-nitro-benzene (15.0 g, 48.7 mmol, 1 eq.) and cyclopropylboronic acid (4.60 g, 53.5 mmol, 1.1 eq.) in toluene (120 ml) added palladium(II) acetate (1.09 g, 4.87 mmol, 0.1 eq.), tricyclohexylphosphine (4.10 g, 16.4 mmol, 0.3 eq.), phosphate potassium (31.0 g, 146 mmol, 3 eq.) and water (15 ml). The reaction mixture was stirred at 120°C for 12 hours. The reaction mixture was concentrated in vacuo, and water (100 ml) was added to the residue. The mixture was extracted with EtOAc (100 mlx3), and the combined organic layers were washed with brine (50 mlx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (9-17% EtOAc/petroleum ether) to give 1-(benzyloxy)-2-cyclopropyl-4-nitrobenzene (10.60 g, 39.36 mmol, 80.7% yield) as red oil. MS (ESI) m/z 270.5 [M+1] ⁺ .

4-Amino-2-cyclopropylphenol.

Palladium on activated carbon (3.00 g, 3.94 mmol, 10 wt.%, 0.1 eq.) and ammonium hydroxide (1 ml). The reaction mixture was stirred for 3 hours under a hydrogen atmosphere (50 psi)

- 113 044376 at 40°C. The mixture was filtered and concentrated in vacuo. The crude product was stirred in

4% EtOAc/petroleum ether at 25°C for 0.5 h. The mixture was then filtered to obtain the desired product (4.60 g, 30.8 mmol, 78.3% yield) as a yellow solid. MS (IER) m/z 150.1

[M+1]+.

2-((3-Cyclopropyl-4-hydroxyphenyl)amino)-2-methylpropanenitrile.

To a mixture of 4-amino-2-cyclopropylphenol (4.50 g, 30.1 mmol, 1 eq) in 2-hydroxy-2methylpropanenitrile (28.2 g, 332 mmol, 30.3 mL, 11 eq) was added magnesium (18.1 g, 151 mmol, 5 eq.). The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated in vacuo and poured into water (50 ml), the mixture was extracted with ethyl ether (30 mlx3) and concentrated in vacuo to give crude 2-((3-cyclopropyl-4 -hydroxyphenyl)amino)-2methylpropanenitrile (10.0 g) as red oil. MS (ESI) m/z 217.6 [M+1] ⁺ .

5-(3-(-3-Cyclopropyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

A mixture of 2-((3-cyclopropyl-4-hydroxyphenyl)amino)-2-methylpropanenitrile (5.00 g, 23.1 mmol, 1 eq.) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (5.83 g , 25.4 mmol, 1.1 eq.) in DMF (30 ml) was stirred at 25°C for 1 hour. After this time, hydrochloric acid/MeOH (4 M, 11.5 ml, 2 eq.) was added. , and the reaction mixture was stirred at 80°C for 12 hours. The mixture was concentrated under vacuum. The residue was purified by preparative reverse phase liquid chromatography (40-70% acetonitrile + 0.05% hydrochloric acid in water, 25 min), the collected fractions were concentrated in vacuo, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl ether (300 ml x 3 ) and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Compound 5-(3-(3-cyclopropyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile (5.20 g, 11.6 mmol , yield 50.4%) was obtained as a white solid. MS (ESI) m/z 447.1 [M+1] ⁺ .

5-(3-(4-(2-Bromoethoxy)-3-cyclopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

To a mixture of 5-(3-(3-cyclopropyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)3-(trifluoromethyl)picolinonitrile (1.00 g, 2.24 mmol, 1 eq.) and 1,2-dibromoethane (8.42 g, 44.8 mmol, 3.38 mL, 20 eq.) in acetonitrile (10 mL) was added potassium carbonate (0.93 g, 6.72 mmol, 3 eq.). The reaction mixture was stirred at 80°C for 48 hours. The mixture was filtered and concentrated under vacuum, the residue was purified by preparative reverse phase liquid chromatography (57-87% acetonitrile + 0.05% hydrochloric acid in water, 20 min). Compound 5-(3-(4-(2-bromoethoxy)-3-cyclopropylphenyl)4,4-dimethyl-5-oxo-2-thioxoimide zolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.30 g , 0.51 mmol, 22.7% yield, hydrochloric acid) was obtained as a white solid. MS (ESI) m/z 555.0 [M+1] ⁺ .

(3S)-tert-Butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3(trifluoromethyl)piperazine-1-carboxylate.

To a mixture of tert-butyl (38)-3-(trifluoromethyl)piperazine-1-carboxylate (0.08 g, 0.31 mmol, 1 eq.) and 2chloro-N-(3-((2,6-dioxopiperidine- 3-yl)amino)phenyl)acetamide (0.12 g, 0.41 mmol, 1.3 eq.) in DMF (2 ml) was added DIPEA (0.20 g, 1.57 mmol, 0.27 ml, 5 eq.) and sodium iodide (14.1 mg, 0.09 mmol, 0.3 eq.). The reaction mixture was stirred at 80°C for 12 hours. The mixture was poured into water and extracted with ethyl ether (20 mlx2), and the combined organic phases were concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH/DCM) to give (3S)-tert-butyl 4-(2-((3-((2,6dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl) -3-(trifluoromethyl)piperazine-1-carboxylate (0.04 g, 77.9 µmol, 24.7% yield) as a yellow oil. mS (iEr) m/z 536.3 [M+Na]+.

N-(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide.

To a mixture of (3S)-mepm-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3(trifluoromethyl)piperazine-1- carboxylate (0.07 g, 0.13 mmol, 1 eq.) in DCM (5 ml) was added hydrobromic/acetic acid (0.5 ml, 33% v/v). The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated in vacuo to give N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2((8)-2-(trifluoromethyl )piperazin-1-yl)acetamide (0.10 g, crude, hydrobromic acid) as a white solid.

2-((S)4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-cyclopropylphenoxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide.

To a mixture of N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((S)-2-(trifluoromethyl)piperazin-1yl)acetamide (0.10 g, 0.20 mmol, 1 equiv., hydrobromic acid) and 5-(3-(4-(2-bromoethoxy)-3cyclopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl) picolinonitrile (0.13 g, 0.24 mmol, 1.2 eq.) in DMF (2 ml) was added DIPEA (0.61 mmol, 0.11 ml, 3 eq.) and sodium iodide (0.01 g, 0.06 mmol, 0.3 eq.). The reaction mixture was stirred at 50°C for 12 hours. The mixture was filtered and the residue was purified by standard methods to obtain

- 114 044376

2-((S)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl )-2-cyclopropylphenoxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide (45.3 mg, 47.90 µmol, yield 23.7%, purity 97%, hydrochloric acid). MS (ESI) m/z 886.2 [M+1]+.

1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.69 (br.d, J=2.4 Hz, 1H), 9.23 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 7.19-7.12 (m, 1H), 7.16 (s, 1H), 7.02-6.97 (m , 1H), 6.97-6.91 (m, 1H), 6.83 (s, 1H), 6.82-6.76 (m, 1H), 6.40 (br. d, J=7, 6 Hz, 1H), 4.52 (s, 2H), 4.24 (dd, J=4.8, 11.2 Hz, 1H), 3.91-3.54 (m, 7H), 3, 24-3.12 (m, 2H), 2.79-2.69 (m, 1H), 2.63-2.56 (m, 1H), 2.24-2.03 (m, 3H), 1.95-1.81 (m, 1H), 1.49 (s, 6H), 0.99-0.89 (m, 2H), 0.61 (d, J=4.4 Hz, 2H) .

Example 45: 2-((S)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl) -2-cyclopropylphenoxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide

Benzyl (3-(2-chloroacetamido)phenyl) carbamate.

A mixture of 2-chloroacetic acid (3.02 ml, 26.8 mmol) and HATU (11.7 g, 30.9 mmol) in DMF (20 ml) was stirred at 25°C for 12 hours. Benzyl ( 3aminophenyl)carbamate (5.00 g, 20.6 mmol) and DIPEA (10.7 ml, 61.9 mmol). The reaction mixture was stirred at 25°C for 4 hours. The mixture was filtered and concentrated under vacuum, the residue was purified by preparative reverse phase liquid chromatography (40-70% acetonitrile + 0.05% hydrochloric acid in water, for 20 minutes). The collected fractions were concentrated, pH adjusted to 8 with saturated sodium bicarbonate solution and extracted with EtOAc (100 mlx3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give benzyl (3-(2chloroacetamido)phenyl) carbamate (3.50 g, 10.9 mmol, 53.2% yield) as a white solid. MS (ESI) m/z 319.1 [M+1] ⁺ (S)-tert-Butyl 4-(2-((3-(((benzyloxy)carbonyl)amino)phenyl)amino)-2-oxoethyl) -3(trifluoromethyl)piperazine-1-carboxylate.

To a mixture of tert-butyl (3S)-3-(trifluoromethyl)piperazine-1-carboxylate (0.40 g, 1.57 mmol) and benzyl (3-(2-chloroacetamido)phenyl)carbamate (0.70 g, 2 .20 mmol) sodium iodide (71.0 mg, 0.47 mmol) and DIPEA (0.82 ml, 4.72 mmol) were added to DMF (5 ml). The reaction mixture was stirred at 90°C for 12 hours. The mixture was poured into water and extracted with EtOAc (20 mlx3). The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (0-15% EtOAc/petroleum ether). (S)-tert-butyl 4-(2-((3-(((benzyloxy)carbonyl)amino)phenyl)amino)2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.44 g, crude) was obtained as a yellow oil. MS (ESI) m/z 559.2 [M+Na] ⁺ .

(S)-tert-Butyl 4-(2-((3-aminophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.

A mixture of (S)-tert-butyl 4-(2-((3-(((benzyloxy)carbonyl)amino)phenyl)amino)-2-oxoethyl)-3(trifluoromethyl)piperazine-1-carboxylate (0.44 g , 0.83 mmol) and palladium on activated carbon (0.10 g, 10 wt.%) in MeOH (10 ml) was stirred at 25°C under hydrogen atmosphere for 12 hours. The mixture was filtered and concentrated in vacuum to obtain (S)-tert-Butyl 4-(2-((3-aminophenyl)amino)-2oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.28 g, 0.69 mmol, 83.9% yield ) as a crude, colorless oil. MS (ESI) m/z 347.1 [M+1] ⁺ .

(3S)-tert-Butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3(trifluoromethyl)piperazine-1-carboxylate.

To a mixture of (S)-tert-butyl 4-(2-((3-aminophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1carboxylate (0.28 g, 0.69 mmol) and 3- Bromopiperidine-2,6-dione (0.40 g, 2.09 mmol) in DMF (5 ml) was added sodium bicarbonate (0.17 g, 2.09 mmol). The reaction mixture was stirred at 60°C for 48 hours, then the mixture was poured into water and extracted with EtOAc (30 mlx3). The combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (60% EtOAc/petroleum ether) to give (3S)-tert-butyl 4-(2-((3-((2,6dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl )-3-(trifluoromethyl)piperazine-1-carboxylate (0.18 g, 0.35 mmol, 51.2% yield) as a light yellow oil. MS (ESI) m/z 514.2 [M+1] ⁺ .

N-(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide.

To the mixture (3B)-tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3(trifluoromethyl)piperazine-1- carboxylate (0.18 g, 0.13 mmol, 1 eq.) in DCM (5 ml) was added hydrobromic acid/acetic acid (0.48 ml, purity 33%). The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated in vacuo to give crude N-(3-((2,6-115 044376 dioxopiperidin-3-yl)amino)phenyl)-2-((S)- 2-(trifluoromethyl)piperazin-1-yl)acetamide (0.30 g, hydrobromic acid) as a red solid.

4-(3-(3-Cyclopropyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

A mixture of 2-((3-cyclopropyl-4-hydroxyphenyl)amino)-2-methylpropanenitrile (5.00 g, 23.1 mmol, 1 eq.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (5.80 g , 25.4 mmol, 1.1 eq.) in DMF (30 ml) was stirred at 25°C for 1 h. Then hydrochloric acid/MeOH (4 M, 11.56 ml, 2 eq.) was added and the reaction the mixture was stirred at 80°C for 12 hours. The residue was purified by preparative reverse phase chromatography (40-70% acetonitrile + 0.05% hydrochloric acid in water, 25 min). The collected fractions were concentrated in vacuo and adjusted to pH 8 with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl ether (300 mlx3) and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-(3-(3cyclopropyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo- 2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (4.90 g, 11.0 mmol, 47.6% yield) as a white solid. MS (ESI) m/z 446.2 [M+1] ⁺ .

4-(3-(4-(2-Bromoethoxy)-3-cyclopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

To a mixture of 4-(3-(3-cyclopropyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)2-(trifluoromethyl)benzonitrile (1.00 g, 2.24 mmol, 1 eq.) and 1,2-dibromoethane (8.43 g, 44.9 mmol, 3.39 mL, 20 eq.) in acetonitrile (10 mL) was added potassium carbonate (0.93 g, 6.73 mmol, 3 eq.). The reaction mixture was stirred at 80°C for 24 hours. The mixture was filtered and concentrated in vacuum, the residue was purified by preparative reverse phase chromatography (57-87% acetonitrile + 0.05% hydrochloric acid in water, 20 min) to obtain 4-( 3-(4-(2-bromoethoxy)-3-cyclopropylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.650 g, 1.10 mmol, yield 49 .2%, hydrochloride) as a white solid. MS (ESI) m/z 554.0 [M+1] ⁺ .

2-((8)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1yl)-2- cyclopronylphenoxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide.

To a mixture of N-(3-((2,6-dioxopiperudin-3-yl)amino)phenyl)-2-((S)-2-(trifluoromethyl)piperαzin-1yl)acetamide (0.12 g, 0.25 mmol, 1 equiv., hydrobromic acid) and 4-(3-(4-(2-bromoethoxy)-3cyclopropylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl )benzonitrile (0.16 g, 0.28 mmol, 1.13 eq., hydrochloride) in DMF (2 ml) was added DIPEA (0.13 ml, 3 eq.) and sodium iodide (0.01 g, 0. 76 mmol, 0.3 eq.). The reaction mixture was stirred at 60°C for 12 hours. The mixture was filtered and purified by standard methods to obtain 2-((S)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)- 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl)-2(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxoniperudin- 3-yl)amino)phenyl)acetamide (0.09 g, 90.5 µmol, yield 35.8%, purity 97%, hydrochloride). MS (ESI) m/z 885.3 [M+1] ⁺ .

^1H NMR (400 MHz, DMSOC) δ 11.10 (s, 1H), 10.79 (s, 1H), 9.70 (br s, 1H), 8.39 (d, J=8.4 Hz , 1H), 8.27 (d, J=1.6 Hz, 1H), 8.06 (dd, J=1.6, 8.4 Hz, 1H), 7.15 (s, 2H), 7 .04-6.93 (m, 2H), 6.84 (s, 1H), 6.82-6.76 (m, 1H), 6.40 (d, J=7.6 Hz, 1H), 4.54 (s, 3H), 4.24 (dd, J=4.4, 11.2 Hz, 1H), 3.66-3.44 (m, 6H), 3.41-3.24 ( m, 2H), 3.23-3.14 (m, 1H), 2.79-2.68 (m, 1H), 2.64-2.56 (m, 1H), 2.25-2. 01 (m, 3H), 1.97-1.81 (m, 1H), 1.47 (s, 6H), 1.00-0.89 (m, 2H), 0.61 (d, J= 3.6 Hz, 2H).

Example 46: 2-((2S,6R)-4-((S)-1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2thioxoimidazolidin-1-yl)-2-ethylphenoxy)propan-2-yl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide and 2-((2S,6R)-4-((R)-1-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine- 1-yl)-2-ethylphenoxy)propan-2-yl)2,6-dimethylniperazin-1-yl)-N-(3-((2,6-dioxopuperidin-3-yl)amino)phenyl)acetamide (2S ,6R)-tert-butyl 4-((S)-1-methoxy-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (2S,6R)-tert-butyl 4-(( R)-1-methoxy-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate.

To a mixture of (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (1.20 g, 5.60 mmol) and (R)-methyl 2-chloropropanoate (0.9 ml, 8.40 mmol ) in DMF (10 ml) was added DIPEA (2.9 ml, 16.8 mmol) one

- 116 044376 portion at 25°C. The mixture was heated to 60°C and stirred for 12 hours. The mixture was poured into water (20 ml) and the aqueous phase was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc 3:1) to give a mixture of (2S,6R)-tert-butyl 4-((S)-1-methoxy-1-oxopropan-2-yl)-2,6- dimethylpiperazine-1-carboxylate and (2S,6R)-tert-butyl 4-((R)-1-methoxy-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (0.70 g, 2.33 mmol, yield 41.6%) as a light yellow oil.

¹ H NMR (400 MHz, CDCI3) δ 4.04-4.12 (m, 2H), 3.70 (s, 3H), 3.36 (k, J=7.2 Hz, 1H), 2, 54-2.67 (m, 3H), 2.38 (dd, J=11.6, 4.4 Hz, 1H), 1.47 (s, 9H), 1.25-1.31 (m, 9H).

(2S,6R)-tert-Butyl 4-((S)-1-hydroxypropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (2S,6R)tert-butyl 4-((R)- 1-Hydroxypropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate.

To a solution of the above mixture (0.68 g, 2.26 mmol) in THF (10 ml) was added lithium aluminum hydride (0.13 g, 3.40 mmol) in portions at 0°C. The reaction mixture was stirred at 0°C for 1 hour. THF (12 ml) and anhydrous sodium sulfate (10 g) were added to the reaction mixture. Water (2 ml) was then added dropwise to the stirred mixture at 0°C, and the mixture was stirred at 25°C for 0.5 hours. The suspension was filtered and the filter cake was washed with EtOAc (20 ml). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc, 1:1) to give a mixture of (2S,6R)-tert-butyl 4-((S)-1-hydroxypropan-2-yl)-2 ,6-dimethylpiperazine-1-carboxylate and (2S,6R)-tert-butyl 4-((R)-1-hydroxypropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (0.56 g, 2.04 mmol, yield 90.2%) as a colorless oil.

¹ H NMR (400 MHz, CDCl·,) δ 4.15 (k, J=6.0 Hz, 2H), 3.43-3.51 (m, 1H), 3.33-3.42 (m , 1H), 3.25 (s, 1H), 2.82-2.92 (m, 1H), 2.77 (dd, J=11.2, 4.4 Hz, 1H), 2.40-2, 58 (m, 2H), 2.29 (dd, J=11.2, 4.4 Hz, 1H), 1.58 (s, 1H), 1.48 (s, 9H), 1.23-1 .36 (m, 6H), 0.88 (d, J=6.8 Hz, 3H).

(2S,6R)-tert-Butyl 4-((S)-1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1 -yl)-2-ethylphenoxy)propan-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (2S,6R)tert-butyl 4-((R)-1-(4-(3-(4 -cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2-ethylphenoxy)propan-2-yl)-2,6-dimethylpiperazine-1-carboxylate.

To a mixture of 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.50 g, 1.15 mmol) and the mixture obtained above (0.47 g, 1.73 mmol) in toluene (4 ml) was added (E)-diazen-1,2-diylbis(piperidin-1-ylmethanone) (0.58 g, 2 .31 mmol) at 25°C in a nitrogen atmosphere. The mixture was cooled to 0°C and tributylphosphane (0.57 ml, 2.31 mmol) was added dropwise. The mixture was then heated to 110°C and stirred for 12 hours. The mixture was concentrated under reduced pressure at 45°C. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc 2:1) to give a mixture of (2S,6R)-t-butyl 4-((S)-1-(4-(3-(4-cyano-3-(trifluoromethyl )phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propan-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (2S,6R)-tert- butyl 4-((R)-1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy) propan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (0.70 g, 1.02 mmol, 88.2% yield) as a light yellow solid. MS (ESI) m/z 688.2 [M+1]+.

1H NMR (400 MHz, CDC13) δ 7.95-8.01 (m, 2H), 7.85 (dd, J=8.4, 2.0 Hz, 1H), 7.03-7.11 ( m, 2H), 6.93 (d, J=8.4 Hz, 1H), 4.05-4.11 (m, 3H), 3.85-3.96 (m, 1H), 3.05-3 .19 (m, 1H), 2.62-2.74 (m, 5H), 1.58 (s, 6H), 1.47 (s, 9H), 1.27-1.32 (m, 9H ), 1.21-1.25 (m, 3H).

4-(3-(4-((S)-2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)propoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo- 2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile and 4-(3-(4-((R)-2-((3S,5R)-3,5dimethylpiperazin-1-yl)propoxy)-3-ethylphenyl )-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile.

To a solution of the mixture obtained above (0.70 g, 1.02 mmol, 1 eq.) in DCM (15 mL), TFA (7.70 g, 67.5 mmol, 5 mL, 66.4 eq.) was added. one portion at 0°C in an N2 atmosphere. The mixture was stirred at 25°C for 1 hour. The mixture was purified by semipreparative reverse phase HPLC (29-49% acetonitrile in water + 0.1% TFA, 10 min). The mixture was concentrated under reduced pressure at 45°C to remove acetonitrile, and the aqueous phase was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with DCM (50 ml x 3 ) and the combined organic phases were washed with brine (50 ml x 3 ), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The desired mixture of products 4-(3-(4-((S)-2-((3 S,5R)-3,5-dimethylpiperazin-1 -yl)propoxy)-3-ethylphenyl)-4,4dimethyl-5- oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile and 4-(3-(4-((R)-2-((3S,5R)3,5-dimethylpiperazin-1-yl)propoxy )-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2(trifluoromethyl)benzonitrile (0.48 g, 0.81 mmol, yield 79.4%, purity 99 %) was isolated as a light yellow oil. MS (IER) m/z 588.2 [M+1] ⁺

Enantiomer 1 and 2: 4-(3-(4-((S or R)-2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)propoxy)-3ethylphenyl)-4,4-dimethyl -5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. The above mixture (0.48 g, 0.81 mmol) was purified by chiral SLC (column: PhenomenexCellulose-2 (250 mmx30 mm, 10 μm); mobile phase: 50% 0.1% ammonia in 2-propanol, 3 ,7 min), with 117 044376 obtaining 2 peaks for which chirality was not determined.

Enantiomer 2 (0.27 g, 0.46 mmol, 55.8% yield, 99.6% purity) was obtained as a light yellow oil.

^1H NMR (400 MHz, CDCl3) δ 7.95-8.01 (m, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.03-7.11 (m, 2H ), 6.93 (d, J=8.4 Hz, 1H), 4.09-4.14 (m, 1H), 3.89-3.99 (m, 1H), 3.01-3.14 ( m, 1H), 2.87-2.98 (m, 2H), 2.75-2.85 (m, 2H), 2.70 (k, J=7.2 Hz, 2H), 2.02 -2.09 (m, 2H), 1.58 (s, 6H), 1.22-1.26 (m, 6H), 1.08 (d, J=6.0 Hz, 6H).

Enantiomer 1 (0.14 g, 0.24 mmol, 28.8% yield, 96.1% purity) was obtained as a light yellow oil.

1H NMR (400 MHz, CDCl3) δ 7.95-8.02 (m, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.03-7.12 (m, 2H) , 6.93 (d, J=8.4 Hz, 1H), 4.10-4.13 (m, 1H), 3.91-3.97 (m, 1H), 3.03-3.15 (m , 1H), 2.89-3.00 (m, 2H), 2.81 (t, J=12.4 Hz, 2H), 2.70 (k, J=7.60 Hz, 2H), 2 .05-2.18 (m, 2H), 1.58 (s, 6H), 1.21-1.26 (m, 6H), 1.09 (d, J=6.0 Hz, 6H);

Enantiomer 2: 2-((2S,6R)-4-((S or R)-1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo- 2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propan-2-yl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl) acetamide

To a mixture of the above enantiomer 2 (0.22 g, 0.37 mmol, 1 eq.) and 2-chloro-X-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide (0.17 g, 0.56 mmol, 1.5 eq.) in DMF (5 ml) was added DIPEA (0.15 g, 1.12 mmol, 0.2 ml, 3 eq.) and potassium iodide (0.03 g, 0.19 mmol, 0.5 eq.) in one serving at 25°C. The mixture was heated to 50°C and stirred for 12 hours. The mixture was cooled to 25°C and the residue was poured into water (10 ml). The aqueous phase was extracted with EtOAc (10 ml x 3) and the combined organic phases were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by standard methods to give the enantiomer 2 2((2S,6R)-4-((S or R)-1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)propan-2-yl)-2,6-dimethylpiperazin-1-yl)-X-(3-((2,6dioxopiperidin-3-yl) amino)phenyl)acetamide (0.12 g, 0.13 mmol, 34.9% yield, 99.0% purity, hydrochloride). MS (ESI) m/z 847.3 [M+1]+.

1H NMR (400 MHz, DMSO-d6+D2O) δ 8.37 (d, J=8.4 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.06 (dd , J=8.0, 1.6 Hz, 1H), 7.10-7.26 (m, 3H), 7.00-7.08 (m, 1H), 6.90-6.95 (m , 1H), 6.78-6.87 (m, 1H), 6.46 (dd, J=8.0, 2.0 Hz, 1H), 4.40-4.47 (m, 1H), 4.30-4.38 (m, 1H), 4.25 (dd, J=11.2, 4.8 Hz, 1H), 4.10-4.22 (m, 2H), 3.86- 4.08 (m, 3H), 3.55-3.80 (m, 4H), 2.68-2.79 (m, 2H), 2.54-2.65 (m, 2H), 2. 03-2.13 (m, 1H), 1.84-1.96 (m, 1H), 1.51 (d, J=6.8 Hz, 3H), 1.49 (s, 6H), 1 .32 (d, J=4.8 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H).

Enantiomer 1 was obtained by the same method (0.058 g, 0.063 mmol, 16.82% yield, 95.29% purity, hydrochloride). MS (ESI) m/z 847.4 [M+1]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.79 (s, 1H), 8.38-8.40 (d, J=8.0 Hz, 1H), 8.29 (d, J=1 .6 Hz, 1H), 8.068.08 (d, J=8.4 Hz, 1H), 7.17-7.23 (m, 3H), 7.02-7.06 (m, 1H), 6 .96 (ush, s, 1H), 6.81-6.83 (d, J=8.0 Hz, 1H), 6.44-6.46 (d, J=8.8 Hz, 1H), 4.36-4.43 (m, 2H), 4.24-4.28 (m, 1H), 3.85 (m, 2H), 3.66 (m, 7H), 2.69-2, 78 (m, 3H), 2.57-2.61 (m, 1H), 2.08-2.11 (m, H), 1.86-1.95 (m, 1H), 1.50 ( s, 9H), 1.30 (m, 6H), 1.16-1.20 (d, J=7.6 Hz, 3H).

Example 47: 2-((2S,6R)-4-((R)-2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl- 4-oxo2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazin-1-yl)-X-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide and 2-((2S,6R)-4-((S)-2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)2,6-dimethylpiperazin-1-yl)-X-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (2S ,6R)-tert-butyl 4-((S)-2-hydroxypropyl)-2,6-dimethylpiperazine-1-carboxylate and (2S,6R)-tert-butyl 4-((R)-2-hydroxypropyl)-2, 6-dimethylpiperazine-1-carboxylate.

A mixture of (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (1.50 g, 7.00 mmol) and (S)-2methyloxirane (588 μL, 8.40 mmol) in water (10 ml ) was stirred for 20 hours at 70°C. Water (10 ml) was added to the reaction mixture, and then the mixture was extracted with DCM (10 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of (2S,6R)-tert-butyl 4-((S)-2-hydroxypropyl)-2,6-dimethylpiperazine-1carboxylate and (2S, 6R)-tert-Butyl 4-((R)-2-hydroxypropyl)-2,6-dimethylpiperazine-1-carboxylate (1.80 g, 6.61 mmol, 94.4% yield) as a crude colorless oil.

- 118 044376 ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.08-4.14 (m, 2H), 3.79-3.88 (m, 1H), 3.40 (s, 1H), 2 .73-2.76 (d, J=11.2 Hz,

1H), 2.56-2.58 (m, 1H), 2.43-2.46 (m, 1H), 2.21-2.30 (m, 2H), 2.08-2.12 ( d, J=11.2, 4.4 Hz, 1H), 1.46 (s, 9H),

1.27-1.31 (m, 6H), 1.14-1.16 (d, J=6.0 Hz, 3H).

(2S,6R)-tert-Butyl 4-((R)-2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo -2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazine-1-carboxylate and (2S,6R)-tert-butyl 4-((S)-2-(4-(3-(6- cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazine-1-carboxylate.

To a solution of the mixture obtained above (0.60 g, 2.20 mmol, 1 eq.) and 5-(3-(3-ethyl-4-hydroxyphenyl)-4,4dimethyl-5-oxo-2-thioxoimidazolidine-1- yl)-3-(trifluoromethyl)picolinonitrile (0.96 g, 2.20 mmol, 1 eq.) in anhydrous THF (1 ml) was added PPh ₃ (0.69 g, 2.64 mmol, 1.2 eq. ), then (E)-diisopropyldiazene 1,2-dicarboxylate (1.34 g, 6.61 mmol, 1.28 ml, 3 eq.) at 0°C, and then the reaction mixture was heated to 20°C for 12 hours in a nitrogen atmosphere. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by semipreparative reverse phase HPLC (48-68% acetonitrile in water + 0.1% TFA, 10 min) and repurified by semipreparative reverse phase HPLC (43-63% acetonitrile in water + 0.1% TFA, 10 min ). The pH of the collected fractions was adjusted to 7-8 with saturated sodium bicarbonate, and the fractions were concentrated to remove organic volatiles. The aqueous solution was extracted with EtOAc (30 mlx3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of (2S,6R)tert-butyl 4-((R)-2-(4-(3 -(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazine-1- carboxylate and (2S,6R)tert-butyl 4-((S)-2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazine-1-carboxylate (0.45 g, 0.65 mmol, 29.6% yield) as a brown solid, and chiral SLC showed 31% ee. MS (ESI) m/z 689.2 [M+1] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 9.10 (s, 1H), 8.37 (s, 1H), 6.99-7.06 (m, 3H), 4.57-4.62 (m , 1H), 4.07-4.10 (m, 2H), 2.65-2.73 (m, 5H), 2.51-2.56 (m, 1H), 2.27-2.33 (m, 2H), 1.60 (s, 6H), 1.47 (s, 9H), 1.44-1.45 (d, J=6.0 Hz, 1H), 1.26-1, 27 (m, 6H), 1.20-1.24 (m, 3H).

Enantiomers 1 and 2: (2S,6R)-tert-butyl 4-((R or S)-2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3yl)-5,5- dimethyl 4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazine-1carboxylate.

Two enantiomers (2S,6R)-tert-butyl 4-((R)-2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5dimethyl-4-oxo -2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazine-1carboxylate (0.45 g, 0.65 mmol, 1 eq.) and (2S,6R)-tert-butyl 4 -((S)-2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2 -ethylphenoxy)propyl)2,6-dimethylpiperazine-1-carboxylate (0.20 g, 0.29 mmol, 0.44 eq.) was separated by chiral SLC (column: Chiralpak AD-3 (50x4.6 mm I.D, 3 µm); mobile phase: phase A carbon dioxide, and phase B isopropanol (0.05% diisopropylamine); gradient elution: 5-40% IP (0.05% DIPEA) in carbon dioxide; flow rate: 3 ml/min; wavelength: 220 nm; column temperature: 35°C; back pressure: 100 bar). The two enantiomers were then further purified by chiral HPLC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: 20% 0.1% ammonia in isopropanol, 4.5 min, 60 min). The chirality of the two products was not determined.

Enantiomer 1 (0.34 g, 0.49 mmol, 75.4% yield, 99.7% purity) was obtained as a brown solid with 100% ee.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.10 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 7.05-7.07 (m, 2H), 6.99-7.01 (m, 1H), 4.56-4.63 (m, 1H), 4.05-4.11 (m, 2H), 2.61-2 .73 (m, 5H), 2.51-2.56 (m, 1H), 2.27-2.33 (m, 2H), 1.60 (s, 6H), 1.47 (s, 9H ), 1.44-1.45 (d, J=6.0 Hz, 3H), 1.25-1.27 (m, 6H), 1.22-1.23 (m, 3H);

Enantiomer 2 (0.18 g, 0.26 mmol, 39.8% yield, 99.4% purity) was obtained as a brown solid with 100% ee.

¹ H NMR (400 MHz, CDCU) δ 9.10 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 7.05-7.07 ( m, 2H), 6.99-7.01 (m, 1H), 4.56-4.63 (m, 1H), 4.07-4.10 (m, 2H), 2.65-2, 73 (m, 5H), 2.51-2.56 (m, 1H), 2.27-2.33 (m, 2H), 1.60 (s, 6H), 1.47 (s, 9H) , 1.44-1.45 (d, J=6.0 Hz, 3H), 1.25-1.27 (m, 6H), 1.22-1.23 (m, 3H).

Enantiomers 1 and 2 5-(3-(4-(((R or S)-1-((3S,5R)-3,5-Dimethylpiperazin-1-yl)propan-2-yl)oxy)-3ethylphenyl) -4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.

To a solution of enantiomer 1, (2S,6R)-tert-butyl 4-((R or S)-2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5,5 -dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)2,6-dimethylpiperazine-1-carboxylate (0.34 g, 0.49 mmol, 1 eq.) in DCM (6 ml) TFA (3.08 g, 27.0 mmol, 2 ml, 54.7 eq.) was added and the mixture was stirred for 2 hours at 20°C. The reaction mixture was poured into saturated ammonium chloride (10 ml) and extracted with DCM (10 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude enantiomer 1 5-(3-(4-(((R or S)-1-((3S,5R)-3,5-dimethylpiperazine -1yl)propan-2-yl)oxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3- 119 044376 (trifluoromethyl)picolinonitrile (0.24 g, 0.41 mmol, 82.6% yield) as a brown solid. MS (ESI) m/z 589.2 [M+1]+.

Enantiomer 2: 5-(3-(4-(((R or S)-1-((3S,5R)-3,5-dimethylpiperazin-1-yl)propan-2-yl)oxy)-3ethylphenyl)- 4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile was obtained by the same methods as a yellow oil. (130 mg, crude) MS (ESI) m/z 589.3 [M+1] ⁺ .

Enantiomers 1 and 2: 2-((2S,6R)-4-((R or S)-2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5, 5dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3((2,6-dioxopiperidin-3-yl)amino )phenyl)acetamide.

To a solution of enantiomer 1, 5-(3-(4-(((R or S)-1-((3S,5R)-3,5-dimethylpiperazin-1-yl)propan-2yl)oxy)-3-ethylphenyl )-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile (0.24 g, 0.41 mmol, 1 eq.), and 2-chloro-N-[ 3-[(2,6-dioxo-3piperidyl)amino]phenyl]acetamide (0.12 g, 0.41 mmol, 1 eq.) in DMF (2.5 ml) was added DIPEA (0.16 g, 1. 22 mmol, 213 µl, 3 eq.) and then potassium iodide (0.03 g, 0.20 mmol, 0.5 eq.). The reaction mixture was stirred for 12 hours at 60°C, and then concentrated under reduced pressure to obtain a residue. The residue was purified by standard methods to obtain enantiomer 1 2-((2S,6R)-4-((R or S)2-(4-(3 -(6-cyano-5-(trifluoromethyl)pyridin-3-yl)- 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethylphenoxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3yl) amino)phenyl)acetamide (0.14 g, 0.15 mol, 38.4% yield, 97.0% purity, hydrochloride). MS (ESI) m/z 848.4 [M+1]+;

¹ H NM (400 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 9.25-9.26 (d, J=2.0 Hz, 1H), 8.83-8.84 ( d, J=2.0 Hz, 1H), 7.27-7.29 (m, 1H), 7.16-7.21 (m, 2H), 7.03-7.07 (m, 1H) , 6.98 (s, 1H), 6.86-6.88 (d, J=8.0 Hz, 1H), 6.46-6.48 (d, J=6.8 Hz, 1H), 5.19 (s, 1H), 4.25-4.29 (m, 5H), 3.73 (m, 3H), 3.48 (m, 3H), 2.67-2.79 (m, 3H), 2.57-2.63 (m, 1H), 2.07-2.11 (m, 1H), 1.86-1.96 (m, 1H), 1.53 (s, 6H) , 1.30-1.38 (m, 9H), 1.15-1.19 (t, J=7.8 Hz, 3H).

Enantiomer 2: 2-((2S,6R)-4-((R or S)-2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5dimethyl- 4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3((2,6-dioxopiperidin-3-yl)amino)phenyl )acetamide (0.088 g, 0.104 mmol, 45.20% yield, 100% purity, hydrochloride) was prepared by the same method. MS (ESI) m/z 848.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSOC) δ 11.05-10.35 (m, 2H), 9.25 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz , 1H), 7.31-7.23 (m, 1H), 7.23-7.13 (m, 2H), 7.09-6.95 (m, 2H), 6.87 (d, J =8.0 Hz, 1H), 6.47 (d, J=7.2 Hz, 1H), 5.20 (s, 1H), 4.45-4.00 (m, 5H), 3.94 -3.25 (m, 6H), 2.79-2.54 (m, 4H), 2.14-2.03 (m, 1H), 1.97-1.83 (m, 1H), 1 .52 (s, 6H), 1.34-1.24 (m, 9H), 1.16 (t, J=7.6 Hz, 3H).

Example 48: 2-((2R,6S)-4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo- 2thioxoimidazolidin-1-yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide

1-(Benzyloxy)-2-bromo-4-nitrobenzene.

Potassium carbonate was added to a mixture of 2-bromo-4-nitrophenol (50.0 g, 0.229 mol, 1 eq.) and bromomethylbenzene (47.0 g, 0.27 mol, 1.2 eq.) in acetonitrile (500 ml). (63.4 g, 0.46 mol, 2 eq.), and the reaction mixture was stirred for 12 hours at 80°C. The reaction mixture was concentrated under reduced pressure to remove acetonitrile. Water was added, the mixture was filtered, and the filter cake was washed with water. The crude product was triturated with petroleum ether/EtOAc (20:1), stirring at 25°C for 30 min and then filtered to give 1-(benzyloxy)-2-bromo-4-nitrobenzene (68.0 g, 0.22 mol, yield 96.2%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.48-8.49 (d, J=2.8 Hz, 1H), 8.16-819 (dd, J=9.2 Hz, 2.8 Hz, 1H), 7.35-7.48 (m, 5H), 6.99-7.02 (d, J=9.2 Hz, 1H), 5.28 (s, 2H).

1-(Benzyloxy)-2-cyclobutyl-4-nitrobenzene.

To a solution of 1-(benzyloxy)-2-bromo-4-nitrobenzene (5.00 g, 16.2 mmol, 1 eq.) and cyclobutylboronic acid (2.43 g, 24.3 mmol, 1.5 eq.) in toluene (50 ml) and water (10 ml), cesium carbonate (15.8 g, 48.6 mmol, 3 eq.) was added, followed by Pd(dppf) ₂ Cl ₂ (1.19 g, 1.62 mmol , 10 mol.%). The reaction mixture was stirred for 48 hours at 100°C under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by semipreparative reverse-phase HPLC (55-85% acetonitrile in water + 0.1% TFA, 25 min). The pH of the collected fractions was adjusted to 7-8 with saturated sodium bicarbonate, the fractions were concentrated to remove organic volatiles, and the aqueous solution was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(benzyloxy)-2-cyclobutyl-4-nitrobenzene (2.50 g, 8.82 mmol, 13.6% yield) as white - 120 044376 th solid. MS (ESI) m/z: 284.1 [M+1]+.

1H NMR (400 MHz, CDCl ₃ ) δ 8.07-8.13 (m, 2H), 7.36-7.45 (m, 5H), 6.90-6.92 (d, J=8, 8 Hz, 1H), 5.17 (s,

2H), 3.72-3.83 (m, 1H), 2.35-2.42 (m, 2H), 2.12-2.22 (m, 2H), 2.01-2.09 ( m, 1H), 1.83-1.91 (m, 1H).

4-(Benzyloxy)-3-cyclobutylaniline.

Ammonium chloride (2.36 g, 44.1 mmol, 5 eq.), then iron (1.48 g, 26.4 mmol, 3 eq.). The reaction mixture was stirred for 1 hour at 60°C. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 8:1-3:1) to give 4(benzyloxy)-3-cyclobutylaniline (1.90 g, 7.50 mmol, 84.9% yield) as a brown oil . MS (ESI) m/z: 254.1 [M+1] ⁺ .

2-((4-(Benzyloxy)-3-cyclobutylphenyl)amino)-2-methylpropanenitrile.

To a mixture of 4-(benzyloxy)-3-cyclobutylaniline (1.10 g, 4.34 mmol) in 2-hydroxy-2methylpropanenitrile (4.0 mL, 43.8 mmol) was added magnesium sulfate (1.31 g, 10. 8 mmol). The mixture was heated to 60°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo and the residue was poured into water (30 ml). The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction mass was used directly in the next step without additional purification. The compound 2-(4-benzyloxy-3-cyclobutylanilino)-2-methylpropanenitrile (1.50 g, crude) was obtained as a yellow oil. MS (ESI) m/z 294.2 [M+1-] ⁺ .

5-(3-(4-(Benzyloxy)-3-cyclobutylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

A solution of 2-(4-benzyloxy-3-cyclobutylanilino)-2-methylpropanenitrile (1.50 g, 4.68 mmol) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (1.29 g, 5.62 mmol ) in DMF (10 ml) was stirred at 25°C for 1 hour. Hydrochloric acid in MeOH (4 M, 5.85 ml) was added to the solution and the reaction mixture was stirred at 80°C for 1 hour. The residue was poured into water (50 ml) and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by semipreparative reverse phase HPLC (85-98% acetonitrile in water + 0.2% hydrochloric acid, for 12 min). The residue was poured into saturated aqueous sodium bicarbonate (30 ml) and the aqueous phase was extracted with EtOAc, which was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Compound 5-(3-(4-(benzyloxy)-3-cyclobutylphenyl)-4,4-dimethyl-5-oxo-2thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.18 g, 2.14 mmol, yield 45.8%) was obtained as a yellow oil. MS (ESI) m/z 551.3 [M+1] ⁺ .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.09-9.14 (d, J=2.4 Hz, 1H), 8.37-8.40 (d, J=2.4 Hz, 1H) , 7.34-7.48 (m, 5H), 7.05-7.12 (m, 2H), 6.96-7.02 (m, 1H), 5.11 (s, 2H), 3 .75-3.88 (m, 1H), 2.31-2.43 (m, 2H), 2.06-2.19 (m, 3H), 1.78-1.87 (m, 1H) , 1.62 (s, 6H).

5-(3-(3-Cyclobutyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3(trifluoromethyl)picolinonitrile.

To a solution of 5-(3-(4-(benzyloxy)-3-cyclobutylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1yl)-3-(trifluoromethyl)picolinonitrile (1.18 g, 2. 14 mmol) in DCM (15 ml) at -70°C under nitrogen, tribromoborane (1.61 g, 6.43 mmol) was added. The reaction mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched by adding saturated sodium bicarbonate solution (30 ml) at -20°C and further diluting with water (20 ml). The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel chromatography (0-25% EtOAc/petroleum ether) to give 5-(3-(3-cyclobutyl-4hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)- 3-(trifluoromethyl)picolinonitrile (0.53 g, 1.15 mmol, 53.7% yield) as a yellow solid. MS (ESI) m/z 461.2 [M+1] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 9.09-9.12 (d, J=2.4 Hz, 1H), 8.37-8.39 (d, J=2.0 Hz, 1H), 7.03-7.06 (d, J=2.4 Hz, 1H), 6.98-7.02 (m, 1H), 6.87-6.91 (d, J=8.4 Hz, 1H), 5.08 (s, 1H), 3.65-3.75 (m, 1H), 2.38-2.47 (m, 2H), 2.08-2.23 (m, 3H) , 1.86-1.94 (m, 1H), 1.62 (s, 6H).

tert-Butyl 2-((2R,6S)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To a solution of 5-(3-(3-cyclobutyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)3-(trifluoromethyl)picolinonitrile (0.33 g, 0.71 mmol, 1 eq.), tert-butyl 2-((2R,6S)-4-(2-hydroxyethyl)2,6-dimethylpiperazin-1-yl)acetate (0.39 g, 1.43 mmol, 2 eq. .) and PPh ₃ (0.37 g, 1.43 mmol, 2 eq.) in THF (2 ml) was added (E)-diisopropyldiazene-1,2-dicarboxylate (0.28 g, 1.43 mmol, 2 eq.) at 0°C.

The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, and the crude product was purified by a semipreparative

- 121 044376 reverse-phase HPLC (50-70% acetonitrile in water + 0.1% TFA, 10 min). The residue was poured into saturated aqueous sodium bicarbonate and the aqueous phase was extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Tert-butyl compound 2((2R,6S)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin1-yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (0.16 g, 0.22 mmol, 32.0% yield) was obtained as a yellow solid. MS (ESI) m/z 715.5 [M+1] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 9.12-9.19 (d, J=2.0 Hz, 1H), 8.64-8.68 (d, J=2.0 Hz, 1H), 7.11-7.19 (m, 2H), 7.00-7.06 (d, J=8.8 Hz, 1H), 4.15-4.23 (t, J=5.2 Hz, 2H), 3.72-3.82 (m, 1H), 3.44 (s, 2H), 2.97-3.09 (m, 2H), 2.88-2.96 (m, 2H) , 2.80-2.86 (t, J=5.6 Hz, 2H), 2.31-2.42 (m, 2H), 2.02-2.16 (m, 5H), 1.80 -1.89 (m, 1H), 1.57 (s, 6H), 1.47 (s, 9H), 1.06-1.13 (d, J=6.4 Hz, 6H).

2-((2R,6S)-4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid.

A solution of tert-butyl 2-((2R,6S)-4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2 -thioxoimidazolidin-1-yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (0.16 g, 0.23 mmol, 1 eq.) was treated with hydrochloric acid in dioxane (4 M, 3.32 ml, 57.1 eq.) and stirred at 25°C for 10 hours. The reaction mixture was concentrated under reduced pressure to give crude 2-((2R,6S)-4-(2-(4-(3 -(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazine-1- yl)acetic acid (0.16 g, crude, hydrochloride) as a white solid. MS (ESI) m/z 659.1 [M+1] ⁺ .

2-((2R,6S)-4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1 -yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-δ(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide.

To a mixture of 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.08 g, 0.34 mmol, 1.5 equiv, hydrochloride), 2((2R,6S)-4-(2 -(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)-2-cyclobutylphenoxy)ethyl)-2, 6-Dimethylpiperazin-1-yl)acetic acid (0.15 g, 0.22 mmol, 1 eq.), HATU (0.13 g, 0.34 mmol, 1.5 eq.) in DMF (1 ml) DIPEA (0.14 g, 1.14 mmol, 5 eq.) was added and the reaction mixture was stirred at 25°C for 12 hours. The mixture was poured into water (50 ml), the aqueous phase was extracted with EtOAc, and the combined organic layers were washed brine (30 mlx5), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by standard methods to give 2-((2R,6S)-4-(2-(4-(3-(6-cyαno-5-(trifluoromethyl)pyridin-3-yl)-5,5dimethyl-4-oxo -2-thioxoimidazolidin-1-yl)-2-cyclobutylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide ( 72.0 mg, 0.08 mmol, yield 36.0%, purity 98%). MS (ESI) m/z 860.3 [M+1] ⁺ .

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.76 (s, 1H), 9.34 (s, 1H), 9.25 (s, 1H), 8.82 (s, 1H), 7 .07-7.17 (m, 3H), 6.96-7.04 (m, 2H), 6.76-6.82 (d, J=8.0 Hz, 1H), 6.37-6 .44 (d, J=8.0 Hz, 1H), 5.84-5.92 (d, J=7.6 Hz, 1H), 4.28 (us s, 1H), 4.14 (s , 2H), 3.64-3.75 (m, 1H), 3.21 (s, 2H), 2.85-2.95 (d, J=10.8 Hz, 2H), 2.73 ( ush s, 5H), 2.542.64 (m, 1H), 2.29-2.36 (m, 2H), 1.76-2.09 (m, 8H), 1.52 (s, 6H), 0.96-1.02 (d, J=5.6 Hz, 6H),

Example 49: 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpinerazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide tert-Butyl (3S,5R)- 4-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate.

To a solution of tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylateα (1.20 g, 5.60 mmol, 1.00 eq.) in DMF (7.2 ml) was added tert-butyl 2 -bromoacetate (1.31 g, 6.72 mmol, 0.993 ml, 1.20 eq.), sodium iodide (0.25 g, 1.68 mmol, 0.30 eq.) and DIPEA (2.17 g, 16.8 mmol, 2.93 ml, 3.00 eq.) at 15°C. The resulting mixture was stirred at 60°C for 12 hours. The mixture was diluted with water (21.0 ml) and extracted with EtOAc (5.0 mlx2), and the combined organic layers were washed with brine (5.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 100:1-0:1) to give tert-Butyl (3S,5R)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5- dimethylpiperazine-1-carboxylate (1.80 g, crude) as a yellow oil.

tert-Butyl 2-((2S,6R)-2,6-dimethylpiperazin-1 -yl)acetate.

To a solution of tert-butyl (3S,5R)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethylninerasin-1carboxylate (1.80 g, 5.42 mmol, 1.00 eq. ) in MeOH (18.0 ml) was added hydrochloric acid/MeOH (18.0 ml) at 10°C. The resulting mixture was stirred at 10°C for 12 hours. The mixture was quenched with saturated sodium bicarbonate to pH 8, concentrated under reduced pressure and then extracted with EtOAc (10.0 mlx2). The combined organic layers were washed with brine (10.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

tert-Butyl 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)acetate (1.08 g, 4.73 mmol, 86.3% yield) was obtained as a yellow oil.

¹ H NMR (400 MHz, MeOD) δ 3.44 (s, 2H), 2.81-2.89 (m, 4H), 2.44 (t, J=1.6 Hz, 2H), 1.477 ( s, 9H), 1.05 (d, J=3.0 Hz, 6H).

2-Bromo-1-(2-bromoethoxy)-4-nitrobenzene.

To a solution of 2-bromo-4-nitrophenol (1.60 g, 7.34 mmol, 1.0 eq.) in acetonitrile (12.8 ml) was added potassium carbonate (2.03 g, 14.7 mmol, 2.0 eq. 0 eq.) and 1,2-dibromoethane (13.8 g, 73.4 mmol, 5.54 ml, 10.0 eq.) at 15°C. The mixture was stirred at 90°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give a yellow oil. Petroleum ether (10.0 ml) was added to the oil with stirring to form a yellow solid, which was filtered and purified by silica gel column chromatography (petroleum ether/EtOAc, 50:1-0:1). 2-Bromo-1-(2-bromoethoxy)-4nitrobenzene (1.93 g, 5.94 mmol, 80.9% yield) was obtained as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J=2.8 Hz, 1H), 8.19-8.22 (dd, J=9.2 Hz, J=2.8 Hz , 1H), 6.94 (d, J=9.2 Hz, 1H), 4.45 (t J=6.4 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H) .

tert-Butyl 2-((2S,6R)-4-(2-(2-br<w-4-nitrophenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To a solution of tert-butyl 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)acetate (1.08 g, 4.73 mmol, 1.0 eq.) in acetonitrile (7.7 ml) added potassium carbonate (1.31 g, 9.46 mmol, 2.0 eq) and 2-bromo-1-(2-bromoethoxy)4-nitrobenzene (1.54 g, 4.73 mmol, 1.0 eq) .) at 15°C. The resulting mixture was stirred at 90°C for 12 hours. The reaction mixture was filtered, the filter cake was washed with acetonitrile (2.0 mlx2), and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (100:1-0:1 petroleum ether/EtOAc) to give tert-butyl 2((2S,6R)-4-(2-(2-bromo-4-nitrophenoxy)ethyl)-2 ,6-dimethylpiperazin-1-yl)acetate (2.08 g, 4.40 mmol, 93.1% yield) as a yellow solid.

^1H NMR (400 MHz, CDC13) δ 8.46 (d, J=2.4 Hz, 1H), 8.17-8.20 (m, 1H), 6.94 (d, J=9.2 Hz, 1H), 4.25 (t, J=5.6 Hz, 2H), 3.43 (s, 1H), 2.97-3.00 (m, 2H), 2.84-2.88 (m , 4H), 2.09 (t, J=10.4 Hz, 2H), 1.46 (s, 9H), 1.09 (d, J=6.4 Hz, 6H).

tert-Butyl 2-((2S,6R)-2,6-dimethyl-4-(2-(4-nitro-2-vinylphenoxy)ethyl)piperazin-1-yl)acetate.

A mixture of tert-butyl 2-((2S,6R)-4-(2-(2-bromo-4-nitrophenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate (2.07 g, 4.38 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.35 g, 8.76 mmol, 1.49 ml, 2.0 eq.) , potassium carbonate (2.79 g, 13.1 mmol, 3.0 eq.) and Pd(dppf)Cl2СH2Cl2 (0.18 g, 0.22 mmol, 0.05 eq.) in dioxane (12.4 ml ) and water (6.20 ml) were stirred at 90°C under N ₂ atmosphere for 12 hours. The mixture was diluted with water (5.00 ml) and extracted with EtOAc (10.0 mlx2). The combined organic layers were washed with brine (5.00 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 100:1-0:1) to give tert-butyl 2-((2S,6R)-2,6dimethyl-4-(2-(4-nitro-2- vinylphenoxy)ethyl)piperazin-1-yl)acetate (1.80 g, crude) as a brown oil. MS (ESI) m/z 420.2 [M+1]+.

¹ H NMR (400 MHz, CDCl·,) δ 8.35 (d, J=2.8 Hz, 1H), 8.11-8.14 (m, 1H), 6.90-7.26 (m , 2H), 5.86 (d, J=0.8 Hz, 1H), 5.40 (d, J=0.8 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.44 (s, 2H), 2.97-3.00 (m, 2H), 2.80-2.84 (m, 4H), 2.04 (t, J=10.4 Hz, 2H) , 1.46 (s, 9H), 1.09 (d, J=6.4 Hz, 6H).

tert-Butyl 2-((2R,6S)-4-(2-(4-amino-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To a solution of tert-butyl 2-((2S,6R)-2,6-dimethyl-4-(2-(4-nitro-2-vinylphenoxy)ethyl)piperazin-1yl)acetate (1.80 g, 4.30 mmol, 1.0 eq.) in MeOH (18.0 ml) was added palladium on activated carbon (0.18 g, 10 wt.%, 1.0 eq.). The suspension was degassed under vacuum and purged several times with H ₂ . The mixture was then stirred under H2 (50 psi) at 30°C for 12 hours. The reaction mixture was filtered, washed with MeOH (3.0 mlx3) and concentrated under reduced pressure to give crude tert-butyl 2-(( 2R,6S)-4-(2-(4-amino-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate (1.68 g) as a black oil. MS (ESI) m/z 392.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl·,) δ 6.66 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 6.47-6, 50 (m, 1H), 4.01 (t, J=6.0 Hz, 2H), 2.83-2.86 (m, 2H), 2.74 (d, J=4.0 Hz, 2H ), 2.72 (t, J=5.6 Hz, 2H), 2.55-2.57 (m, 2H), 2.01 (t, J=10.8 Hz, 2H), 1.46 (s, 9H), 1.16 (t, J=7.2 Hz, 2H), 1.15 (d, J=7.6 Hz, 6H).

Methyl 2-((4-(2-((3R,5S)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)-3ethylphenyl)amino) -2-methylpropanoate.

To a solution of tert-butyl-2-((2R,6S)-4-(2-(4-amino-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate (1.68 g, 4.29 mmol, 1.0 eq.) in methyl 2-bromo-2-methylpropanoate (4.19 g, 23.2 mmol, 3.0 mL, 5.4 eq.) was added sodium bicarbonate (1.08 g, 12. 9 mmol, 0.50 ml, 3.0 eq.), and the resulting mixture was stirred at 90°C for 48 hours. The reaction mixture was filtered and washed with EtOAc (3.0 mlx2), and the filtrate was concentrated under reduced pressure to give a residue , which was purified by silica gel column chromatography (petroleum ether/EtOAc 10:1-0:1). Methyl 2-((4-(2-((3R,5S)-4-(2-(tertbutoxy)-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)amino) -2-methylpropanoate (1.05 g,

- 123 044376

2.14 mmol, 50.0% yield) was obtained as a brown oil. MS (ESI) m/z 492.2 [M+1]+.

1H NMR (400 MHz, CDCl3) δ 6.65 (d, J=8.8 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 6.43-6.46 (m , 1H), 4.01 (t, J=5.6 Hz, 2H), 3.69 (s, 3H), 3.42 (s, 2H), 2.94-2.98 (m, 2H) , 2.84 (d, J=10.4 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H), 2.54-2.56 (m, 2H), 2.01- 2.04 (m, 3H), 1.49 (s, 6H), 1.46 (s, 9H), 1.14 (t, J=7.6 Hz, 3H), 1.08 (d, J =6.4 Hz, 6H).

tert-Butyl 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1- yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To the solution methyl 2-((4-(2-((3R,5S)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethylpiperazin-1yl)ethoxy)-3-ethylphenyl) amino)-2-methylpropanoate (1.05 g, 2.14 mmol, 1.0 eq.) in EtOAc (8.4 ml) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.97 g, 4. 27 mmol, 2.0 eq.) and TEA (0.65 g, 6.41 mmol, 0.89 ml, 3.0 eq.). The resulting mixture was stirred at 70°C for 12 hours. The reaction suspension was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether/EtOAc 100:1-0:1).

tert-Butyl 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1- yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (0.71 g, 1.04 mmol, 48.5% yield) was obtained as a brown oil.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.96-7.98 (m, 2H), 7.83-7.85 (m, 1H), 7.05-7.08 (m, 2H), 6.92 (d, J=8.4 Hz, 1H), 4.11-4.15 (m, 3H), 3.44 (s, 2H), 2.96-2.98 (m, 2H) , 2.80-2.87 (m, 4H), 2.65-2.70 (m, 2H), 2.03-2.08 (m, 3H), 1.91 (s, 2H), 1 .57 (s, 6H), 1.46 (s, 9H), 1.10 (d, J=6.0 Hz, 6H).

2-((2R,6S)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-mioxoimidazolidin1-yl)- 2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid hydrochloride.

To a solution of tert-butyl 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3-(τtrifluoromethyl)phenyl)-5,5-dimethyl-4-oxo2-thioxoimidazolidine- 1-yl)-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (0.70 g, 1.02 mmol, 1.0 eq.) in DCM (4.9 ml) was added hydrochloric acid/dioxane (4 M, 4.90 ml, 19.3 eq.) dropwise at 0°C. The resulting mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure, treated with petroleum ether (5.00 ml) and stirred for 10 minutes. The suspension was filtered and the filter cake was dried to give 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo -2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,6dimethylpiperazin-1-yl)acetic acid hydrochloride (0.56 g, 0.80 mmol, 82.7% yield) as a yellow solid . MS (ESI) m/z 632.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-de) δ 8.39 (d, J=8.0 Hz, 1H), 8.29 (d, J=1.2 Hz, 1H), 8.08 (d, J =6.8 Hz, 1H), 7.12-7.21 (m, 3H), 4.50 (m, 2H), 4.00-4.05 (m, 2H), 3.67-3, 75 (m, 2H), 3.58-3.59 (m, 2H), 2.63-2.69 (m, 2H), 1.50 (s, 6H), 1.24-1.25 ( m, 6H), 1.15-1.20 (m, 4H), 0.81-0.87 (m, 2H).

2-((2R,6S)-4-(2-(4-(3-(4-Cyano-3-(mfluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-mioxoimidazolidin1-yl)- 2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide.

To a solution of 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2-ethylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid hydrochloride (550 mg, 0.82 mmol, 1.0 eq.) in DMF (3.3 ml) was added HATU (378 mg , 0.99 mmol, 1.2 eq.), 3((3-aminophenyl)amino)piperidine-2,6-dione (199 mg, 0.91 mmol, 1.1 eq.) and DIPEA (63.8 mg, 4.94 mmol, 86.0 μl, 6.0 eq.), and the resulting mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched with water (10.0 ml) at 0°C and then filtered . The filter cake was dissolved in EtOAc (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by standard methods to obtain. 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-ethylphenoxy)ethyl)-2,6dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (160 mg, 0.19 mmol, yield 23 .3%). MS (ESI) m/z 833.2 [M+1] ⁺ .

1H NMR (400 MHz, DMSO-a ₆ ) δ 10.8 (s, 1H), 9.34 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.29 ( s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.10-7.17 (m, 3H), 7.00-7.03 (m, 3H), 6.79 (d, J=8.4 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 4.27-4.30 (m, 1H), 4.15-4.17 ( m, 2H), 3.20 (s, 2H), 2.90 (d, J=10.4 Hz, 2H), 2.59-2.74 (m, 10H), 1.89-2.07 (m, 4H), 1.49 (s, 6H), 1.16 (t, J=7.6 Hz, 3H), 0.98 (d, J=6.0 Hz, 6H).

Example 50: 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)-2-ethyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide.

(3R,5S)-1-(2-(Benzyloxy)ethyl)-3,5-dimethylpiperazine.

To a mixture of (2S,6R)-2,6-dimethylpiperazine (8.00 g, 70.1 mmol, 1 eq.) and ((2-bromoethoxy)methyl)benzene

- 124 044376 (15.1 g, 70.1 mmol, 1 eq.) DIPEA (27.1 g, 210 mmol, 3 eq.) was added to DMF (80 ml) and the mixture was stirred at 60°C for 4 h. The residue was poured into water (100 ml). The aqueous phase was extracted with EtOAc (100 mlx3), and the combined organic layers were washed with brine (100 mlx5), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (EtOAc/petroleum ether 0-60%) to give (3R,5S)-1-(2-(benzyloxy)ethyl)3,5-dimethylpiperazine (10.1 g, 40.8 mmol, yield 58.2%) as a yellow oil. MS (ESI) m/z 249.2 [M+1]+.

^1H NMR (400 MHz, CDCI3) δ 7.38-7.28 (m, 5H), 4.55 (s, 2H), 3.62-3.56 (t, J=6.0 Hz, 2H ), 2.99-2.90 (m, 2H), 2.85-2.82 (m, 1H), 2.81-2.78 (m, 1H), 2.63-2.57 (t , J=6.0 Hz, 2H), 1.67-1.60 (t, J=10.8 Hz, 2H), 1.06-1.00 (d, J=6.4 Hz, 6H) .

tert-Butyl 2-((2S,6R)-4-(2-(benzyloxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To a mixture of tert-butyl-2-bromoacetate (7.97 g, 40.8 mmol, 1 eq.) and (3R,5S)-1-(2-(benzyloxy)ethyl)-3,5dimethylpiperazine (10.1 g , 40.8 mmol, 1 eq.) in DMF (100 ml) was added potassium iodide (6.78 g, 40.8 mmol, 1 eq.) and DIPEA (15.8 g, 122 mmol, 3 eq.) one portion at 25°C in a nitrogen atmosphere. The mixture was heated to 25°C and stirred for 5 hours. The residue was poured into water (200 ml) and the aqueous phase was extracted with EtOAc (100 mlx3). The combined organic layers were washed with brine (100 mlx5), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/petroleum ether) to give tert-butyl-2-((2S,6R)-4-(2(benzyloxy)ethyl)-2,6-dimethylpiperazin-1-yl) acetate (12.2 g, 33.6 mmol, 82.5% yield) as a colorless oil. MS (ESI) m/z 363.3 [M+1] ⁺ .

1H NMR (400 MHz, CDCI3) δ 7.36-7.28 (m, J=5H), 4.54 (s, 2H), 3.60-3.55 (t, J=6.0 Hz, 2H), 3.42 (s, 2H), 3.02-2.92 (m, 2H), 2.80-2.74 (m, 2H), 2.59-2.53 (t, J= 6.0 Hz, 2H), 1.94-1.85 (t, J=10.8 Hz, 2H), 1.46 (s, 9H), 1.11-1.05 (d, J=6 ,4 Hz, 6H).

tert-Butyl 2-((2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To a solution of tert-butyl 2-((2S,6R)-4-(2-(benzyloxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (6.00 g, 16.5 mmol, 1 eq. ) in MeOH (120 ml) was added Pd/C (1.20 g, 10 wt%) and palladium hydroxide (1.20 g, 20 wt%) under nitrogen atmosphere. The suspension was degassed in vacuo and purged with hydrogen several times, after which the mixture was stirred under a hydrogen atmosphere (15 psi) at 25°C for 24 hours. The reaction mixture was filtered and the filtrate was concentrated to give crude tert-butyl 2(( 2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperazin-1-yl)acetate (8.06 g, 29.6 mmol, 89.4% yield) as a yellow oil.

1H NMR (400 MHz, CDCl·,) δ 3.62-3.56 (t, J=5.2 Hz, 2H), 3.46 (s, 2H), 3.07-2.95 (m, 2H), 2.77-2.71 (d, J=9.6 Hz, 2H), 2.50-2.45 (m, 2H), 1.98-1.90 (t, J=10, 8 Hz, 2H), 1.47 (s, 9H), 1.12-1.06 (d, J=6.4 Hz, 6H).

tert-Butyl 2-((2S,6R)-4-(2-(2-bromo-5-methyl-4-nitrophenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate.

To a solution of tert-butyl 2-((2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperazin-1-yl)acetate (4.00 g, 14.7 mmol, 1 eq.) in anhydrous THF (40 ml), sodium 2-methylpropan-2-olate (2.12 g, 22.0 mmol, 1.5 eq.) was added under nitrogen atmosphere at 0°C, and the reaction mixture was stirred at 25°C for 1 h. After this, 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (5.16 g, 22.0 mmol, 1.5 eq.) in anhydrous THF (10 ml) was added and the reaction mixture was stirred further 12 hours at 25°C. The residue was poured into saturated ammonium chloride solution (80 ml) and stirred for 10 minutes. The aqueous phase was extracted with EtOAc (50 mlx3), and the combined organic layers were washed with brine (50 mlx1), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by semipreparative reverse phase HPLC (30-45% acetonitrile in water + 0.05% hydrochloric acid, 15 min) to give tert-butyl 2-((2S,6R)-4-(2-(2-bromo -5-methyl-4-nitrophenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate (2.20 g, 4.52 mmol, 30.8% yield) as a yellow oil. MS (ESI) m/z 486.2 [M+1] ⁺ .

1H NMR (400 MHz, CDCl·,) δ 8.34 (s, 1H), 6.76 (s, 1H), 4.26-4.20 (t, J=5.6 Hz, 2H), 3 .45 (s, 2H), 3.052.94 (m, 2H), 2.91-2.83 (m, 4H), 2.63 (s, 3H), 2.14-2.06 (t, J =10.8 Hz, 2H), 1.47 (s, 9H), 1.13-1.08 (d, J=6.0 Hz, 6H).

tert-Butyl 2-((2S,6R)-2,6-dimethyl-4-(2-(5-methyl-4-nitro-2-vinylphenoxy)ethyl)piperazin-1yl)acetate.

To a mixture of tert-butyl 2-((2S,6R)-4-(2-(2-bromo-5-methyl-4-nitrophenoxy)ethyl)-2,6-dimethylpiperazin1-yl)acetate (1.78 g, 3.66 mmol, 1 eq.) in dioxane (10 ml) and water (5 ml) was added 4,4,5,5-tetramethyl-2vinyl-1,3,2-dioxaborolane (1.13 g, 7.32 mmol, 2 eq.), sodium carbonate (0.77 g, 7.32 mmol, 2 eq.) and Pd(dppf)Cl ₂ (0.27 g, 0.36 mmol, 0.1 eq.) in one serving at 25°C in a nitrogen atmosphere. The mixture was heated to 100°C and stirred for 12 hours. The residue was poured into water (50 ml) and the aqueous phase was extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 mlx1), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (0-50% EtOAc/petroleum ether). Compound tert-butyl 2-((2S,6R)-2,6-dimethyl-4-(2-(5methyl-4-nitro-2-vinylphenoxy)ethyl)piperazin-1-yl)acetate (1.50 g, 3.46 mmol, 94.5% yield) was obtained as a yellow oil. MS (ESI) m/z 434.4 [M+1] ⁺ .

- 125 044376 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 6.98-6.86 (m, 1H), 6.73 (s, 1H), 5.89-5 .80 (dd, J=18.0, 1.2 Hz,

1H), 5.40-5.33 (dd, J=11.2, 0.8 Hz, 1H), 4.22-4.17 (t, J=6.0 Hz, 2H), 3.45 (s, 2H), 3.04-2.95 (m, 2H), 2.86-2.79 (m, 4H), 2.64 (s, 3H), 2.10-2.05 (m , 2H), 1.47 (s, 9H), 1.12-1.08 (d, J=6.4 Hz, 6H).

tert-Butyl 2-((2S,6R)-4-(2-(4-amino-2-ethyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate.

To a solution of tert-butyl 2-((2S,6R)-2,6-dimethyl-4-(2-(5-methyl-4-nitro-2vinylphenoxy)ethyl)piperazin-1-yl)acetate (1.50 g , 3.46 mmol, 1 eq.) in THF (20 ml) was added Pd/C (0.45 g, 10 wt.%) under a nitrogen atmosphere. The suspension was degassed in vacuo and purged with hydrogen three times, and the mixture was stirred under a hydrogen atmosphere (50 psi) at 25°C for 24 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by semipreparative reverse phase HPLC (1-28% acetonitrile in water + 0.2% formic acid, 11 min) and the desired fractions were poured into saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was extracted with EtOAc (30 ml) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Compound tert-butyl 2-((2S,6R)-4-(2-(4-amino-2-ethyl-5-methylphenoxy)ethyl)2,6-dimethylpiperazin-1-yl)acetate (0.88 g, 2.17 mmol, yield 62.7%) was obtained as a colorless oil.

¹ H NMR (400 MHz, CDCl3) δ 6.59 (s, 1H), 6.52 (s, 1H), 4.05-3.99 (t, J=6.0 Hz, 2H), 3, 44 (s, 2H), 3.042.93 (m, 2H), 2.89-2.82 (br. d, J=10.4 Hz, 2H), 2.76-2.71 (t, J=5 .6 Hz, 1H), 2.60-2.50 (k, J=7.6 Hz, 2H), 2.14 (s, 3H), 2.05-1.96 (t, J=6, 8 Hz, 2H), 1.47 (s, 9H), 1.19-1.13 (t, J=7.6 Hz, 3H), 1.12-1.07 (d, J=6.4 Hz, 6H).

Methyl 2-((4-(2-((3S,5R)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)-5-ethyl2- methylphenyl)amino)-2-methylpropanoate.

A mixture of tert-butyl 2-((2S,6R)-4-(2-(4-amino-2-ethyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate (0.88 g, 2 .17 mmol, 1 eq.), methyl 2-bromo-2-methylpropanoate (1.96 g, 10.8 mmol, 5 eq.) and DIPEA (1.40 g, 10.8 mmol, 5 eq.) were stirred at 100°C for 24 hours. The residue was poured into water (30 ml). The aqueous phase was extracted with EtOAc (20 mlx3), and the combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by semipreparative reverse phase HPLC (20-50% acetonitrile in water + 0.2% formic acid, 11 min) and the desired fractions were poured into saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was extracted with EtOAc (30 ml) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give methyl 2-((4(2-((3S,5R)-4-(2-(t-butoxy )-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)-5-ethyl-2methylphenyl)amino)-2-methylpropanoate (0.38 g, 0.76 mmol, 35.2% yield) in in the form of yellow oil. MS (ESI) m/z 560.4 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl3) δ 6.62 (s, 1H), 6.36 (s, 1H), 4.04-3.98 (t, J=6.0 Hz, 2H), 3, 71 (s, 3H), 3.44 (s, 2H), 3.02-2.92 (m, 2H), 2.88-2.82 (d, J=10.0 Hz, 2H), 2 ,76-2.71 (t, J=5.6 Hz, 2H), 2.59-2.51 (k, J=7.2 Hz, 2H), 2.16 (s, 3H), 2, 05-1.96 (t, J=10.8, 2H), 1.54 (s, 6H), 1.47 (s, 9H), 1.16-1.11 (t, J=7.6 Hz„ZN), 1.11-1.06 (d, J=6.0 Hz, 6H).

tert-Butyl 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1- yl)-2-ethyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

A mixture of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.26 g, 1.13 mmol, 1.5 eq.), methyl 2-((4-(2((3S,5R)-4-(2- (tert-butoxy)-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)-5-ethyl-2methylphenyl)amino)-2-methylpropanoate (0.38 g, 0.75 mmol, 1 eq. ), TEA (0.23 g, 2.25 mmol, 3 eq.) and EtOAc (3 ml) were stirred at 60°C for 10 hours. The residue was poured into water (50 ml). The aqueous phase was extracted with EtOAc (30 mlx3) and the combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative TLC (1:1 petroleum ether/EtOAc) to give tert-butyl 2-((2S,6R)-4(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethyl-5methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (0.21 g, 0.30 mmol , yield 39.8%) as a yellow oil. MS (ESI) m/z 702.5 [M+1] ⁺ .

^1H NMR (400 MHz, CDCl3) δ 8.01-7.95 (m, 2H), 7.90-7.85 (dd, J=8.4, 2.0 Hz, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 4.16-4.13 (m, 2H), 3.50 (s, 2H), 3.02-2.96 (m, 2H), 2.91-2.84 (m, 2H), 2.83-2.78 (m, 2H), 2.70-2.56 (m, 2H), 2.28 (s, 3H), 2. 10-2.06 (m, 2H), 1.69 (s, 3H), 1.51 (s, 3H), 1.48 (s, 9H), 1.23-1.18 (t, J= 7.6 Hz, 3H), 1.12-1.10 (d, J=6.0 Hz, 6H).

2-((2S,6R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)- 2-ethyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid.

To a mixture of tert-butyl 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine- 1-yl)-2-ethyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (0.21 g, 0.30 mmol, 1 eq.) in DCM (0.5 ml) added hydrochloric acid in dioxane (4 M, 0.3 ml, 4 eq.). The mixture was stirred at 25°C for 1 hour. The reaction was concentrated to give crude 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5 ,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethyl-5methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.26 g, HCl) as brown solid matter. MS (ESI) m/z 646.3 [M+1] ⁺ .

- 126 044376

2-((2S,6R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)- 2-ethyl-5-methylphenoxy)ethyl)-2,6-dimethylninerasin-1-yl)-N-(3-((2,6-dioxoniperidin-3yl)amino)phenyl)acetamide.

To a mixture of 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.11 g, 0.43 mmol, 1.27 eq, HCl), 2((2S,6R)-4-(2 -(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2ethyl-5-methylphenoxy)ethyl)-2, 6-Dimethylpiperazin-1-yl)acetic acid (0.26 g, 0.34 mmol, 1 eq., HCl), HATU (0.21 g, 0.54 mmol, 1.58 eq.) in DMF (2 ml) DIPEA (0.23 g, 1.81 mmol, 5.28 eq.) was added and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered. The residue was purified by standard methods to obtain Compound 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2 -thioxoimidazolidin-1-yl)-2-ethyl-5-methylphenoxy)ethyl)2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl) acetamide (0.12 g, 0.14 mmol, yield 39.7%, purity 98%). MS (ESI) m/z 847.3 [M+1]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 9.34 (s, 1H), 8.42-8.36 (d, J=8.0 Hz, 1H) , 8.34-8.29 (d, J=1.2 Hz, 1H), 8.13-8.07 (m, 1H), 7.04-6.95 (m, 4H), 6.82 -6.75 (d, J=9.2 Hz, 1H), 6.44-6.37 (m, 1H), 5.92-5.84 (d, J=7.6 Hz, 1H), 4.33-4.23 (m, 1H), 4.19-4.08 (m, 2H), 3.02 (s, 2H), 2.94-2.85 (d, J=10.0 Hz, 2H), 2.79-2.68 (m, 5H), 2.64-2.53 (m, 3H), 2.23 (s, 3H), 2.14-2.07 (m, 1H), 2.05-1.97 (t, J=10.8 Hz, 2H), 1.95-1.82 (m, 1H), 1.60 (s, 3H), 1.42 (s , 3H), 1.18-1.11 (t, J=7.6 Hz, 3H), 1.02-0.93 (d, J=6.0 Hz, 6H).

Example 51: 2-((2S,6R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)-2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((2S,6R)-4-(2-(2-Bromo-5-methyl-4-nitrophenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To a mixture of sodium tert-butoxide (0.79 g, 8.26 mmol, 1.5 eq.) in THF (5 ml) was added tert-butyl 2((2S,6R)-4-(2-hydroxyethyl)-2 ,6-dimethylpiperazin-1-yl)acetate (1.50 g, 5.51 mmol, 1 eq.), and the mixture was stirred at 0°C for 1 hour. Then 1-bromo-2-fluoro-4 was added -methyl-5-nitrobenzene (1.93 g, 8.26 mmol, 1.5 eq.) in THF (10 ml) and the mixture was stirred at 15°C for an additional 1 hour. The residue was poured into saturated ammonium chloride solution (30 ml) and stirred for 10 minutes. The aqueous phase was extracted with EtOAc (30 mlx3) and the combined organic phases were washed with saturated brine (40 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by semipreparative reverse phase HPLC (30-43% acetonitrile + 0.225% formic acid in water, 10 min) and the collected fractions were adjusted to pH 7 with saturated sodium bicarbonate and then extracted with EtOAc (50 ml x 3 ). The combined organic layers were washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2-((2S,6R)-4-(2-(2-bromo-5-methyl -4-nitrophenoxy)ethyl)-2,6dimethylpiperazin-1-yl)acetate (1.19 g, 2.45 mmol, 44.4% yield) as a yellow solid. MS (ESI) m/z 486.0 [M+H]+.

1H NMR (400 MHz, DMSO-I6) δ=8.28 (s, 1H), 7.28 (s, 1H), 4.31 (br s, 2H), 2.85 (br s, 4H), 2.72 (br s, 2H), 2.56 (s, 5H), 1.96-1.68 (m, 2H), 1.41 (s, 9H), 0.97 (d, J=6 ,1 Hz, 6H).

tert-Butyl 2-((2S,6R)-2,6-dimethyl-4-(2-(5-methyl-4-nitro-2-(prop-1-en-2yl)phenoxy)ethyl)piperazine-1 -yl)acetate.

To a mixture of tert-butyl 2-((2S,6R)-4-(2-(2-bromo-5-methyl-4-nitrophenoxy)ethyl)-2,6-dimethylpiperazin1-yl)acetate (1.19 g, 2.45 mmol, 1 eq.) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.62 g, 3.67 mmol, 1.5 eq.) in dioxane (12 ml) and water (1.2 ml) was added Pd(dppf)Cl ₂ (0.09 g, 0.12 mmol, 0.05 eq.) and sodium carbonate ( 0.78 g, 7.34 mmol, 3 eq.), and the mixture was stirred at 100°C for 8 hours. The reaction mixture was filtered, the filtrate was diluted with water (50 ml) and extracted with EtOAc (30 mlx3). The combined organic phases were washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (25% EtOAc/petroleum ether) to give tert-butyl 2-((2S,6R)-2,6dimethyl-4-(2-(5-methyl-4-nitro-2-(prop-1 -en-2-yl)phenoxy)ethyl)piperazin-1-yl)acetate (1.20 g, 2.35 mmol, 95.9% yield, 87.5% purity) as a yellow oil. MS (ESI) m/z 448.2 [M+H]+.

tert-Butyl 2-((2S,6R)-4-(2-(4-amino-2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate.

To a mixture of tert-butyl 2-((2S,6R)-2,6-dimethyl-4-(2-(5-methyl-4-nitro-2-(pron-1-en-2yl)phenoxy)ethyl)piperazine -1-yl)acetate (0.95 g, 1.86 mmol, 1 eq.) in MeOH (20 ml) was added palladium on activated carbon (0.20 g, 10 wt.%) under a hydrogen atmosphere (50 lb/ sq. inch). The mixture was stirred at 25°C for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (100% EtOAc/petroleum ether),

- 127 044376 tert-butyl 2-((2S,6R)-4-(2-(4-amino-2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate (0.50 g , 1.11 mmol, yield 59.9%, purity 93.3%) was obtained as a white solid.

MS (ESI) m/z 420.4 [M+H]+.

Methyl 2-((4-(2-((3S,5R)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)-5isopropyl-2- methylphenyl)amino)-2-methylpropanoate.

Mixture of tert-butyl 2-((2S,6R)-4-(2-(4-amino-2-isopropyl-5-methylphenoxy)ethyl)-2,6dimethylpiperazin-1-yl)acetate (0.50 g, 1 .19 mmol, 1 eq.) and methyl 2-bromo-2-methylpropanoate (0.43 g, 2.38 mmol, 0.31 ml, 2 eq.) in DIPEA (1.5 ml) was stirred at 130°C for 8 hours. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (67% EtOAc/petroleum ether) to give methyl 2-((4-(2-((3S,5R)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5dimethylpiperazine -1-yl)ethoxy)-5-isopropyl-2-methylphenyl)amino)-2-methylpropanoate (0.30 g, 0.52 mmol, 43.8% yield, 90.4% purity) as a red oil. MS (ESI) m/z 520.5 [M+H] ⁺ .

tert-Butyl 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1- yl)-2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.

To the mixture of methyl 2-((4-(2-((3S,5R)-4-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethylpiperazin-1yl)ethoxy)-5-isopropyl- 2-methylphenyl)amino)-2-methylpropanoate (0.25 g, 0.48 mmol, 1 eq.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.22 g, 0.96 mmol, 2 eq.) in EtOAc (0.5 ml) was added TEA (0.14 g, 1.44 mmol, 0.20 ml, 3 eq.) and the mixture was stirred at 80°C for 8 hours. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (50% EtOAc/petroleum ether). tert-Butyl 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5dimethyl-4-oxo-2-thioxoimidazolidine-1- yl)-2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin1-yl)acetate (0.25 g, 0.29 mmol, 61.5% yield, 84.7% purity) was obtained as yellow oils MS (ESI) m/z 716.5 [M+H] ⁺ .

2-((2S,6R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)- 2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid.

To a solution of tert-butyl 2-((2R,6S)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo2-thioxoimidazolidine- 1-yl)-2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (0.25 g, 0.29 mmol, 1 eq.) in DCM (1 ml) added TFA (1.54 g, 13.5 mmol, 1 ml, 45.6 eq.), and the mixture was stirred at 15°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (30 ml), extracted with EtOAc (30 mlx3), and the combined organic layers were washed with brine (40 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2-((2S,6R) -4-(2-(4-(3(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-isopropyl-5methylphenoxy)ethyl )-2,6-dimethylpiperazin-1-yl)acetic acid (0.19 g) as a white solid. MS (ESI) m/z 660.2 [M+H] ⁺ .

2-((2S,6R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)- 2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide.

To a mixture of 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2-isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.19 g, 0.29 mmol, eq.) and 3-((3-aminophenyl)amino) piperidine-2,6-dione (0.06 g, 0.25 mmol, 0.85 eq., hydrochloride) in DMF (2 ml) was added HATU (0.12 g, 0.32 mmol, 1.1 eq. ) and DIPEA (0.11 g, 0.88 mmol, 0.15 mL, 3 eq.), and the mixture was stirred at 15°C for 8 hours. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3 ). The combined organic layers were washed with brine (40 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by standard methods to give 2-((2S,6R)-4(2-(4-(3- (4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2isopropyl-5-methylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl )-C-(3-((2,6-dioxopiperidin-3yl)amino)phenyl)acetamide (0.07 g, 0.08 mmol, yield 26.7%, purity 95.6%, hydrochloride). MS (ESI) m/z 861.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.33 (d, J=1.5 Hz, 1H ), 8.15-8.08 (m, 1H), 7.06 (s, 1H), 7.05-7.02 (m, 1H), 7.02-6.98 (m, 2H), 6.84 (USD, J=8.0 Hz, 1H), 6.46 (USD, J=7.8 Hz, 1H), 4.48 (USD, 2H), 4.27 (USD , J=4.9, 11.5 Hz, 1H), 3.68-3.64 (m, 2H), 3.63-3.51 (m, 4H), 3.37-3.21 (m , 3H), 2.75 (ush s, 2H), 2.62 (ush s, 2H), 2.27 (s, 3H), 2.10 (td, J=4.4, 8.8 Hz, 1H), 1.95-1.86 (m, 1H), 1.61 (s, 3H), 1.42 (s, 3H), 1.29 (br s, 6H), 1.19 (dd, J=7.0, 8.6 Hz, 6H).

Example 52: 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidine-1- yl)-2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K-(3-(2,6- 128 044376 dioxopiperidin-3-ylamino)phenyl)acetamide

2-Bromo-6-fluoro-4-nitrophenol.

Bromine (8.95 g, 56.0 mmol, 1.1 eq) was added to a solution of 2-fluoro-4-nitrophenol (8.00 g, 50.9 mmol, 1 eq.) in acetic acid (25 mL). . The reaction mixture was stirred at 15°C for 3 hours. The reaction solution was poured into water (100 ml) to form a yellow suspension. The suspension was filtered and the filter cake was washed with water (50 ml). The collected filter cake was dried under reduced pressure to obtain crude 2-bromo-6-fluoro-4-nitrophenol (9.80 g, 41.5 mmol, 81.5% yield) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (dd, J=2.8, 1.2 Hz, 1H), 8.17 (dd, J=10.4, 2.4 Hz, 1H).

2-(Benzyloxy)-1-bromo-3-fluoro-5-nitrobenzene.

A mixture of 2-bromo-6-fluoro-4-nitrophenol (9.80 g, 41.5 mmol, 1 eq.), (bromomethyl)benzene (8.52 g, 49.8 mmol, 1.2 eq.), potassium carbonate (11.5 g, 83.0 mmol, 2 eq.) and acetonitrile (100 ml) were stirred at 90°C for 2 hours. The suspension was filtered and the filtrate was concentrated. The crude product was purified by silica gel flash column chromatography (5% EtOAc/petroleum ether) to give 2(benzyloxy)-1-bromo-3-fluoro-5-nitrobenzene (12.0 g, 36.8 mmol, 88.6 yield %) as a light yellow solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ 8.32 (dd, J=2.4, 1.2 Hz, 1H), 8.31-8.21 (m, 1H), 7.55-7 .45 (m, 2H), 7.447.33 (m, 3H), 5.35 (d, J = 1.59 Hz, 2H).

2-Fluoro-4-nitro-6-vinylphenol.

To a solution of 2-(benzyloxy)-1-bromo-3-fluoro-5-nitrobenzene (5.0 g, 15.3 mmol, 1 eq.) and 4,4,5,5tetramethyl-2-vinyl-1,3 ,2-dioxaborolane (4.72 g, 30.6 mmol, 2 eq.) in dioxane (50 ml) and water (10 ml) was added Pd(dppf)Cl ₂ (1.12 g, 1.53 mmol, 0 .1 eq.) and potassium phosphate (9.76 g, 46.0 mmol, 3 eq.). The mixture was stirred at 90°C for 12 hours under a nitrogen atmosphere. Water (100 ml) was added to the reaction mixture and the mixture was extracted with EtOAc (200 mlx3). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-4% EtOAc/petroleum ether) to give 2fluoro-4-nitro-6-vinylphenol (2.00 g, 10.9 mmol, 71.2% yield) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.24-8.19 (m, 1H), 7.93 (dd, J=9.6, 2.4 Hz, 1H), 7.03-6.93 (m, 1H), 6.35-5.94 (m, 2H), 5.55 (d, J=10.8 Hz, 1H).

tert-Butyl 2-((2S,6R)-4-(2-(2-fluoro-4-nitro-6-vinylphenoxy)ethyl)-2,6-dimethylpiperazin-1 yl)acetate.

To a solution of 2-fluoro-4-nitro-6-vinylphenol (1.80 g, 9.83 mmol, 1 eq.), tert-butyl 2-((2S,6R)-4-(2hydroxyethyl)-2,6 -dimethylpiperazin-1-yl)acetate (2.94 g, 10.8 mmol, 1.1 eq.) and ammonium di-hexadecyldithiophosphate (4.96 g, 19.6 mmol, 2 eq.) in toluene (5 ml ) tributyl phosphate (3.98 g, 19.6 mmol, 2 eq.) was added at 0°C under nitrogen. The mixture was stirred at 110°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the crude product was purified by semipreparative reverse phase HPLC (35-65% acetonitrile in water + 0.225% formic acid, 8 min). The pH of the aqueous phase was adjusted to 7 by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc (100 mlx3) and the combined organic phases were washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-((2S,6R)-4-(2-( 2-Fluoro-4-nitro-6-vinylphenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (1.90 g, 4.34 mmol, 44.2% yield) as a yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.27-8.22 (m, 1H), 8.10 (dd, J=11.6, 2.8 Hz, 1H), 7.11 (dd , J=17.6, 11.2 Hz, 1H), 6.10 (d, J=17.6 Hz, 1H), 5.51 (d, J=11.2 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 3.31 (s, 2H), 2.75-2.65 (m, 4H), 2.59 (t, J=5.2 Hz, 2H) , 1.71 (t, J=10.4 Hz, 2H), 1.39 (s, 9H), 0.92 (d, J=6.4 Hz, 6H).

tert-Butyl 2-((2S,6R)-4-(2-(4-amino-2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazin-1 yl)acetate.

To a solution of tert-butyl 2-((2S,6R)-4-(2-(2-fluoro-4-nitro-6-vinylphenoxy)ethyl)-2,6dimethylpiperazin-1-yl)acetate (1.90 g, 4.34 mmol, 1 eq.) in MeOH (20 ml) was added Pd/C (0.20 g, 10 wt.%) under nitrogen atmosphere. The suspension was degassed in vacuo and purged with hydrogen three times, after which the mixture was stirred under a hydrogen atmosphere (15 psi) at 30°C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to give the crude product . The residue was purified by flash chromatography on silica gel (0-25% EtOAc/petroleum ether) to give tert-butyl 2-((2S,6R)-4-(2-(4-amino-2-ethyl-6-fluorophenoxy)ethyl )-2,6-dimethylpiperazin1-yl)acetate (1.30 g, 3.17 mmol, 73.1% yield) as a colorless oil.

- 129 044376 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.24-6.15 (m, 2H), 4.98 (s, 2H), 3.84 (t, J=5.6 Hz , 2H), 3.34 (s, 2H),

2.90-2.80 (m, 2H), 2.76 (d, J=10.0 Hz, 2H), 2.54-2.51 (m, 4H), 1.75 (t, J= 10.4 Hz, 2H), 1.41 (s, 9H), 1.09 (t,

J=7.6 Hz, 3H), 0.96 (d, J=6.0 Hz, 6H).

tert-Butyl 2-((2S,6R)-4-(2-(4-((2-cyanopropan-2-yl)amino)-2-ethyl-6-fluorophenoxy)ethyl)-2,6dimethylpiperazine-1 - yl)acetate.

A mixture of tert-butyl 2-((2S,6R)-4-(2-(4-amino-2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazin-1yl)acetate (0.80 g, 1 .95 mmol, 1 eq.), 2-hydroxy-2-methylpropanenitrile (4.66 g, 54.7 mmol, 5 ml, 28.1 eq.) and magnesium sulfate (0.59 mg, 4.88 mmol, 2.5 eq.) was stirred at 60°C for 12 hours. Water (30 ml) was added to the reaction mixture and the mixture was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude tert-butyl 2-((2S,6R)-4-(2-(4-((2-cyanopropane- 2yl)amino)-2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (1 g) as a yellow oil. MS (ESI) m/z 477.4 [M+1]+.

2-((2S,6R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)- 2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid.

To a solution of tert-butyl 2-((2S,6R)-4-(2-(4-((2-cyanopropan-2-yl)amino)-2-ethyl-6-fluorophenoxy)ethyl)2,6-dimethylpiperazine -1-yl)acetate (1.00 g, 2.10 mmol, 1 eq.) in DMF (5 ml) was added 4-isothiocyanato2-(trifluoromethyl)benzonitrile (0.48 g, 2.10 mmol, 1 eq. ), and the mixture was stirred at 25°C for 1 hour. Then hydrochloric acid in MeOH (4 M, 5.56 ml, 10.6 eq.) was added and the mixture was stirred at 80°C for 12 hours. The reaction mixture concentrated in vacuo and the crude product was purified by semipreparative reverse phase HPLC (30-60% acetonitrile in water + 0.225% hydrochloric acid, 20 min) to give 2-((2S,6R)-4-(2-(4-( 3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1-yl)-2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazine-1 -yl)acetic acid (0.18 g, 0.28 mmol, 13.2% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J=8.4 Hz, 1H), 8.27 (dd, J=1.6 Hz, 1H), 8.07 (dd, J=8.4, 1.6 Hz, 1H), 7.27 (dd, J=11.6, 2.0 Hz, 1H), 7.10 (s, 1H), 4.54 (s, 2H ), 4.02-3.77 (m, 3H), 3.66 (s, 1H), 3.53 (s, 2H), 3.293.08 (m, 2H), 2.74 (k, J= 7.6 Hz, 2H), 1.52 (s, 6H), 1.35 (s, 2H), 1.28-1.15 (m, 9H).

2-((2S,6R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl)- 2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)-K-(3-(2,6-dioxopiperidin-3ylamino)phenyl)acetamide.

To a solution of 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolidin-1-yl )-2-ethyl-6-fluorophenoxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.17 g, 0.26 mmol, 1 eq.) and 3-((3-aminophenyl)amino )piperidine-2,6-dione (0.074 g, 0.29 mmol, 1.1 eq, hydrochloride) in DMF (2 ml) was added HATU (0.11 g, 0.29 mmol, 1.1 eq) and DIPEA (0.17 g, 1.31 mmol, 5 eq.). The mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, the filtrate was concentrated and purified by standard methods to give 2-((2S,6R)-4-(2-(4-(3-(4-cyano-3 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethyl-6-fluorophenoxy)ethyl)2,6-dimethylpiperazin-1-yl)-K-(3 -(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide (0.08 g, 0.09 mmol, 35.9% yield). MS (ESI) m/z 851.4 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 10.56 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.10-8.03 (m, 1H), 7.27 (dd, J=12.0, 2.4 Hz, 1H), 7.12- 6.99 (m, 3H), 6.88 (d, J=8.0 Hz, 1H), 6.48 (d, J=8.0 Hz, 1H), 4.60-4.51 (s , 2H), 4.28 (dd, J=11.2, 4.8 Hz, 5H), 3.80 (d, J=10.4 Hz, 2H), 3.65-3.37 (m, 4H), 2.80-2.69 (m, 3H), 2.64-2.55 (m, 1H), 2.09 (m, 1H), 1.91 (m, 1H), 1.52 (s, 6H), 1.38 (d, J=5.2 Hz, 6H), 1.19 (t, J=7.2 Hz, 3H).

Analyzes

Cellular analysis.

VCAP Analysis of AR Decomposition. Test compounds were predispensed into a 96-well Corning CellBind clear-bottom plate (Cat#3300) using an acoustic dispenser to create a 10-point series of concentrations at a 1:3 dilution for each compound. The final maximum concentration of each compound was 5 μM. DMSO with a final concentration of 0.1% was used as a control. VCaP cells cultured in DMEM with 8% fetal bovine serum (FBS) were seeded at 50 thousand cells per well in a volume of 200 μl in a plate with a compound and incubated at 37°C in a CO2 incubator for 24 hours. The medium was carefully removed from the cells and the plate was placed on ice. 100 µl of ice-cold 1x cell lysis buffer from Cell Signaling Technologies (Cat #9803) was added to each cell well and the plate was incubated at 4°C on a shaker for 1 hour. Fifteen µl of cell lysate was used for AR ELISA detection using the kit PathScan Total Sandwich AR ELISA (Cell Signaling Technology, Cat #12580). AR levels in compound-treated wells were normalized to those of the DMSO control and expressed as percentage of control (PoC) (y). A four-parameter logistic model (sigmoidal dose-response model) was used to determine the _DC50 and _EC50 of a compound using the following equation:

- 130 044376 y = (A+((BA)/(l+((C/x) ^A D))))

A=Y _min (lowest AR level normalized to DMSO control in response to compound treatment as determined by curve fitting);

B=Y _max (maximum AR level as determined by curve fitting);

c=eC5o;

D=Hill slope;

x=compound concentration;

EC ₅₀ = concentration of compound when y=(Y _max -Y _min )/2;

DC ₅₀ =compound concentration when y=50% DMSO control (50% AR degradation);

y=AR protein level normalized to DMSO control.

The lowest measured AR level normalized to the DMSO control in response to compound treatment, referred to as the Y value, was used to characterize the efficiency of compound-mediated AR degradation.

Each of the piperidinedione compounds in the table was tested in the VCAP AR degradation assay and found to be active. All compounds in the table have a DC ₅₀ <1 µM and Y <50% of the DMSO control.

Prostate cancer cell proliferation assay. VCAP or ENZR cells were seeded at 10 thousand cells per well in 96-well CellBind plates (Costar) using DMEM + 8% FBS. The cells were incubated overnight at 37°C and the test compound was serially diluted and added to the well. After seven days of incubation, the assay medium was removed by inversion and the plate was frozen overnight at -80°C. The plates were thawed at room temperature and 100 μl of deionized water (ddH ₂ O) was added to each well. The plates were incubated at 37°C in a CO2-free incubator for 1 hour and then frozen at -80°C overnight. The plates were thawed to room temperature and 100 μl of TNE buffer (NaCl, Tris, EDTA) + Hoescht dye (1.0 mg/ml, 1:400) was added to each well. The fluorescent signal was measured at 460 nm. All data were normalized as a percentage of DMSO control. A four-parameter logistic model (sigmoidal dose-response model) was used to determine the GI ₅₀ value of a compound using the following equation:

y = (A+((BA)/(1+((C/x) ^a D))))

A=Y _min (lowest cell viability in luminescent units normalized to DMSO control in response to compound treatment determined by curve fitting);

B=Y _max (maximum cell viability, measured as unit luminescence, normalized to the DMSO control, as determined by curve fitting);

C=EC50;

D=Hill slope;

GI ₅₀ =concentration of compound when Y=(Y _max +Yt ₀ )/2;

EC ₅₀ = concentration of compound when y=(Y _max -Y _min )/2;

IC ₅₀ =compound concentration when Y=50% of DMSO control;

y=cell viability measured in luminescence units and normalized as a percentage of DMSO control;

t ₀ = time when the connection was added;

Yt ₀ = value of y at time t ₀ .

Piperidinedione compounds have been or will be tested in, and have shown or will show activity in, prostate cancer cell proliferation assays.

In vivo assays.

Analysis of AR decomposition. In vivo AR degradation assays were performed in NSG mice bearing VCaP prostate cancer tumor xenografts. Male NSG mice were inoculated with VCaP cells in the lateral region above the right paw. After inoculating the animals, tumors were allowed to grow to approximately 500 mm before randomization. Randomized animals were administered test compounds in 20% Labrasol, 80% 25 mM citrate buffer, pH 3. Compounds were administered orally once daily for 3 days. After the final dose of compound was administered, plasma and tumors were collected and processed for AR degradation assay. Intratumoral AR levels were measured by Western blotting. Statistical analysis was performed using one-way analysis of variance (ANOVA).

Piperidinedione compounds have been or will be tested in an in vivo AR degradation assay and have been or will be shown to be active in it.

VCaP prostate cancer xenograft model. The xenograft study was performed in male NSG mice bearing VCaP prostate cancer tumor xenografts. Male NSG mice were inoculated subcutaneously with VCaP cells in the lateral area over the right hind paw. After inoculation of animals, tumors were allowed to grow to approximately 200 mm ³ before randomization. During randomization, mice with VCaP tumors ranging in size from 75 to 250 mm were pooled together and randomized to different treatment groups. The test compounds, prepared in 20% labrasol, 80% 25 mM citrate buffer pH 3, were administered in a dose volume of 5 ml/kg. Compounds were administered orally once daily for the duration of the study. Tumors were measured twice weekly using calipers, and tumor volume was calculated using the formula WxL/2. Statistical analysis was performed using one-way or two-way analysis of variance (ANOVA).

Piperidinedione compounds have been or will be tested in the VCAP prostate cancer xenograft model and have been or will be shown to be effective treatments for prostate cancer in these models.

Activity table.

Each of the piperidinedione compounds presented in the table was tested in one or more of the AR degradation assays shown above, such as the VCAP AR degradation assay, and was found to be active therein.

It was shown that all compounds presented in the table have a DC ₅₀ <1 µM and Y <50% of the DMSO control, with some compounds having a DC ₅₀ C value: DC ₅₀ <0.10 µM, some DC ₅₀ V: 0.10 µM <DC ₅₀ <0.50 µM, and for others the DC ₅₀ A value is 0.50 µM <DC ₅₀ <1.0 µM.

Additionally, compounds have been shown to have an AR degradation efficiency value of Y<50% of the DMSO control, with some compounds having 0<Y<25% (marked *), some compounds having 25%<Y<35% (marked ** ), while others have 35%<Y<50% (marked with ***). _____

Co units No. Connection structure Connection name MN ⁺ Exp. DC 50 Y 1 FF /s- 1 Η Η №-4\ / .Ν 1 ,Η - 7 ι ι . _Ν J ϋ JJ - Ο ' Ο Ν '0 Η 2-(4-(2-(4-(3-(4-Cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- fluorophenoxy)ethyl)pip erazin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 795.2 WITH ** *

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2 V o Μ Η ν=7 α Υ|1 ίι Π ίι ' ί I -ν' '-Ο Ν 0 Η 2-(4-(2-(4-(3-(6-Cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidine1- yl)phenoxy)ethyl)piper azin-1-yl)-N(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 778.0 WITH ** 3 SA Γ%„ν > η η No.-4 / ν-Ν. L.S1 _Μ , ,Ν - Ν 1ΓΙ ν j d and g ι ι ΑΝ)' ΟΝΟ Η 2-(4-(2-(2-chloro-4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1- yl)phenoxy)ethyl)piper azin-1-yl)-N(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 811.3 WITH * 4 FF J\/ ⁰ / g Λ Λ / Η Η m^C _x g Ν _F . ν Ν Ii I . Ν 1 S 1. I ί 1 U ι 0 Ν 0 .'ι ^Η M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2fluorophenoxy)ethyl)pip erazin-1 -yl)acetamide 829.6 WITH *

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5 V 0 Ά. νΛ, FyY s ilA _l n J o tJ A X O^N^O H 2-(4-(2-(2-chloro-4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidine1- yl)phenoxy)ethyl)piper azin-1-yl)-M-(3-(2,6dioxopiperidin-Zylamino)phenyl)acetamide 812.1 WITH * 6 V 0 O-n'i η h s lAzx A J o U a A H 2-(4-(2-(4-(7-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- fluorophenoxy)ethyl)pip erazin -1-yl)-M-(3-(2,6dioxopiperidin-Zylamino)phenyl)acetamide 808.4 WITH ** 7 F. F n VP №—C И h. -. s ^r ΧΧ^ν । J o.: ι J. 0 ο N ^0 H 2-(4-(2-(2-Chloro-4-(7-(4cyano-3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octane5- yl)phenoxy)ethyl)piper azin-1-yl)-M-(3-(2,6dioxopiperidin-Zylamino)phenyl)acetamide 823.4 WITH *

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8 EF fX П Γ~ \ jy ι ...... and h N-~-^ / 1 ., - N .- ft - 0 rl _N f J » ' 1 L r - ONO H 2-(4-(2-(4-(7-(4-cyano3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl)-2- fluorophenoxy)ethyl)pip erazin -1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 807.4 WITH ** 9 And \ _ _N ~t— d HH N ----- ' ^f „N, i II ΊΓ Г С Π ΪΎ Τι ^s XT l. AJ ο XJXX Η 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)piperazin-1-yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 817.2 WITH * 10 Xf o ^F A U- XVn T η h r YV । Π ΐ ' ! ι Ό Ο N 0 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 805.2 WITH *

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eleven FF / \ _ hi l Η H ^{1 N ljf} -s NL - \ - ii! [ _N n [1 1 1 0 ''ONO H 2-(4-(2-(2-bromo-4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1- yl)phenoxy)ethyl)piper azin-1-yl)-14-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 855.0 WITH ** 12 V / x ы IF Η H ,'> « xX ХХ'ХЛ v^v ^N vX. -- ' Ί ^F I ί I И Ί T 1 s l AJ o (JAA ν' O^N^O 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- (trifluoromethyl)phenox and)ethyl)piperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.3 IN ** * 13 FF „ A ⁰ 1 W- /\ _hi l Η H ' I ί I _N 7 S II 1 L - C - -ONO H 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-fluoro-5- methylphenoxy)ethyl)piperazin-1-yl)-M-(3(2,6-dioxopiperidin3ylamino)phenyl)acetamide 809.2 WITH 4=

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14 Ef η Fv ^N 4z%z ^CI ^= ⁷ fl Y Ί 1 1 Y 1 TYI S CYto /К NJ 0 LJYX Cl ^H 2-(4-(2-(2-chloro-4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidine- 1- yl)phenoxy)ethyl)piper azin-1-yl)-I-(3-chloro 5(2,6-dioxopiperidin3- ylamino)phenyl)acetamide 846.2 WITH * 15 YU “^- ^; Ύ« Y _N ΥΫ ΥΊ '-1' er N' 0 | H 2-(4-(2-(4-(3-(4-Cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- fluorophenoxy)ethyl)pip erazin-1-yl)-K-(3-(2,6dioxopiperidin-3ylamino)-5- methyl phenyl)acetamide 809.3 WITH **

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16 e ^F n fX }=h ,/τ η h r^N'%r ^N Y^ ^N v% ® L . ..< L l. n J ' o XJ JL Jb O^N^O Ji ^H 2-(4-(2-(2-chloro-4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1- yl)phenoxy)ethyl)piper azin-1-yl)-M-(3-chloro5-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 846.2 WITH * 17 _F V 0 / ^T~ J 1 j । । ^Ν Η^^ ^Ν γ4Λ ^s iA _l nj 0 LJ f X. Ύ) O^N^O H 2-(4-(2-(4-(3 -(4-cyano- 3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)piperazine-1-nn)-N(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 819.4 WITH *

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18 1 _b o μ - ¹ L 1 '1 Ln D JL xA JL J --- ^N uD - ^{n and F} |T\ o 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- isobutylphenoxy)ethyl) piperazin-1 -yl)-M-(3 (2,6-dioxopiperidin3- ylamino)phenyl)acetam eid 833.4 WITH * 19 FF ρ» NX C* > ^F A_ rW * nn VA r Ϊ II ] 1 A^O'' ~ ^N . ' ° A O N O f' ^N 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- fluorophenoxy)ethyl)pip erazin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 813.3 WITH * 20 FF ^F Y °VjO № _ _rj rhh μ M i | y NN, -- 1 "IAS n JL - 0 ' P ONG H ' 2-(4-(2-(2-chloro-4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1- yl)phenoxy)ethyl)piper azin-1 -yl)-M-(2-chloro5-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 845.2 WITH *

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21 FF fA _ % ' ^N _v N ll , 1 K, N ' 11 J .ill) - Ο Ω N O H (2S)-2-(4-(2-(2-xnop-4- (3-(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1- yl)phenoxy)ethyl)piper azin-1-yl)-N(3-(2,6dioxopiperidin-3ylamino)phenyl)propane Ministry of Foreign Affairs 825.2 WITH * 22 FF „ _F V 0 WY Τη Г ¥ i ΥΎ Ti s I. X l n J o UAX (ΚΉ^Ο H 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 806.4 WITH * 23 FF θ, , ^F V K4Xv-N IHH №&—4 Λ N -. - _x N . , N , i [ j . X < l:. i. ii ' 0 -' - ']' 0 N 0 I h Cl M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1yl)phenoxy)ethyl)piper azin-1-yl)acetamide 811.2 With *

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24 FF ^F X_„ °w- №— ' N .,- N . N n-- / Ί .1 '' π 1 p I 4 h L 1 N 1 0 I / ¹ 1 o , ο N υ (1! ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin n-3 -yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidine1- yl)phenoxy)ethyl)piper azin-1-yl)acetamide 812.2 WITH * 25 /Vn I η h №-4 /T^vNx^CI _M „N _N , Γ ΪΎ ' 1 Π [| ' J 1 ά 0 * Ο N Ό Η (2C)-2-(4-(2-(2-chloro-4(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidine- 1- yl)phenoxy)ethyl)piper azin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)propane Ministry of Foreign Affairs 825.2 WITH ** * 26 FF _F X 4/ N^-4 ^Z , _kl r< N Λ ϊ YY f 1 Ti ' ³ AVa ^{j 0} g-o-'L 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-fluoro-5- methylphenoxy)ethyl)piperazin-1-yl)-1H-(3(2,6-dioxopiperidin- 3- ylamino)phenyl)acetam eid 810.2 With **

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27 RF _n FX, IE-y < -N % ^ _[f - Α η S % AXN j О ¹¹ - <' ^5^-0- -, ¹ 0 N '0 Η (S)-2-(4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pe razin-1-yl)-LG-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 805.0 WITH * 28 _F y V/ / |_| // ,-, .,Ν ,- _N, - / t J «ΙΌ ii —'- '- '- 0 N '0 (R)-2-(4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pe razin-1-yl)-LG-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 805.0 WITH * 29 FF ^f A=, A ^ns 4AVyv^ s *LxA λ n J o G ^; A 1.H 2-(4-(2-(2-sec-butyl-4(3-(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidine1- yl)phenoxy)ethyl)piper azin-1-yl)-LG-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.2 A **

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thirty EF ~ M 1 ' . HH m— ^J N - x -,, χ NN - O \K A Y u ¹ M ' Ο T 0' N 0 Ii ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2cyclopropylphenoxy)ethyl)piperazin-1yl)acetamide 851.2 WITH * 31 У ° , ^F )X _ /\-Л1 T Γ~Ί Η H ^ns Xj /vA X ^N Xr ^N W ^N n! s (A l AJ o UXXX^qX^x O^N^O 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- cyclobutylphenoxy)ethyl)piperazine-1 -nn)-N(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 831.2 WITH * 32 FF V 0 1 'Y i XX*Z~THH W Г YY IVI r IY 1 s к А l n J о UJ Ж X ax' Ж-х cmNm) Cl ^H I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridinn-3-yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)acetamide 840.2 WITH *

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33 N^- ^J '' “ ^N ~ —* - . N - N - / UN 1 8 ri JJI П s - (Г N '0 H 2-(4-(2-(4-(3-(6-Cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)piperazin-1-yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 818.2 WITH * 34 V □ HH ^ΝΞ£ ν_/ y ^N Y% ^/ ~ ^x/ ί^ ^Ν ^Ύ ^Ν s Hl a. nJ o % .LX O^N^O H 2-(4-(2-(4-(3 -(4-cyano- 3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1-yl)-2- propylphenoxy)ethyl)p-iperazin-1-yl)-N-(3 (2,6-dioxopiperidin- 3- ylamino)phenyl)acetam eid 819.4 WITH * 35 FF D V/ Γ^^Ν' H 7 ^H NS^Y/ γΝγγχ a _n a,N yЪ ^N y% SI -X a NJ O IJXX H M-(2-chloro-3-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)acetamide 839.2 IN **

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36 f Ίί 7 G H K If 1 T Ί s A n J o l L f X n 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- cyclobutylphenoxy)ethyl)piperazin-1-yl)-I(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 832.6 WITH * 37 V 0 ^F AV/ Х^—ч <—4—^'' //Xv—Ν T NN NS—< / χχ _Ν '< A .- n ^w y ΤΎ fj d । j I n 2-(4-(2-(2-sec-butyl-4(3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidine1- yl)phenoxy)ethyl)piper azin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 834.6 A ** *

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38 FF /7 _ NHH Ν^Ξ— N _M . К _x r< ^N '“ li I . _N J ίΜ ί L - '0 ''- -ONO H 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- propylphenoxy)ethyl)p-iperazin-1-yl)-I-(3 (2,6-dioxopiperidin3- ylamino)phenyl)acetamide 820.6 WITH * 39 V 0 ^F < A GL n H ^N Hry ^N Y'/ ⁴ n''A _Ί ^{3 0} v _o a _n a _o H 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopentylphenoxy)ethyl)piperazin-1-yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.2 IN ** 40 FF °» / ^F A_ k£- GLU T η h -АГУу^ - N, _rf « _f| S 11, N ¹ O 1 J 1 J ' T 0 NU 1 H C 1 M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)acetamide 839.2 WITH *

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41 ^ns A_/ y ^N YV^ η ¥ T ^m Г 1 3 ¥^ ₀ ' ^Λ ν ^Ιί ¥ ° _π ' - □ NO Η N-(2-χπορ-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)acetamide 839.2 WITH * 42 FF „ f¥ %/ rVj/l η h nH/Vw Γ ^νΖ ϊ¥υ ^ν Γι ^s ¥¥AL 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 823.2 WITH * 43 ° / Η Η ^ns ¥J^ ⁿ yV^ ^ ⁿ ^Vy¥% ^f ¥, ^s (¥«¥□ FF Η 2-((S)-4-(2-(4-(3-(4Cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)-3 methylpiperazin-1-yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 819.2 WITH *

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44 ⁰ / A l Η Η F^Ty ³ %Α ₀ -' ^{Ν 0} ΟΝΟ FF Η 2-((R)-4-(2-(4-(3-(4- cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)- 3 methylpiperazin-1 -yl)- N-(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 819.0 WITH * 45 0 ^NE A^ [^Ν' ^Ν g - ^{Ν F} “7\ ³ VA _O --^ _v ^N -V ·., ⁰ FF n 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 819.3 WITH *

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46 η η Uy-y g 7 μΊ [ F-D % ⁰ ΟΝΟ FF Η 2-((S)-4-(2-(4-(3-(4Cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 819.2 WITH * 47 cS/ ⁰ 1 ¥-4 ^Ν з ^у ТХ ν § ι ιΐ ^ΈΓ - - π Ο·' Ν 0 Η M-(2-chloro-5-(2,6- dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)acetamide 840.2 WITH * 48 0 ¥ s' lA^u s U/A F F Η 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)-3 (hydroxymethyl)piper zin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 835.2 WITH *

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49 0 . n A. - Μ ~Ι I NN ^Ηα ν' ι Γί:Ί 1 F~% ' 0 - ° ' 0 Ν%0 FF Η 2-((S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)- 3 (hydroxymethyl)piper zin-1-yl)-I-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 835.0 WITH ** 50 χζ ο 0 X { .—ο ο 2-((S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2(hydroxymethyl)piper zin-1-yl)-I-(3-(2,6cyoxopiperidin-3ylamino)phenyl )acetam id 835.0 A ** *

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51 °' / _F ys MSDA ^FF OH ^H 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2(hydroxymethyl)piper zin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 835.0 IN ** * 52 FF fX %/ κι HH «ΗΤγ ^Ν γγ· /n OU J- N - ¹ O / ¹ -, - - O ^? N Ό H 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-2,4- dioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 789.4 WITH

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53 FF NS- -> NL . N, M. ; li I _N J Д ϋ LL - '0 ' ONO H 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)piperazin-1-yl)-LG(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 820.2 WITH * 54 SCH I i Tl AND Τη I o_/H> M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)4-oxo-2-thioxo -7oxa-1,3diazaspiro[4.4]nonan1-yl)-2fluorophenoxy)ethyl)piperazin-1-yl)acetamide (THP enantiomer 1) 857.2 WITH *

- 152 044376

55 V o A HH s o LJ _n A _M A _n 0 y 0 N 0 Cl H N-(3-χπορ-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)4-oxo-2-thioxo -7oxa-1,3diazaspiro[4.4]nonan1-yl)-2fluorophenoxy)ethyl)piperazin-1-yl)acetamide (THP enantiomer 2) 857.2 IN ** 56 р5/ °i Γη G'' 1 HH '•H>V ^N YV' nYvYn S k l NJ O k Jk A, Ο^Ν^Ο Η 2-(4-(2-(4-(7-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- Cyazaspiro[3,4]octan5-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 818.3 WITH * 57 FF n fA A / Ul-^T 1 n n oVtYTI S Ts _ly J O k U A >k ^H _o g\^k^ and _Ο ^ _Ν ·^ _Ο n (2S)-2-(4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)propanamide 819.4 With *

- 153 044376

58 l : Η Η S G A N J O 1J J A O D o (2R)-2-(4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)propane amide 819.4 WITH * 59 I „1 1 ί GP ABOUT O/g-'T! θ s 2-(4-(2-(4-(3 -(4-cyano- 3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1-yl)-2-(1,1- difluoroethyl)phenoxy)ethyl)piperazin-1-yl)N-(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 841.2 WITH *

- 154 044376

60 Ш -η 1 I ΤΙ I'm pv O oJ ”Λ 23* > 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidine- 1-yl)-2-(1,1- difluoroethyl)phenoxy)ethyl)piperazin-1-yl)N-(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 842.2 WITH * 61 ° G\_iM n η ^-γΝν-γΝγΧ = ΜννΧ ο γοήΑ 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 823.0 WITH *

- 155 044376

62 V o If nn S to Λ NJ 0 % 11 A A. Cl ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin n-3 -yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)piperazin-1yl)acetamide 876.2 WITH * 63 Λ w Mi Η H ^N У i ι ii i Ύ1 T Ί S to Λ NJ 0 H, AND AX 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 824.8 WITH *

- 156 044376

64 V o FX \\ ! T η h «ΑΑ fw ΑΑγΑτΊ ^S U _O ZX,NJ O , AAA _o H 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 824.2 WITH * 65 N 1 H „ Ak O^^N.,0 SC¥ 0 X < nmA/nA^f ^A^AA-AE 1 n h A ^: ΓΥ FF 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- fluorophenoxy)ethyl)pip erazin-1-yl)-M-(3cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 820.2 IN **

- 157 044376

66 Η s GT 1 2 Г il Y Y „ L=l 1 JL JJ i n 1X1 1 J №—4 UL-A/ AxAn-AzN'v L/T A nn F—G\ F F ° 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2-(2,2difluoroethyl)phenoxy)e gyl)piperazin-1-yl)- N-(5-(2,6- dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 860.5 WITH * 67 -p 7 j ¹ ^Du. 0 $=o {Ya M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(2,2difluoroethyl)phenoxy)ethyl)piperazin-1yl)acetamide 876.5 WITH *

- 158 044376

68 ,-- _n 4 0 N O N. 1 JJ 4 ni . J i ---1l _t .| N NN' 4 ^N 1 HH F- _a FF ° 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2-(2,2- difluoroethyl)phenoxy)e gil)piperazin-1 -yl)N-(3-(2,6- dioxopiperidin-3ylamino)-5- fluorophenyl)acetamide 860.5 WITH * 69 _F XJ °Ά4 Tv 41 η h yNΤ ^Ν Τί ^Ν ΎΤΓ ^Ν ΎΤ ^S jA/AL ⁰ I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(5-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-3-ethylpyridinium 2yloxy)ethyl)piperazine -1-yl)acetamide 840.2 WITH * 70 0. i f ^x \ TT HH №— ^J Π ^N -N , - - N ,- N ,- - £ LI : П £ ,L ΐ JJ ' n- - | ' | O'-N 0 F 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2,3fluorophenyl)acetamide 841.2 WITH 4=

- 159 044376

71 V q / Η Η AZ γΥ γΝγ s L -A n J o J ^ J F F SG^rO 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(2- fluoroethyl)phenoxy)ethyl)piperazine-1-nn)-N(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 842.5 WITH * 72 „4 b L.U. y5fl L.U. ll*t M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(2fluoroethyl)phenoxy)ethyl)piperazin-1yl)acetamide 858.6 WITH *

- 160 044376

73 fXf °\ ! · i *1 U |-| p ρ^τΥτΊ ^s Cpzp θ W o+n+o 4 h F 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 851.3 WITH * 74 0 /=vXr n h ^Ns VVfp HJrWn ^{s 0} kJ _O A _N A _O FFH N-(3-xaop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridin n-3 -yl) -5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1yl)acetamide 854.3 WITH *

- 161 044376

75 o , z ^N =W^T n n V ΐ| i^'V'Ti'VYA FA ^{S 0} o^N^O FF Η 2-((R) 4-(2-(4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6- dioxopiperidin-3ylamino)-5- fluorophenyl)acetamide 838.2 WITH * 76 N-, Уб Ν=^\ / Η H Y F-тС ^S Χχ^ο--··\^ ^Ν ^ %, ⁰ FX> o^N^OFFH 2-((R) 4-(2-(4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(5-(2,6- dioxopiperidin-3ylamino)-2- fluorophenyl)acetamide 838.2 WITH *

- 162 044376

77 ,rf- IZ LL I 1 Sh 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 852.3 WITH * 78 ' _H ι^ Η H №— ^r N - ,, -- Ν N s ^f Ί J '. i! J Г 1 II, ο Ν O sb ⁿ N-(3-xaop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin n-3 -yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2dimethylpiperazin-1 yl)acetamide WITH *

- 163 044376

79 1 -η 1 ΙΑ ¹ A У I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2,2dimethylpiperazin-1yl)acetamide 867.3 WITH ** 80 KF _o ^F A, p CW 1 1 FHH Ha fyH mWn ⁸ VVjU 0 ψοΗ ^Χ ο F 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidine- 1-yl)-2-(1,1- difluoroethyl)phenoxy)ethyl)piperazin-1-yl)N-(3-(2,6- dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 860.0 WITH *

- 164 044376

81 o "A>Wr· ,—AVn sn A. λ A 1. o UAA A xZ '., ^w XX oAX) FFH 2-((R) 4-(2-(4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetam eid 820.3 WITH * 82 A 0 fA \\ / #AN ι U Η H Ha y ^N γΗ πνγΥτΊ S T X _ n J o JJ J. L O^N^O F 2-(4-(2-(4-(3 -(6-cyano- 5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidine- 1-yl)-2-(1,1- difluoroethyl)phenoxy)ethyl)piperazin-1-yl)N-(5-(2,6- dioxopiperidin-3ylamino)-2,3difluorophenyl)acetamide 878.0 WITH *

- 165 044376

83 pF θ GAL/H'' Η η /γν ^Ύ ^ν ύΠτ ^ν ΤΊ st ,Α _Λ ν Α— ΰ As. JA Α -'-'χ ^{0 0} 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2dimethylpiperazin-1 yl)-I-(5-(2,6dioxopiperidin-3ylamino)-2,3difluorophenyl)acetamide 870.2 WITH * 84 ь -η 1 ι τι Х ₃ <уЧ># M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)piperazin-1 yl)acetamide 852.2 WITH *

- 166 044376

85 Vn ΜΗχΧζρ Χ^ ^Ν Τϊ ^Ν Γ1 S 11 _l n J o % JJ Jx y O^'^'O N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(7-(6-cyano-5(trifluoromethyl)pyridin n-3-yl)-8 -oxo-6thioxo-5,7diazaspiro[3,4]octan5-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)acetamide 852.4 WITH * 86 V 0 \ .— /%_« ' H H Hz πζΧγΗτΧ S XX /x N J О X JI X X 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidine1- yl)phenoxy)ethyl)piper azin-1-yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 796.2 WITH ** 87 _ ? uy^x/I y M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5-dimethyl -4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1yl)acetamide 853.2 WITH *

- 167 044376

88 1 -η 1 j “Π And 4 ΣΙ ___( 2-(4-(3-(4-(3-(4-Cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethylphenyl)propyl)pip erazin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 821.4 WITH * 89 Ο , ΛΥμΗ Η νΗ^Γ γ ^Ν γ°γ^ ρ _Ν ^γΝ^Ν^ ^S 0 Μ^Αθ M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(3-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2ethylphenyl)propyl)piperazine -1- yl)acetamide 838.2 WITH * 90 ν^. Ν--— ¹¹ ^ ^Ν ίΐ ., Ν Ν - Γ 1| η 1 Ν π [ I ] ι 1Л ' Υ ^Ν ° , 0 Ά Ο FF 1 Η 2-((R)-4-(2-(4-(3-(4- cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6- dioxopiperidine-3- ylamino)-5fluorophenyl)acetamide 837.4 WITH *

- 168 044376

91 _F \J θ t ³ o M ₀ DD ₀ Cl ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin n-3 -yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- (hydroxymethyl)phenoxy)ethyl)piperazin-1 yl)acetamide 842.0 WITH ** * 92 f\ ^F °\ ! ? ^{H hh n} Hn=/ Υ ^Ν ΥΥ^ P^G/P S LA .an J o A Y AA y O^N^O Cl ” M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3-yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(1hydroxyethyl)phenoxy)ethyl)piperazin-1yl)acetamide 856.3 IN ** *

- 169 044376

93 A o _; 'J'D I C _N HAW ^s idp o y oAA N-(3-χπορ-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin n-3 -yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)piperazin-1yl)acetamide 854.1 WITH * 94 FF /U 0 ί >γΜ 1 n n No-< _A - ^Ν A ' Υ ρχγΝ^Ν^. ^s Uo^C ¹ o CHALA Cl ⁿ I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2isopropylphenoxy)ethyl)piperazin-1yl)acetamide 853.2 IN ** 95 a / ^/ >° Ll^/Aa c- - L 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.4 With *

- 170 044376

96 FF ₀ ^F AJ KD «Η/Υγ¥ Ο^γΥτΊ ³ ° W 2-(4-(2-(4-(3 -(4-cyano2-methyl-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- fluorophenoxy)ethyl)pip erazin-1 -yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 809.4 WITH ** * 97 3 χζ o b/xz Wo C-V Q “ 1 (¾ 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,2dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 834.4 WITH *

- 171 044376

98 U 0 l NN αΎυΥυΊ ® II, ZK N J--7 0 C JL X Χ^-Ο^Ά ^{7 0} fl ⁰ 2-(7-(2-(4-(3-(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-4,7diazaspiro[2.5]octan4-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 831.4 WITH ** 99 U θ , Г —\ Λ / ТУ — n'i^ n n ^Ν ΓΤι ΓLTTj Xi ^S 0 θ^Αθ 2-(7-(2-(4-(3-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-4,7diazaspiro[2.5]octan4-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 832.4 WITH *

- 172 044376

100 o Ν=\ ?—р _{η η} ^Ν % 7^ γ ^Ν γίγ ^Ν γ-\ <- / s Ιί >4 ·· Ν J. ΰ X- d Α X F-Ν ^u F^z Ο^'Ν^ Ο FF 1 Η 2-((R)-4-(2-(4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(5-(2,6- cyoxopiperidin-3ylamino)-2,3- cifluorophenyl)acetamide 856.4 WITH * 101 νΖ ^Ν Η}γγνΑ ^S Xs^oZx^NxxAy ⁰ Tx _ο Ά _ν Αο ci ⁿ I-(3-chloro-5-(2,6cyoxopiperidin-3ylamino)phenyl)-2-(7(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-4,7cyazaspiro[2.5]octan4-yl)acetamide 865.3 WITH *

- 173 044376

102 FF \/ O ^F VjX FV /T η h ^NS ~v Vpp Oi> ^N TVri S •L.xA Λ N J<—7 0% J J. J 'A/ ^u O^N^O Cl ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(7(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin n-3 -yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-4,7diazaspiro[2.5]octan4-yl)acetamide 866.2 WITH * 103 0 _π β 7 m ' h n e -/ SX L a, NJ 6 lk J JI ^FF Cl ^H N-(3-xaop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(7-(4cyano-3(trifluoromethyl)phenyl)8-oxo-6 -thioxo-5,7diazaspiro[3,4]octan5-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 yl)acetamide 865.4 WITH *

- 174 044376

104 -η ΐ Ρ 2-((R)-4-(2-(4-(7-(4cyano-3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1-yl)N-(3-(2,6- dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 849.4 WITH * 105 ⁰ π —χ Hz— ¹ _{Η Η} NSX / yNv/x Ar WA FFH 2-((R)-4-(2-(4-(7-(4cyano-3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6- dioxopiperidin-3ylamino)phenyl)acetamide 831.4 WITH *

- 175 044376

106 0 j—, Η Η ρ^/ζ ^s \Д0' ^/ xx ⁿ E-h ^ό Tx qAnA ₀ ^F Cl ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(7-(6cyano-5(trifluoromethyl)pyridinn-3-yl) -8-oxo-6thioxo-5,7diazaspiro[3,4]octan5-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 yl)acetamide 866.3 WITH * 107 0 _π N :i«\ ^*1 h H A _f ^N p γγγ ^Ν γ% F-D X ^x4 _O —XxZ ^u ΧΛ' O^N^O FFH 2-((R)-4-(2-(4-(7-(6cyano-5(trifluoromethyl)pyridin-3-yl)-8-oxo6-thioxo-5,7diazaspiro[3,4]octan5-yl) -2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 850.2 WITH *

- 176 044376

108 ο _π s 4 w l NJ o 1J f X F-D :,, υ ο^Ν^Ο FFH 2-((R)-4-(2-(4-(7-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo6-thioxo-5,7- diazaspiro[3,4]octane- 5-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 832.31 WITH * 109 ^F v 0 ^f A >o /V-ы T and h nH/ ³ UAA u/ai H 2-(7-(2-(4-(3-(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-4,7diazaspiro[2.5]octane4-Ni)-N-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 849.3 WITH *

- 177 044376

BY V o fW Q / HH Η ¥ TY r Y YY fl s 1 _l n J—? o t D A A |l H 2-(7-(2-(4-(3-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)-4,7 diazaspiro[2.5] octan4-yl)-M-(3-(2,6dioxopiperidin-3yl amino) -5- fluorophenyl)acetamide 850.3 WITH * 111 ⁰ / rv,>4 _HH %/ γγγ^ γ»Ύγγ ^Ν γ> еУ ^s O ₀ —“>- ⁰ MoAL FFH 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-((S)-2,6dioxopiperidin-3ylamino)phenyl)acetam eid 819.0 WITH *

- 178 044376

112 0 n n ^N =K=/ У γγ^ YV Ά ц ^s ΐΧ^Οχο U _o aX FFH 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-((R)-2,6dioxopiperidin-3ylamino)phenyl)acetam eid 819.0 WITH * 113 (Pi to 1) 114 (Pi to 2) K 0 ^F A_ M- - H=/ r ^N TV O'VT/ri ^s M- _o ^nA 0 ψ _ο ΑΛο ά ⁿ or RF ^Ήν kd, _N Y>yr. , . J .k , ?. ,. ϊ 1 .1 .AISL 8 I 1. 0 '- I Ο N 0 i ^H (2C)-P-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)propanamide or (28)-P-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)propanamide 854.2 854.0 WITH WITH * *

- 179 044376

115 EF? Η f L/ l. J _ Jono «UK 1 -SO l « Ι 'ί ^{t g} Ns-A V Λ - ~N - N - Η ^{N N} 0 ' N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((lS,4S)-5-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5diazabicyclo[2.2.1]hep tan-2-yl)acetamide 852.3 IN ** 116 FF η ^F X_ Vb /AlLt I Η h №-J=/ y ^N yy^ nVn ^N TJ s ILA n J o 4.JAA -γ cAnA} PH (2S)-2-(4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)propanes d 838.2 WITH *

- 180 044376

117 - rAYY _N =/ /G ¥ η ι 7 u and I T 1 S 1 xA xx NJ o O A A ^p x/ ^u 'X^' ο^Ν^Ο / Η (2R)-2-(4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)propanes d 838.2 WITH * 118 FF _c % 0 . g 'U x\ / /0 ;Ml” 1 Η Η №=— \ Τν ^Ν χΑΖΧ Α _Μ Υ ^Ν χΑχ ^Ν χΑ Γ ¥ η Γι II ί ι 1 ^s γΑλά· ^ν Υ ^ό U λΥΧ Χ^ 'Q XX XX \Ζ QX Ν XQ Η (2S)-2-(4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)propanamide 820.7 WITH *

- 181 044376

119 FF A 9 > XI AAl ? η h H=r γ ^Ν γγ> AGUNGA s IL A l n J o LA AA ^v XX O^N^O H (2R)-2-(4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)propanamide 820.4 WITH * 120 EF? H A _s xxA— _o Αθ _γ γ ^mz А^РнчА^Аххх AmААА^АА «Α-γγ й ^η « I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((lR,4R)-5-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5diazabicyclo[2.2.1]hep tan-2-yl)acetamide 852.0 IN **

- 182 044376

121 0 1 hh NS—X g X'. ·Χ -,, ^N - Tr ® XX « “ s γυ i ^F YY X) -ONO FFH 2-((2R,5S)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)- 2,5dimethylpiperazin-1yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 833.0 WITH * 122 ⁰ / ns—'''''рДууД ¥ ³ Uo^Ao mDA FFH 2-((2S,5R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)- 2,5cymethylpiperazin-1yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 833.0 IN **

- 183 044376

123 o / ΓΑ-Ν ⁴ ! Η Η ^NS y=/ ^N y ^{4 S} SG~M-Ho FF Cl N N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R, 5S)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2,5cymethylpiperazin-1yl)acetamide 868.0 WITH * 124 O / /Pkl'' N n ^N r^/ ^N TT '^ϊ^ΎΥΤΊ p% S kA. ,α N A. O A A ^F VY O^N^O ^FV Cl ^H M-(3-chloro-5-(2,6cyoxopiperidin-3ylamino)phenyl)-2((2S,5R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2,5cimethylpiperazin-1yl)acetamide 867.0 IN *

- 184 044376

125 ⁰ / ^NS ^ γγ ^v r ΆρΆ'Ί fX ^s hА,-- ⁿ θ - X ,, J „ 0 -^ · ^» 'ONO FFH 2-((2S,5S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.0 IN * 126 ⁰ / /X-Ni Η H ^Ν ΗΖΥγγ YxV n^a ^F Y ^S Y^ _o -^^ ^N Yx 2 pj q^nY FF i H I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2S,5S)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2,5dimethylpiperazin-1yl)acetamide 867.0 WITH *

- 185 044376

127 0 1 ν') η η NS—\ Γ .... _ Ν . Ν - _F A ' ¹ ¥ » ί S Vil Γ\_ -- 0 '- - '-ΟΝΟ FF Η 2-((2R,5R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)- 2,5dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.0 WITH * 128 0 / γ- _{Η Η} NS-Д ΓV ^N v¥A ν Α ^Ν '' ^Ν _F 7 f El »i.lill O' - , 0 Ν _ F ϊ 1, Η N-(3-xaop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,5R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2,5dimethylpiperazin-1yl)acetamide 867.0 WITH *

- 186 044376

129 ⁰ / Tp Λ ρρΤ _{Ί c} / s kA , ν J ο f · .1 ¹ A -- - O' N 0 FFH 2-((2R,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.0 WITH * 130 0 . | and h ^NS XJ γΝγγχ f-4 ^s LT lА X o LJXX ^F A ^v γ ο^νΆ FF ci ^H M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,6R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)acetamide 867.0 WITH *

- 187 044376

131 o / N=\ Ar _{n n} ΥΡΎΤΑ .YAn fA xA(Pto- ^N t O' N 0 FF Cl ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-((8)4-(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 yl)acetamide 854.1 WITH * 132 A 0 p- g ·~Α \\ 1 AuAn s ⁰ - (L to H 2-(4-(2-(4-(7-(4-cyano3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 817.0 WITH * 133 F^Z O, №— ⁷ - _N -' A --. N, . bA Ί „ _N ] A ¹ J - 0 - ^N ' ° ' । ONO 1 hCl M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-2methylpropanamide 867.2 IN **

- 188 044376

134 FF FY % _{π NS} —·(Ύ N - N - N : II 1 _N LS ni L and - ϋ N o H 2-(4-(2-(4-(7-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- ethylphenoxy)ethyl)-2,2dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 846.3 WITH * 135 θ J ax KL min ^H NS-CH G V ^N xZ%y- ^F ' Μ - ^NN Λ ί ΥΎ i P 1 Ш [ S Ch.A N ¹ 0 ' ¹ J J- F^V -> 0 N ϋ FF ) H I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5-dimethyl -4-oxo-2thioxoimidazolidin1-yl)-2-(2fluoroethyl)phenoxy)ethyl)-2-methylpiperazin1-yl)acetamide 871.2 WITH *

- 189 044376

136 __U/J. _ F . XN , s'1;i . „ J » ί ϊ 1 J U ^v γ Ο' Ν Ό J, ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 - oxo-2-thioxoimidazolidin1-yl)-2-(2fluoroethyl)phenoxy)ethyl)piperazin-1yl)acetamide 857.3 WITH * 137 N=\ A/-' _HH / \ KJ l Π H N^^x\ . N. N _{4 F} ^'' ¹ kC s ii \i FF -ONO 2-((R)-4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-((S)-2,6dioxopiperidin-3ylamino)phenyl)acetamide 820.0 WITH *

- 190 044376

138 O / fxHr n Η pYyV'Zi 2-((R)-4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-((R)-2,6dioxopiperidin-3ylamino)phenyl)acetamide 820.0 WITH * 139 O . jy ή a /-- Xz^vX-nZ. - / Y' G . / / ( S ΐ F “Z\ 0 0 F F 1 -(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)cyclopropanecarboxamide 831.6 WITH *

- 191 044376

140 ⁰ / η η _f s iLxJL nJ- AH I. X fA o^n^o FF Cl ^H N-(3-xnop-5-(2,6cyoxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridin n-3 -yl) -5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2-(2fluoroethyl)phenoxy)ethyl)-2-methylpiperazin1-yl)acetamide 872.1 WITH * 141 FF r. fA. y/ 7~~~\ / iuu ^NS ^' Λ ^Ν fq V rr ^N f Ί S 1“ L NJ 0 i . i> 1 ^L F 0 NU H 2-(4-(2-(4-(3 -(4-cyano3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(2- fluoroethyl)phenoxy)ethyl)piperazin-1-yl)-LG(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 841.2 WITH *

- 192 044376

142 ο _π ((=47-1-Η Η “Ά ⁷ ΓΧίΑΎΑΎ fA χΑθζχ^ Νχ ⁰ 44 ο^Ν^Ο ^F> ά ^Η N-(3-xaop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(7-(6cyano-5(trifluoromethyl)pyridin n-3-yl) -8-oxo-6thioxo-5,7diazaspiro[3,4]octan5-yl)-2-(2fluoroethyl)phenoxy)ethyl)-2-methylpiperazin1-yl)acetamide 884.2 WITH * 143 ο _π 4'α\3τΊ ft( ^ь ААо-\ЛЗ ... ⁰ 44 0Α _Ν Α _Ό FF Cl Η N-(3-xaop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(7-(4cyano-3(trifluoromethyl)phenyl)8-oxo-6 -thioxo-5,7diazaspiro[3,4]octan5-yl)-2-(2fluoroethyl)phenoxy)ethyl)-2-methylpiperazin1-yl)acetamide 883.2 WITH *

- 193 044376

144 ⁰ / FF Cl ^H I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridin n-3 -yl) -5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 yl)acetamide 854.0 WITH * 145 0 , A ^N ~ ^-N ' N ^p — ¹ YN ₄ * - * - N, -- Ν -χ %AA G < A G A [ F- ⁵ °Α _υ Ά ° ^! , ML FF 1 N M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridin n-3 -yl) -5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1yl)acetamide 854.0 WITH *

- 194 044376

146 O / yr * XX » 1 s hm ι ' 'ΟΝΟ F F N 2-((2S,6S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.0 WITH * 147 Q, kL. ' _ _N 1 NN №— ^{4 N} N - - NN . _ / II 1 . 1 and r 11 .1 I ^ff ; _Ί n I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2S,6S)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)acetamide 867.0 WITH *

- 195 044376

148 XF n n m-X G ^N N - , , N _F _r ί 1 LJ 5 AA ^F X 0^- ι 0 N 0 FF C1 ^H N-(3-xnop-5-(2,6cyoxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5-dimethyl -4-oxo-2thioxoimidazolidin1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)-2methylpiperazin-1yl)acetamide 889.2 WITH * 149 0 . N~ A' 1 _c n and NC— ^J X ^N A ¹ μ NA - --/ 0 4 H ||! ] 1 _c JS 1' I _ tj J 0 1 ¹¹ , J J- FX ' 2 - X \ 0 N □ F ^F Cl ^H I-(3-chloro-5-(2,6dioxopiperidin-Zylamino)phenyl)-2((R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridin n-3 -yl) -5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)-2methylpiperazin-1yl)acetamide 890.3 WITH *

- 196 044376

150 o / _ie _l.-A,- L . 7- PU G AS. » .< s в1 1 N - ΟΝΟ FF N 2-((2S,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.0 WITH * 151 kA. Nr—- / ^-N JN - N - / VI A i g η Fy - 0 ' - ^{Ν υ} ο Ν π F 1- Η 2-((2R, 6S)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 834.0 WITH *

- 197 044376

152 F 1 ^{F Cl} h sr T n -p ο ρΑ AA aVA y“AVA ^F A θ N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5-dimethyl -4-oxo-2thioxoimidazolidin1-yl)-2-(2,2difluoroethyl)phenoxy)egil)-2methylpiperazin-1yl)acetamide 889.0 WITH * 153 I 1 iJ ⁷¹ Уа-Α^ΊΊ __y0 ' / 4_Д 7 2-((R) 4-(2-(4-(3-(4- cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- hyoxoimidazolidin1-yl)-2-(2,2difluoroethyl)phenoxy)e gil)-2- methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 855.0 WITH *

- 198 044376

154 N s « L °D γ° Ν&γΐ KAL/ \=/ X i H H A' F F ° 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)M-(3-cyano 5-(2,6- dioxopiperidin-3ylamino)phenyl)acetamide 844.0 WITH * 155 N III H _s fAT/θ nYr° VIHH _f A Av FF SH-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridin-3-yl)-5, 5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 yl)acetamide 845.0 WITH *

- 199 044376

156 F H n s [ ^J _o OW 0 - '-A ' - A ⁿ A^ _m AA _n AY ' ^N 1 HH - γ-4γ „L o ' 1 F 2-((R) 4-(2-(4-(3-(4- cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-(2,2difluoroethyl)phenoxy)ethyl)-2- methylpiperazin-1 -yl)N-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 873.3 WITH * 157 fA Y / - ^{1 F} „ - YN ' f II J „ _N J s E 1 I ] YO' N 0 1 h UI I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)piperazin-1yl)acetamide 875.3 WITH *

- 200 044376

158 III and Ιχ ΤΊ—^ \=/ T O ? 0 □Y Υγ’ ABOUT THE SAME El o 2-((R) 4-(2-(4-(3-(4- cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-(2,2- difluoroethyl)phenoxy)ethyl)-2- methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 873.3 WITH * 159 Q o—) I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4 -oxo-2thioxoimidazolidin1-yl)-2-(2,2difluoroethyl)phenoxy)ethyl)piperazin-1yl)acetamide 875.3 WITH *

- 201 044376

160 ό ¹ ΙΖ o /A d 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-(2- fluoroethyl)phenoxy)ethyl)piperazin-1-yl)-M(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 823.3 WITH * 161 FF Y 2 / -Ц%' N ⁿ №— ^{J r} „ N - _F - - N - N - 7 ί L . , ΐ J !i : L 1. 0 ΟΝΟ n 2-(4-(2-(4-(3 -(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(2- fluoroethyl)phenoxy)ethyl)piperazin-1-yl)-M(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 824.3 WITH *

- 202 044376

162 o / ... J. . . j.-k, TU ϊ Chl. » J s » ^Ί J । A °'' o yo 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2-methylpiperazin1-yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 833.4 IN ** 163 °VL A G | n n N-Cr— A ¹ _m „ N - N - / Ί| 1 H P [| 1 3 b I ¹ , 1 NJ o 1' ^{1 J} J C ' - -ΟΝΟ FF Η 2-((R)-4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2-methylpiperazin1-yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 834.3 IN *

- 203 044376

164 o / NS—X / > ,, . N - N - _F g / λ ,» is J : ii ^F “7\ U - -ONO FFH 2-((R) 4-(2-(4-(3-(4- cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-(2fluoroethyl)phenoxy)ethyl)-2-methylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino )phenyl)acetamide 837.3 WITH * 165 №_ ^N '» ir ¹ ? AU _r ° Al -NN ¹ N to % 11 , J Ά_ 4 f ' NN 1 -, ^v - ,. II H F μ° SH-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-1-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin-3 -yl)-5,5- dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1yl)cyclopropanecarboxamide 866.71 WITH *

- 204 044376

166 o n n r ^N Vi Κ ^ν ΚγΥΥΤΊ f-К ^s Κο^Κ·.,, ° DD _O K _N K _O FF η 2-((R) 4-(2-(4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(2- fluoroethyl)phenoxy)ethyl)-2-methylpiperazin1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 838.2 WITH * 167 .< 1 1 1^0 J ΟΧλ H 2-((R) 4-(2-(4-(3-(5- chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 786.3 WITH *

- 205 044376

168 0 , Η η - ίΤΧ УмT'l ci ^s LAo^vX... c ₀ Λ _Ν Λ ₀ H 2-((R)-4-(2-(4-(3-(3chloro-4-cyanophenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 -yl )N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 785.1 WITH * 169 θ, ft / N-- H 11 ι \ κι l Η H ^N - - N - N - i ii n '", s ι j J ι F -/ O TONO FFH M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,5R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5dimethylpiperazin-1 yl)acetamide 868.2 WITH *

- 206 044376

170 o / F-D Zhdgth' ZhCh ^and oUG% FF N 2-((2S,6R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2isopropylphenoxy)ethyl) -2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 847.3 WITH * 171 E F N P e UPUU P /CH y S y Ν o R | jT \HPDxChD _y xSD n-UCHH 1 n no 1-4 2-(3-(2-(4-(7-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- ethyl phenoxy)ethyl)-3,8 diazabicyclo[3.2.1]oct an-8-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 844.4 WITH *

- 207 044376

172 G o 2-((lS,4S)-5-(2-(4-(7-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- ethylphenoxy)ethyl)-2,5diazabicyclo[2.2.2]oct an-2-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 844.41 IN ** * 173 XL ** Ύ and r5 ' xXL o 5 / ............ M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2—(3 (2-(4-(3-(6-cyano-5(trifluoromethyl)pyridin n-3 -yl)-5 ,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)- 3,8 diazabicyclo[3.2.1]oct an- 8 - yl)acetamide 866.2 WITH *

- 208 044376

174 τι O O h X 2-(4-(2-(4-(3 -(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2-(2,2difluoroethyl)phenoxy)ethyl)piperazin-1-yl)N-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 859.2 WITH * 175 0 CWT I i n nNGu ^N y%D ρχ ^S XXQZ^Ny.,^ o kJ _O A _N A _O FF Cl ^H I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,5R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2isopropylphenoxy)ethyl)-2,5dimethylpiperazin-1yl)acetamide 881.3 IN *

- 209 044376

176 Ο _π №\^I 1 Η Η ^m Ar γ αΑ AvAa p / s O l, i 1 b kJ XX F4 ^u ο^Ν^Ο FFH 2-((2S,6R)-4-(2-(4-(7(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 860.4 WITH * 177 0 XN_( 1 η h ΝΑΑγ ^Ν γγ g—fs IJ. _Д^ l ν P o IL J dL X ^F X..... XX O^N^O pF H 2-(3-(2-(4-(3-(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-3,8diazabicyclo[3.2.1]oct an-8-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 831.4 IN *

- 210 044376

178 ABOUT . Λ Αί _Р / s кА NJ 0 ^{11 1} к к ^ρ γ Ж^о-'' Ж ⁰ [, 0 2-(3-(2-(4-(3-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)-3,8 diazabicyclo[3.2.1]oct an-8-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 832.4 WITH ** 179 ⁰ / No h N ΉΥγγ- ΛΜγΥτΊ , / ^s S Ech l Ν k J 0% J A X FM y Y OMM ^F N ^{a n} I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((lS,4S)-5-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5diazabicyclo[2.2.2]oct an-2-yl)acetamide 866.2 IN **

- 211 044376

180 rWn p/s ILA l. n A o IA AA FA ^u NZ o^-N^o FFH 2-((2S,6R)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 848.3 WITH * 181 f ΊΊ 1 A y ^zO 2-((2R,5R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5dimethylpiperazin-1 yl)-M-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 858.3 WITH *

- 212 044376

182 o ri №< rJJ n _{m n} R JSU Α Λ NI J 0 < J A. ML FFH 2-((lR,4R)-5-(2-(4-(7(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- ethylphenoxy)ethyl)-2,5diazabicyclo[2.2.2]oct an-2-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 844.4 IN ** 183 VHH F-τζ ^S kpAy ° kJ ₀ A _M A ₀ FFTH 2-((lR,4R)-5-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5diazabicyclo[2.2.2]oct an-2-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 832.4 IN **

- 213 044376

184 h _HH ⁸ o kJ ₀ A _N A ₀ ^F H Cl ^H N-(3-xnop-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((lR,4R)-5-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5diazabicyclo[2.2.2]oct an-2-yl)acetamide 866.2 IN ** 185 q ^|~TI η h ^NS \rs ^y A Yjnwri f-d χΥθζχ,Ν^/ ¹ . Yp o^m A ff ^υ J h Cl M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,5R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,5dimethylpiperazin-1 yl)acetamide 882.2 IN *

- 214 044376

186 N Η ' ^G m 1 ^{1 Γ} - ^{N 0} --, t LL Г I I 1 Г Г V 1 ^{B f} _f -x .Л' 2-((2S,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1 yl)-M-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 858.3 WITH * 187 „ I ^z X / o A 2-((R)-4-(2-(5-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1 -yl)-3-ethylpyridin-2yloxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 820.3 WITH *

- 215 044376

188 < , ο υ N o Λ 1' J '; ι (' |Τ 1 [ J v - ^Ν ? ' ~ ·Ύ L » ι - Ύη η ¹¹ f Q LJ 1 -(4-(2-(4-(7-(6-cyano5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octane- 5-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)cyclopanecarboxamide 844.3 WITH * 189 8 8 | ““ M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,5R)-4-(2-(5-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2gioxoimidazolidin1 -yl)-3 -ethylpyridin-2yloxy)ethyl)-2,5dimethylpiperazin-1 yl)acetamide 868.2 WITH *

- 216 044376

190 -η 1 -η ι [ ^Ζ 7 I ρΥΓ 2-((2S,6R)-4-(2-(4-(7- (6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1 yl)-I-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 864.3 WITH * 191 А/ о №А AV ^N An AA'vAA ΑΧ ^N ί IY Г j T ТТ II ^s <AoaV ⁰ W oA _n a _o ci ^H (2R)-N-(3^op-5-(2,6dioxopiperidin-3ylamino)phenyl)-2-(4(2-(4-(3-(6-cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)pipe razin-1-yl)propanamide 854.3 WITH *

- 217 044376

192 o 0^1 1 N n ⁿ Aj γΟγΥγΊ A s L,A l. n j.. o IL JAA ρ γ \Xq-X ₄ « XX Q^pXg 2-((2R,5R)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,5- dimethylpiperazin-1 yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 848.0 IN ** 193 0 ₍ >A , Γ | HH AY γγΑ Ά(Ό ^ν ΥΎ ^ν τΑ ftC ^s A% ⁰ U qAA, FFH 2-((2R,5R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,5cymethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 847.0 V **

- 218 044376

194 1 Η s „ D <γ _γ ° ν=—ΑΧ _ν Αν Ά^ά XA^AL | Η Η FF 2-((2S,6R)-4-(2-(4-(3- (4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2isopropylphenoxy)ethyl)-2,6dimethylpiperazin-1 yl)-I-(3-cyano-5-( 2,6cyoxopiperidin-3ylamino)phenyl)acetamide 872.3 WITH * 195 _L ^j GU. i M-(3-chloro-5-(2,6cyoxopiperidin-3ylamino)phenyl)-2((2S, 6R)4-(2-(4-(7-(6cyano-5(trifluoromethyl)pyridinn-3-yl )-8-oxo-6hyoxo-5,7cyazaspiro[3,4]octan5-yl)-2isopropylphenoxy)ethyl)-2,6cymethylpiperazin-1yl)acetamide 894.3 WITH *

- 219 044376

196 0 _ fYT ^s 0 M VHF FFH 2-((2S,6R)-4-(2-(4-(7(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- cyclopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 858.3 WITH * 197 ^H Xx/k/Ch.-X l 4¾. θί^Ν^,Ο s (G Y 7 I g ii । YY «mA JA ΑΥγ- Α ^Ν γΕ _Ν ΑΑ- _Ν ΑΥ YY^YL 1 /\ η h ^F AO'' FF 1 -(4-(2-(4-(3 -(4-cyano- 3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- hyoxoimidazolidin1-yl)-2- isphopropyleneoxy)ethyl)piperazin-1-yl)-M(3-(2,6- dioxopiperidin-3ylamino)phenyl)cyclopanecarboxamide 845.3 IN ** *

- 220 044376

198 γ ^s ' Ао-Э <°Д ΑΛ FFH 2-((2S,6R)-4-(2-(4-(7- (6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- cyclopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 876.3 WITH * 199 ^f 4„ W- . A\ / 1 : Η H ^УУ Vaa P YYV ^N n 4 У 4 l j D h JJL ° ^o ^L _N Ae (2R)-2-(4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethyl phenoxy)ethyl)pipe razin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)propane amide 819.3 WITH **

- 221 044376

200 %/_ fXf , ^N= UT ϊ η h ρΥγΥη ργΓ ^s Mo-xU ° w YnY F g H 2-((R)-4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2(trifluoromethyl)piper zin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 874.0 WITH * 201 ............ P/i/X 2-((S)-4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2(trifluoromethyl)piper zin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 874.0 WITH *

- 222 044376

202 0 JAyiZj 1 I in and N--- _γ _/Τ ·Ν γΑ α ^s hD _o hch- ^m A ° DD oD^-De n 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 813.4 WITH * 203 ⁰ / 'T- Well, ' 1 ur ρΑ'-ι S to D. _l m J: η to Y f FY ·,, CR' οΑΎ FF N 2-((2R,5R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- cyclopropylphenoxy)e gil)-2,5dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.0 WITH *

- 223 044376

204 ABOUT . s 0 D _l 1 o 1 J l X F-/ PD-'X/PchL ^u ₀ 44 _n ^ ₀ FFH 2-((2S,6R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2cyclopropylphenoxy)ethyl) -2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.0 WITH * 205 °' / ^Ν Η^ΓΤΎ VATLyVyT У SH n. —. N J-. 0 < JV 4Cl taA-oZ^K^/,,, W (VnV) H 2-((2R,5R)-4-(2-(4-(3(3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2,5- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 811.4 WITH *

- 224 044376

206 0 . FA- χτ Λ 1 n n ^Ν γχ ΓΓϊ ^Ν ΤΤ ^Ν Χ1 Cl ^s 0 Ο Η 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 811.4 WITH * 207 0 . Г\¥т Η Η ^Ν Αγγγχ ci Α·-„ ° νΧ _Ο Χ _Ν Α _Ο Η 2-((2R,5R)-4-(2-(4-(3(3-chloro-4cyanophenyl)-5,5cymethyl-4-oxo-2- hyoxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,5- cymethylpiperazin-1 yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 813.4 IN **

- 225 044376

208 , 1 ~n%I A I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2S,6R)-4-(2-(4-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2isopropylphenoxy)ethyl)-2,6dimethylpiperazin-1 yl)acetamide 881.3 IN * 209 0 ρ-, Ν 1 1 n Η νΗγ / h D 1 μ ι Д II IL F Д ^& 4Α ₀ Χζ« χΑ ° _F ΑΓ 2-((2S,6R)-4-(2-(4-(7- (6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6hyoxo-5,7- diazaspiro[3,4]octan5-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 878.3 IN **

- 226 044376

210 N 311 Η l udch SA -N . US S fY Ν 0 g И Υ Υ Na ill, k η ha L J vA ' G t AAi'^ R—y /71 1 FF ⁰ M-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2S,6R)-4-(2-(4-(7-(6cyano-5(trifluoromethyl)pyridinium-3- yl)-8-oxo-6thioxo-5,7diazaspiro[3,4]octan5-yl)-2isopropylphenoxy)ethyl)-2,6cymethylpiperazin-1 yl)acetamide 885.3 WITH * 211 0 р— | | n n ^ma L/ y ^Ν γΛ Λη ^Ν yv ⁿ yy S LCD D O IJ m X FF jl H 2-((2S,6R)-4-(2-(4-(7- (6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6hyoxo-5,7- Cyazaspiro[3,4]octan5-yl)-2- isopropylphenoxy)ethyl)-2,6- cymethylpiperazin-1 yl)-M-(3-(2,6cyoxopiperidin-3ylamino)-5fluorophenyl)acetamide 878.3 WITH *

- 227 044376

212 N III H >* _l La θίχζΝχ/θ S Г| YN 0 AYY Y ft JI J to O XA 1 J ' % I yay F—Z /71 | FF o M-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2S,6R)-4-(2-(4-(7-(6cyano-5(trifluoromethyl)pyridinium-3- yl)-8-oxo-6thioxo-5,7diazaspiro[3,4]octan5-yl)-2cyclopropylphenoxy)e gil)-2,6cymethylpiperazin-1 yl)acetamide 883.3 WITH * 213 ⁰ 1 ΥΛ-ν^Τ j | Η h ^N ^> Tn j dfiVrYl F 1 H 2-((2S,6R)-4-(2-(4-(3- (4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 865.2 WITH *

- 228 044376

214 ⁰ ! ! and n / /IX j lull ^FF ά « I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,5R)-4-(2-(5-(3-(4cyano-3(trifluoromethyl)phenyl)5,5 -dimethyl-4-oxo-2thioxoimidazolidin1-yl)-3isopropylpyridin-2yloxy)ethyl)-2,5dimethylpiperazin-1yl)acetamide 882.3 IN ** 215 0 _m Ns£\ /H—Λ 1 ы U ! VN 1 A f Η H No.-4 //4.' NN„ - < i CQ.v /ddl F ^F Ct ^M I-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2S,6R)-4-(2-(4-(7-(6cyano-5(trifluoromethyl)pyridinium-3- yl)-8-oxo-6hyoxo-5,7diazaspiro[3,4]octan5-yl)-2cyclopropylphenoxy)e gil)-2,6dimethylpiperazin-1 yl)acetamide 892.3 WITH *

- 229 044376

216 oh..... 0 Af 2-((2R,6S)-4-(2-(5-(3- (4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1 -yl)-3-ethylpyridin-2yloxy)ethyl)-2,6dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl )acetam id 834.3 WITH ** 217 ⁰ / ^N 3>3 A rW _{n n} A ^s 44- an 4 o 1- JXX FA \Α _ο Ά -Z\ _f -AA FFH 2-((2S,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 865.3 A *

- 230 044376

218 o _m D I η η F ^F 1 H 2-((2S,6R)-4-(2-(4-(7(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6thioxo-5,7- diazaspiro[3,4]octan5-yl)-2- cyclopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 876.3 WITH * 219 N 111 ' M F . i Ο N 0 s Ιι ηΓ ' ^N g ° i 1 ff K1- /h L ΛΑ l ιι I d 1 j f j ' μ 1 I O sb Dg 2-((2S,6R)-4-(2-(4-(3(3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- hyoxoimidazolidin1-yl)-2- cyclopropylphenoxy)e gil)-2,6- dimethylpiperazin-1 yl)-M-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 836.4 WITH **

- 231 044376

220 0 >00-Λ 1 NI s/ ^s VN^Ao γ ₀ Υ _Ν Λ α ⁿ 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-N-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.2 WITH ** 221 ⁰ ! .TVnT Al nn Ά ΑγΥ g ?Ά ^Ν ΥΎ ^Ν γΑ o/ S 1D,Х, «A ° AJ YES Η 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- hyoxoimidazolidin1-yl)-2- cyclopropylphenoxy)e gil)-2,6- dimethylpiperazin-1 yl)-M-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 829.2 WITH **

- 232 044376

222 0 / 1 Η Η «Α Vyy ⁴ ΛΥυύΑ α ⁸ ххА-хА-Эх ⁰ _F Αχ ο^νΑ η 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-I-(5-(2,6dioxopiperidin-3ylamino)-2fluorophenyl)acetamide 831.2 IN * 223 ⁰ / ϊ Υί g Α ΤΎ A α ^s ΧΑ _ο χχΑχΑ ° Μ AL Cl 2-((2S,6R)-4-(2-(4-(3(3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-chloro-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 847.2 IN **

- 233 044376

224 °' 1 AA—hli I f H И fa ° kJ _Ο ΡΡ FFH 2-((2R,6S)-4-(2-(5-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-3- isopropylpyridin-2yloxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 847.8 IN ** 225 Q p, A ? HH Npp Ppp PUР Fp ^s Uk^-M··.,, θ kJ P _N PFFH 2-((2R,6S)-4-(2-(4-(7(4-cyano-3(trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl) -2- cyclopropylphenoxy)e gil)-2,6dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 857.3 WITH *

- 234 044376

226 ABOUT . _ K-t- G “ k J .. J ill J < o '1 '1 J to i ^H 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 828.6 WITH * 227 ^z ^_/a............ 2-((2S,6R)-4-(2-(5-(7(4-cyano-3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl)-3- isopropylpyridin-2yloxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 860.3 WITH *

- 235 044376

228 0 , /A_y^T l I n n ^4=/ Uuuu (uuuuuu k J 8 II A l- n Jl o GA A A F-D σΆΆ F F N 2-((2S,6R)-4-(2-(5-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-3- cyclopropylpyridin2-yloxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 846.5 WITH * 229 0, _π Fwi l 1 n n rrVlVYA F-/ ^{s 0} oAA) FFH 2-((2S,6R)-4-(2-(5-(7(4-cyano-3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl)-3- cyclopropylpyridin2-yloxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 858.5 WITH *

- 236 044376

230 0 . 1 ^H Η ^Ν Α PpA ' Г ΑΑϊΎΊ _s / s HL Y l n J o < JYY Fp ΎΥ ^u Υ (ΥΌ FF Η 2-((2R,5R)-4-(2-(5-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-3- isopropylpyridin-2yloxy)ethyl)-2,5dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 848.4 A ** * 231 Ν III Η s Α ° Λ °γV wYl 1 ^{Η Η} F Α 0^ FF 2-((2R,5R)-4-(2-(5-(7(4-cyano-3- (trifluoromethyl)phenyl)8-oxo-6-thioxo-5,7diazaspiro[3,4]octan5-yl)-3- isopropylpyridin-2yloxy)ethyl)-2,5dimethylpiperazin-1yl)-I-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 885.3 IN *

- 237 044376

232 1 Η _s (Υ-γγο Λγ _τ ° ΛΑζ Ja ⁿ YJYJ- _n YJ Υχ ^ν Υ(Ι. ^{Η Η F} ~X F ρ 2-((2R,5R)-4-(2-(5-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-3- isopropylpyridin-2yloxy)ethyl)-2,5dimethylpiperazin-1yl)-LG-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 873.3 IN * 233 0 , F VL. f3,f AVn'A Λ Τ η η A^tVyj A ^s YY ₀ ^a ⁿ Y ° M oAA> FFH 2-((S)-4-(2-(4-(3-(6Cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2- (trifluoromethyl)piper zin-1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 886.2 WITH *

- 238 044376

234 0 / v^'VyVyY _s / s 1(2 a. n J., o LX XX FFH 2-((2R,5R)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,5dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.8 WITH * 235 x^~X> 0 y 2-((2S,6R)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.8 WITH *

- 239 044376

236 (Pi to 1) 237 (Pi to 2) 0 _s / s < А Λ N А 0 ί J А А υ θί^-Α-θ FF j H OR /Ач I Η Η ^F A UAH 2-((2S,6R)-4-((S)-l-(4(3-(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)propan-2yl)-2,6- dimethylpiperazin-1 yl)-P-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide or 2-((2S,6R)-4-((R)-l-(4(3-(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1 -yl)-2-ethylphenoxy) propan-2-yl)-2,6dimethylpiperazin-1 yl)-P-(3-(2,6dioxopiperidin-3ylamino )phenyl)acetamide 847.3 847.3 IN IN ** ** 238 q , Α-^ί—-— // h\ μ Τ /l Η Η ^Ν Ν .--- Ν Ν , s' t 7 И ' ΐ 1 7 I 1. ¹ 0 ^J 'ΟΝΟ FF Η 2-(3-(2-(4-(3-(4-cyano3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-3,8- diazabicyclo[3.2.1]oct an-8-yl)-P-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 843 A *

- 240 044376

239 (Pi to 1) 240 (Pi to 2) O . n xI 1 n n N ¹ JNN, . _f h ^j ? 11 ill ι J O F 7 Cl '>· · 0 N (1 FFH OR f-tC ^s LLqAv-LX. o ₀ X _n A ₀ FFH 2-((2S,6R)-4-((R)-2-(4(3-(6-cyano-5(trifluoromethyl)pyridin-3 -yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2ethylphenoxy)propyl)2,6-dimethylpiperazin1-yl)-P-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide or 2-((2S,6R)-4-((S)-2-(4(3-(6-cyano-5(trifluoromethyl)pyridin-3 -yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2ethylphenoxy)propyl)2,6-dimethylpiperazin1-yl)-P-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 848.3 848.4 WITH IN * **

- 241 044376

241 (Pi to 1) 242 (Pi to 2) °' ! „ D-a u ^l 1 k-, _g ) 1 Td dd! 3 j .1 N ^F Y Mu/Chh x/\ ΟΝΟ FFH OR 0 ΓΑλιΤ I | η h W ¥ AY 1 g TIY TD S HA A n A o kA AA ^F A \γΥζχΖ\ ^u YA FFH 2-((2S,6R)-4-((R)-2-(4(3-(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)propyl)2,6-dimethylpiperazin1-yl)A-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide or 2-((2S,6R)-4-((S)-2-(4(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy )propyl)2,6-dimethylpiperazin1-yl)A-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 847.3 847.3 IN A * ** *

- 242 044376

243 s ΑΥ τ 0 GA Υ γ μ ,Ύ L LA y Α η Λ AL Λ J ^Ν ν-Ϋ F ^f η η '/С/V M-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)-2((2R,5R)-4-(2-(4-(3-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)-2,5dimethylpiperazin-1yl)acetamide 895.3 WITH * 244 Ο №\ _Μ Μ F Η Η kN/uhchA γ^γγη ,./ s VA, l ν Λ ο *1A AA FX HA _o Hu-h/h ^u XX cXNX) FFH 2-((2R,5R)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(1,1difluoroethyl)phenoxy)e gil)-2,5- dimethylpiperazine -1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 870.3 WITH *

- 243 044376

245 0 , F fAf /A_y1 L T n n «On V ^N or AVWn $ j| J nJ ό IL JAA FFH 2-((S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2- (trifluoromethyl)piper zin-1-yl)-M-(3-(2,6dioxopiperidin-Zylamino)phenyl)acetamide 885.3 WITH * 246 xx AP X Xr MXXOX oxx F F H 2-((S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2(trifluoromethyl)piperazin-1-yl)-M-(3-(2,6dioxopiperidin-Zylamino)phenyl )acetam id 873.3 WITH *

- 244 044376

247 I η η r ^N Хр Ay^yVtY ¥ ^s .....ο μ _ο λ _ν α _ο FFH 2-((2S,6R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-ethyl-5fluorophenoxy )ethyl)2,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 851.4 WITH * 248 ⁰ / “ADgAc AAy/A FV X/xV-' V oW) FFH 2-((2S,6R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2-ethyl-6fluorophenoxy )ethyl)2,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 851.4 WITH *

- 245 044376

249 ъ° / 4 .....0 1 2-((2R,6S)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-ethyl-6methylphenoxy )ethyl)2,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 847.3 IN ** * 250 Ν III A^ ^o -A-m - A % Jono to 1X3 4 ϊ o । ^~SU ⁿ G1?^T 1 n '' th CI (U' 2-((2S,6R)-4-(2-(4-(3(3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-cyano-5-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 837.8 WITH *

- 246 044376

251 W' 1 1 Cl ^s T ₀ ^^А ^й А^оЛДс ₽ h 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 830.8 WITH * 252 0 , άΑτΫΓι F~X _Ο ^ _Ν ·^ _Ο FFH 2-((2S,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-(1,1difluoroethyl)phenoxy)ethyl)-2,6dimethylpiperazin-1 yl)-M-(3-(2, 6dioxopiperidin-3ylamino)phenyl)acetamide 868.6 WITH *

- 247 044376

253 g-J ^s ΛΑ XX ,Ν. Λ 0 LJAA T -- ^w ΛΑ 2-((2S,6R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-isopropyl-5methylphenoxy )ethyl)2,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 861.3 IN * 254 ⁰ / _η =4Ύ ^ν ΓΓ _{λ l} L xx I xx th xx ^Ν =ΛΖ Ζγρ ApWA ft ^s /KD _o ^ ⁿ A ° w ΑνΎ FF Η 2-((2S,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-ethyl-5methylphenoxy)ethyl)2,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl )acetam id 847.3 WITH *

- 248 044376

255 0 ( F 1 Η Η X/ ηΥπ η s < XL l Ν X o L J X X FF Η 2-((2S,6R)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2-(1,1- difluoroethyl)phenoxy)ethyl)-2,6- dimethylpiperazine -1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 870.3 WITH * 256 0 , F _Ν ._ DX fXf y ^s wA o U YES FFH 2-((S)-4-(2-(4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2- (trifluoromethyl)pipera zin-1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 888.3 IN **

- 249 044376

257 0 , F XX—νΎ I Τ and И ^NS V ιΥηρΑ ΑΎΥνΤΊ A ^s o MAL FF Η 2-((S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2- isopropylphenoxy)ethyl)-2- (trifluoromethyl)pipera zin-1-yl)-I-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 885.5 A ** * 258 N 111 H _s Dud XX XJL f | n n D ⁰ M-(3-cyano-5-(2,6cyoxopiperidin-3ylamino)phenyl)-2((2S,6R)-4-(2-(4-(3-(6cyano-5(trifluoromethyl)pyridinium n-3 - yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2-(1,1cifluoroethyl)phenoxy)egil)-2,6cymethylpiperazin-1yl)acetamide 894.7 WITH *

- 250 044376

259 0 , / Έ 'T II II _F M Ml. ,1 ' 1 .] I, 1 ^F _r 0 ONO FFH 2-((2R,6S)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2cyclopropylphenoxy)ethyl) -2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 859.3 WITH * 260 <3/ Η TY Ί Г ΐ Π Y Ύ Τι FТу ^S ° L/ ο^νΗ) FF 1 Η 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2ethylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.4 IN *

- 251 044376

261 0 , A NN \ / U ⁿ x/hA U i - » ^NN - - GG kIXL ΐ s and ί ι ι ^F A ' -ONO 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2-ethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 844.8 IN ** 262 Ay ^LJ ⁰ o 2-((R)-4-(2-(4-(7-(6cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6hyoxo-5,7cyazaspiro[3,4]octan5-yl)-2- cyclopropylphenoxy)e gyl)-2-ethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 858.4 IN *

- 252 044376

263 o G7/T L nn FJ ^s kA- _o --^- ^N Pn ⁰ kJ сРнХо FF 1 H 2-((S)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2-ethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.4 WITH * 264 ........ + Si z4 li jX ^/U ” 1 2-((2S,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)4-OXO-2-THIOXO-1,3cyazaspiro[4.5]decan1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 873.4 WITH *

- 253 044376

265 „ I ° ^Ζ Α / -η / Α— C Α Α ..... 2-((2S,6R)-4-(2-(4-(7(6-cyano-5(trifluoromethyl)pyridinn-3-yl)-8-oxo-6thioxo-5,7diazaspiro[3,4] octan5-yl) -2-(1,1- difluoroethyl)phenoxy)ethyl)-2,6dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 881.8 WITH * 266 ⁰ Α> αΑ MWn gl ^s kA χΑΑ ο IL J Α Α ^F A XXXq^Xx χΧΧ XX ο-^Ν^Ο FF Η 2-((2S,6R)-4-(2-(4-(3- (4-cyano-3- (trifluoromethyl)phenyl)4-OXO-2-THIOXO-1,3diazaspiro[4.4]nonan1-yl)-2- cyclopropylphenoxy)e gil)-2,6- dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 871.8 WITH *

- 254 044376

267 0 ΑΧΛγ- D _F E ^s LA l Ekh o (JXX F-D 4^,^ h/H, ο^νΎ FF Η 2-((2S,6R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)4-OXO-2-THIOXO-1,3diazaspiro[4.4]nonan1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 859.8 WITH * 268 ⁰ / ns-OV^yy^ А^у^гх _ρ 7 ^S hA l Ekh Χ-. 0 Ο XX F-D Х^Хх s/ -,, \У Ο'^Ν^Ο FFH 2-((2R,6S)-4-(2-(4-(3(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4oxo-2- hyoxoimidazolidin1-yl)-2- cyclobutylphenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 860.5 WITH **

- 255 044376

269 cj' X 4 k O 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- thioxoimidazolidin1-yl)-2-(1,1- difluoroethyl)phenoxy)ethyl)-2,6- dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetam eid 834.8 WITH * 270 ⁰ / -τΑν ΑύΑτ A ^s χάχα. ° challah FF Η 2-((2R,6S)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-ethyl-3methylphenoxy)ethyl)2,6-dimethylpiperazin1-yl)-N-(3-(2,6dioxopiperidin-3ylamino)phenyl )acetam id 847.3 IN **

- 256 044376

271 0 Тг Ϊ У' ГП and ri FA Ά (AAA) pF H 2-((2S,6R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2-ethyl-3fluorophenoxy )ethyl)2,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 851.3 WITH * 272 ⁰ / 7= ⁷ «11 Г ί I π ι ι 1 _c / s И А, _l n J- о t AAA FA ^u Ά ο*ΑΆ pF H 2-((R)-4-(2-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- cyclopropylphenoxy)ethyl)-2- methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 831.3 WITH *

- 257 044376

273 ° / _l l ' l l N l y Λ ^Ν γΥ Γ'ΆΑ .ΑΥγΥγ% rJ S ΙΑ l ή 7 ο ϋ, JA Α FX ΧΑΑΧχ Α ,, XX ο^ΝΑ FF Η 2-((2R,5R)-4—(3-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenyl)propyl)2,5-dimethylpiperazin1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 831.3 WITH * 274 0. / A ^{I aa} ah Α ^{j [} 7 -Ί U 'Α FF Η (2R)-2-((S)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)propane amide 833.3 With *

- 258 044376

275 ⁰ / “A>Axx AWn p-У ^s Lxk A,A o (JAA ^F A \X _o Xz -XX XX qAA FFH (2S)-2-((S)-4-(2-(4-(3- (4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1-yl)- N-(3-(2,6- dioxopiperidin-3ylamino)phenyl)propane amide 833.3 WITH * 276 0 , =H>Av AyA f-/ ^s LA l. AA o IL JAA ^F A ΧΧ· _ο Χζ X -,, XX oXfr^O FFH 2-((K)-4-(2-(2-chloro-4(3-(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1 -yl)phenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 825.3 WITH * 277 0 AAx” _c and and №—AT y- ^N -xxA |XnA ^N YA” YA $ LA l A a o LJAA A -X -,, O-^N^O FFH 2-((R)-4-(2-(4-(3-(4- cyano-3- (trifluoromethyl)phenyl)- 5,5-dimethyl-4-oxo-2- thioxoimidazolidine- 1-yl)-2- fluorophenoxy)ethyl)-2methylpiperazin-1-yl)- N-(3-(2,6- cyoxopiperidin-3ylamino)phenyl)acetam eid 809.3 With >1=

- 259 044376

278 o Pu/T 1 n n «AU γ ^Ν γγ ΛύΑΑ rjs I PL l n P. o LPXX ^F A ^{w 0} A 2-((2S,6R)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2fluorophenoxy)ethyl)2 ,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 823.4 WITH * 279 0 . pAAA _P / ^s LYz4 Y X o If JYY FY ΎΧΎ Ύχ Ύ o^N-^O FFH 2-((S)-4-(3-(4-(3-(4cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenyl)propyl)-2dimethylpiperazin-1yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 817.3 WITH *

- 260 044376

280 , HI •tj II i Q D' ^! A' (2R)-2-((R)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6dioxopiperidin-3ylamino)phenyl)propane amide 833.3 IN ** * 281 ⁰ / AA^ A ^! yA < HKOZOD FFH (2S)-2-((R)-4-(2-(4-(3- (4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2- thioxoimidazolidin1 -yl)-2- ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)N-(3-(2,6- dioxopiperidin-3ylamino)phenyl)propane amide 833.3 WITH * 282 ⁰ / ^Ν ^“^Η ^Ν γ ^Ν γΑ ^α c—/ s LA l N A o k JAA FFH 2-((2S,6R)-4-(2-(2chloro-4-(3-(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1 -yl)phenoxy)ethyl )2,6-dimethylpiperazin1-yl)-I-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 839.2 With *

- 261 044376

283 q. _f Να-' 3 Ν, - . - - Ν Ν Ρ Ί Ί ' ι !ι Ί Μ . _, ^s Ι.ι - ν I Ο ¹ . 1 . k > ¹ U o- '> υ ν ο FF μ Η 2-((2R,6S)-4-(2-(4-(3- (4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1 yl)-M-(3-(2,6dioxopiperidin-3ylamino)-5fluorophenyl)acetamide 852.2 WITH * 284 ο , ΑΧ Μ- - XV-n i · n n N-4J χ ^Ν γ-γ^. fN ^s 4-α.Χ.ζ υ<ΛΛ FF Η 2-((2R,6S)-4—(3-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenyl)propyl)2 ,6-dimethylpiperazin1-yl)-M-(3-(2,6dioxopiperidin-3ylamino)phenyl)acetamide 831.3 With *

- 262 044376

285 ⁰ / —iWA _F V ^s hchA a o t J Ж Ж ^F Y ν' -4^ O-WW) FFH 2-((2R,6S)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2ethylphenoxy)ethyl)- 2,6dimethylpiperazin-1yl)-M-(3-((8)-2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.3 WITH * 286 <7/o..... ¥ 2-((2R,6S)-4-(2-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazine-1 mi)-N-(3-((R)-2,6dioxopiperidin-3ylamino)phenyl)acetamide 833.3 With *

- 263 044376

287 o , γ ϊ Τι ι ι Τ γγ γη _s / ⁵ XV, l ν Υ ο CH VV F FV WX -V -,, W ο^νΛ) FF Η 2-((2R,6S)-4—(3-(4-(3(4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2fluorophenyl)propyl)2,6-dimethylpiperazin1-yl)-M-(3-(2,6cyoxopiperidin-3ylamino)phenyl)acetamide 821.3 WITH * 288 0 AvWv Χυ ΧΧΧΟΧ Ο γγ ^ρ Υγ 'Y/jX- ''Υ , X ^x O'W) FF Η 2-((2R,6S)-4-(2-(4-(3- (4-cyano-3- (trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2gioxoimidazolidin1-yl)-2- cyclopropylphenoxy)e gil)-2,6- cymethylpiperazine-1 No.i)-N-(3-((R)-2,6cyoxopiperidin-3ylamino)phenyl)acetamide 845.3 WITH *

- 264 044376

289 /3..... Ch ό 2-((2R,6S)-4-(2-(4-(3(4-cyano-3(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2cyclopropylphenoxy)ethyl) -2,6dimethylpiperazine-1 mi)-N-(3-((S)-2,6dioxopiperidin-3ylamino)phenyl)acetamide 845.3 WITH * 290 O / p ^{g s} gCH zx A A o U A Λ CI \χ. _ο ζ\/ ^u XX O^N^O Η 2-((2S,6R)-4-(2-(2chloro-4-(3-(3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2- hyoxoimidazolidine- 1 -yl)phenoxy)ethyl)- 2,6-dimethylpiperazin1-yl)-M-(3-((2,6dioxopiperidin-3yl)amino)phenyl)acet Ministry of Foreign Affairs 806.6 WITH * 291 o F Xa τ > tA - Oh y 2-((2S,6R)-4-(2-(4-(3- (3-chloro-4cyanophenyl)-5,5dimethyl-4-oxo-2thioxoimidazolidin1-yl)-2- ethylphenoxy)ethyl)-2,6dimethylpiperazin-1yl)-M-(3-((2,6dioxopiperidin-3yl)amino)phenyl)acet Ministry of Foreign Affairs 799.3 With *

The descriptions of a number of references cited are incorporated herein by reference in their entirety.

Claims (13)

CLAIM 1. A connection selected from the group consisting of: (S)-2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)piperazin-1-yl)-K-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide; 2-((S)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-3-methylpiperazin-1-yl)-H-(3-(2,6-dioxopiperidin-3ylamino)phenyl)acetamide; 2-((R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1- 265 044376 yl )-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-I-(3-(2,6-dioxopiper idin-3ylamino)phenyl)acetamide; 2-((8)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-I-(3-(2,6-dioxopiper idin-3ylamino)phenyl)acetamide; And K-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-(( R)-4-(2-(4-(3-(6-cyano-5(trifluoromethyl) pyr idin-3 -yl)-5,5-dim ethyl-4-oxo-2-thiooxoimidazolidin-1 -yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)acetamide; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, selected from the group consisting of: (8)-2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)pipe erazin-1 -yl)-I-(3-(2,6-dioxopiper idin-3-ylamino)phenyl)acetamide; 2-((8)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-3-methylpiperazine-1 -ηπ)-Ν-(3 -(2,6-dioxopiper idin-3 ylamino)phenyl)acetamide; 2-((K)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-M-(3-(2,6-dioxopiper idin-3ylamino)phenyl)acetamide; 2-((8)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidin-1yl)-2- ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-M-(3-(2,6-dioxopiper idin-3ylamino)phenyl)acetamide; And K-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-((K)-4-(2-(4-(3-(6-cyano-5(trifluoromethyl) pyr idin-3 -yl)-5,5-dim ethyl-4-oxo-2-thiooxoimidazolidin-1 -yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)acetamide. 3. A compound according to claim 1 or 2, which is (8)-2-(4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4 -oxo-2-thiooxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-K-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide. 4. A compound according to claim 1 or 2, which is 2-((8)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4 -oxo-2-thiooxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-3methylpiperazin-1 -yl)-I-(3-(2,6-dioxopiper idin-3-yl amino)phenyl)acetamide. 5. A compound according to claim 1 or 2, which is 2-((K)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dim ethyl- 4-oxo-2-thiooxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)-I-(3-(2,6-dioxopiper idin-3-yl amino)phenyl)acetamide. 6. A compound according to claim 1 or 2, which is 2-((8)-4-(2-(4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dim ethyl- 4-oxo-2-thiooxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2methylpiperazin-1 -yl)-I-(3-(2,6-dioxopiper idin-3-yl amino)phenyl)acetamide. 7. A compound according to claim 1 or 2, which is M-(3-chloro-5-(2,6-dioxopiperidin-3ylamino)phenyl)-2-((K)-4-(2-(4-( 3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2thiooxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl )acetamide. 8. A pharmaceutical composition containing an effective amount of a compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition according to claim 8, containing an effective amount of a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 10. Use of a compound according to any one of claims 1 to 7 for the treatment of an androgen receptor-mediated disease, wherein the androgen-mediated disease is prostate cancer. 11. Use according to claim 10, characterized in that the prostate cancer is castration-resistant prostate cancer (CRPC). 12. Use of a pharmaceutical composition according to claim 8 or 9 for the treatment of an androgen receptor-mediated disease, wherein the androgen-mediated disease is prostate cancer. 13. Use according to claim 12, characterized in that the prostate cancer is castration-resistant prostate cancer (CRPC).