Cereblon binding compounds, compositions thereof and methods of treatment therewith

Abstract

To provide a compound, a composition containing an effective amount of the compound, and a method for treating or preventing an androgen receptor-mediated disease.SOLUTION: To provide a piperidinedione compound having the following structure, a composition containing an effective amount of the piperidinedione compound, and a method for treating or preventing an androgen receptor-mediated disease.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 043,555, filed June 24, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Provided herein are compounds, compositions comprising effective amounts of such compounds, and methods for treating or preventing androgen receptor-mediated diseases, comprising administering an effective amount of such compounds to a subject in need thereof. Also provided herein are compounds and compositions for use in these methods. [Background technology]

[0003] Androgen receptor signaling is known to play an important role in the pathogenesis of prostate cancer and is involved in the development of other androgen receptor-positive cancers (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3; Non-Patent Document 4). Inhibition of androgen receptor signaling by antiandrogens that antagonize the androgen receptor has been used or proposed for the treatment of prostate cancer.

[0004] The androgen receptor (AR) is normally present in the cytoplasm bound to chaperones such as HSP90 (Non-Patent Document 5). Upon binding of dihydrotestosterone (DHT), the androgen receptor changes its conformation and translocates to the nucleus, where it binds to androgen response elements (AREs), which drive the transcription of canonical targets such as KLK3 (also known as prostate-specific antigen, PSA), TMPRSS2, and KLK2 (Non-Patent Document 6; Non-Patent Document 7).

[0005] Prostate cancer (PCa) is one of the most frequently diagnosed non-skin cancers among men in the United States and the second most common cause of cancer death, with over 200,000 new cases and over 30,000 deaths annually in the United States.

[0006] Androgen deprivation therapy (ADT) is the standard of care for advanced PCa. Patients with advanced PCa receive ADT with either luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, or bilateral orchiectomy. Despite an initial response to ADT, disease progression is inevitable, and the cancer presents as castration-resistant prostate cancer (CRPC). Up to 30% of patients with prostate cancer who receive primary treatment with radiation or surgery will develop metastatic disease within 10 years of primary treatment. Approximately 50,000 patients per year will develop metastatic disease, referred to as metastatic CRPC (mCRPC).

[0007] There remains a significant need for safe and effective methods of treating, preventing, and managing AR-mediated diseases, particularly those that are refractory to standard treatments such as surgery, radiation therapy, chemotherapy, and hormone therapy, while reducing or avoiding the toxicity and / or side effects associated with conventional therapies.

[0008] Citation or identification of a reference in this section of this application shall not be construed as an admission that the reference is prior art to the present application. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Chen Y et al.,Lancet Oncol,2009,10:981-91 [Non-patent document 2] Mills IG, Nat Rev Cancer,2014,14:187-98 [Non-patent document 3] Taplin ME,Nat Clin Pract Oncol,2007,4:236-44 [Non-patent document 4] Wirth MP et al.,Eur Urol,2007,51(2):306-13 [Non-patent document 5] Brinkmann AO et al., J Steroid Biochem Mol Biol,1999,69:307-13 [Non-patent document 6] Tran C et al.,Science,2009,324:787-90 [Non-Patent Document 7] Murtha P et al.,Biochemistry(Mosc.),1993,32:6459-64 Summary of the Invention [Means for solving the problem]

[0010] Formula (I): [ka] (In the formula, R N , R 1 , R 2 , R 3 , R 4 , X, L, V, a, m, and n are as defined herein. or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0011] The compounds of formula (I) or pharmaceutically acceptable salts, tautomers, isotopologues or stereoisomers thereof are useful for treating or preventing androgen receptor mediated disorders in a subject.

[0012] In one aspect, provided herein are compounds described in the present disclosure, such as in Table 1.

[0013] In one aspect, provided herein are pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In one aspect, provided herein are pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration.

[0014] In one aspect, provided herein is a method for treating or preventing an androgen receptor-mediated disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In one aspect, provided herein is a method for treating or preventing an androgen receptor-mediated disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In another aspect, provided herein are compounds for use in methods for treating androgen receptor-mediated diseases. In another aspect, provided herein are compounds for use in methods for treating androgen receptor-mediated diseases.

[0015] In another aspect, provided herein are methods of preparing the compounds described herein.In another aspect, provided herein are methods of preparing the compounds described herein.

[0016] The present embodiments can be more fully understood with reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition As used herein, the terms "comprise" and "comprise" may be used interchangeably. The terms "comprise" and "comprise" shall be interpreted to specify the presence of the stated feature or component as referred to, but not to exclude the presence or addition of one or more features or components or groups thereof. Furthermore, the terms "comprise" and "comprise" shall include examples encompassed by the term "consisting of." Consequently, the term "consisting of" may be used in place of the terms "comprise" and "comprise" to provide more specific embodiments of the present invention.

[0018] The term "consisting of" means that the subject matter comprises at least 90%, 95%, 97%, 98%, or 99% of the recited features or components of which it consists. In another embodiment, the term "consisting of" excludes other features or components from the scope of the succeeding recitation, except those that are not essential to the technical effect being achieved.

[0019] As used herein, the term "or" shall be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will occur only where combinations of elements, functions, steps, or acts are inherently mutually exclusive in some respect.

[0020] An "alkyl" group is a saturated, partially saturated, or unsaturated, straight- or branched-chain acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments, 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, an alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched-chain alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, an alkyl group is an unsaturated alkyl group, also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted.When alkyl groups described herein are said to be "substituted," they include any substituent or substituents as found in the exemplary compounds and embodiments disclosed 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, cyclo and may be substituted with alkylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; 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 can be substituted with any substituent or substituents as found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; 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.

[0021] A "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted. In some embodiments, a cycloalkyl group has 3 to 8 ring members; in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. In some embodiments, a cycloalkyl group is a saturated cycloalkyl group. 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, a cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsubstituted cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. Cycloalkyl groups can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol.

[0022] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6 to 14 carbons and in other cases 6 to 12 or even 6 to 10 carbon atoms in the ring portion of the group. Particular aryls include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0023] A "heteroaryl" group is an aromatic ring system having from 1 to 4 heteroatoms as ring atoms, with the remainder being carbon atoms. In some embodiments, heteroaryl groups contain from 3 to 6 ring atoms, and in other cases from 6 to 9 or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, 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., 1H-benzo[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, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0024] A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to other groups at any ring atom (i.e., any carbon atom or heteroatom of the heterocycle). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups include unsaturated, partially saturated, and saturated ring systems, such as, for example, imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazine-2-oxo- nyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithionyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, iso indolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzo Thiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,Representative non-aromatic heterocyclyl groups include, but are not limited to, 4-dihydroisoquinolin-1(2H)-onyl), quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclyl groups are aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups can be mono-substituted or more than twice substituted, including, but not limited to, pyridyl or morpholinyl groups that are di-, tri-, tetra-, penta-, or hexa-substituted, or di-substituted with various substituents, such as those listed below.

[0025] As used herein and unless otherwise specified, a "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, the cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, and the like.

[0026] As used herein and unless otherwise specified, an "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can be substituted on the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative 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-ylethyl.

[0027] As used herein and unless otherwise specified, a "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. A "heteroarylalkyl" group is a radical of the formula: -alkyl-heteroaryl, where alkyl and heteroaryl are defined above. A "heterocycloalkylalkyl" group is a radical of the formula: -alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above. Substituted heterocyclylalkyl groups can be substituted on the alkyl, heterocyclyl, or both the alkyl and heterocyclyl portions of the group. Representative heterosilylalkyl groups include, but are not limited to, morpholin-4-ylethyl, morpholin-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0028] "Halogen" is fluorine, chlorine, bromine or iodine.

[0029] A "hydroxyalkyl" group is an alkyl group as defined above that is substituted with one or more hydroxy groups.

[0030] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

[0031] An "alkoxyalkyl" group is an -(alkyl)-O-(alkyl), where alkyl is defined above.

[0032] An "amino" group is a group of the formula: -NH, -NH(R # ) or -N(R # )2 radical, where each R #are independently an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) group as defined above, each of which is independently substituted or unsubstituted.

[0033] In one embodiment, an "amino" group is an "alkylamino" group, which is a radical of the formula: -NH-alkyl or -N(alkyl), where each alkyl is independently defined above. The terms "cycloalkylamino," "arylamino," "heterocyclylamino," "heteroarylamino," "heterocycloalkylamino," and the like are as described above for "alkylamino," where the term "alkyl" is replaced by "cycloalkyl," "aryl," "heterocyclyl," "heteroaryl," "heterocycloalkyl," and the like, respectively.

[0034] A "carboxy" group is a radical of the formula: --C(O)OH.

[0035] As used herein and unless otherwise specified, an "acyl" group refers to a group of the formula: -C(O)(R # ) or a radical of —C(O)H, where R # is defined above. A "formyl" group is a radical of the formula: --C(O)H.

[0036] As used herein, and unless otherwise specified, an "amide" group refers to a group of the formula: -C(O)-NH, -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 # ) radical, where each R # are independently defined above.

[0037] In one embodiment, an "amide" group has the formula: -C(O)-NH, -C(O)-NH(R # ), -C(O)-N(R # )2 radical, where each R # are independently defined above.

[0038] In one embodiment, an "amide" group has the formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H or -N(R # )-C(O)-(R # ) where each R # are independently defined above.

[0039] A "sulfonylamino" group is a group of the formula: -NHSO(R # ) or -N(alkyl)SO2(R # ), where each alkyl and R # is defined above.

[0040] A "urea" group is a group 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 a radical of —NH(CO)NH, where each alkyl and R # are independently as defined above.

[0041] With the exception of alkyl groups, when groups described herein are said to be "substituted," they can be substituted with any suitable substituent or substituents. Illustrative substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; 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; oxygen (=O); B(OH), O(alkyl)aminocarbonyl; monocyclic or fused rings. cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., 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.

[0042] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I) include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Therefore, specific examples of salts include hydrochloride, formate, and mesylate. Others are well known in the art, see, e.g., Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0043] As used herein and unless otherwise specified, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound provided herein 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 that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that 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 stereoisomer 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 stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. The compounds may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the embodiments disclosed herein.

[0044] The use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268(ELEliel,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).

[0045] It should be noted that the compounds may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of E and Z isomers.

[0046] "Tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of isomeric forms may vary depending on the environment in which the compound is present, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, called tautomers of each other: [ka]

[0047] As will be readily understood by one skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the invention.

[0048] It should be noted that the compounds provided herein may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 It can be radiolabeled with a radioisotope such as deuterium ( 2 H), carbon-13( 13 C) or nitrogen-15( 15N). As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than 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, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, an isotopologue of a compound is provided, e.g., an isotopologue is a deuterium, carbon-13, and / or nitrogen-15 enriched compound. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) is replaced with deuterium (D or 2 H), i.e., the compound is enriched with deuterium in at least one position.

[0049] Regardless of stereoisomeric or isotopic composition, it is understood that each compound referred to herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Similarly, it is understood that the isotopic composition can vary independently of the stereoisomeric composition of each compound referred to herein. Furthermore, the isotopic composition is limited to the elements present in each compound or its salt, but can vary in other ways independently of the selection of a pharmaceutically acceptable salt of each compound.

[0050] It should be noted that in the event of a discrepancy between a depicted structure and the name of that structure, greater emphasis shall be placed on the depicted structure.

[0051] As used herein, "treating" 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 halting further progression or worsening of those symptoms, or alleviating or eradicating the cause of the disorder, disease, or condition itself. In one embodiment, the disorder is an androgen receptor-mediated disease or symptom thereof described herein.

[0052] As used herein, "preventing" refers to a method of delaying and / or preventing the onset, recurrence, or spread of a disorder, disease, or condition, in whole or in part; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is an androgen receptor-mediated disease or symptom thereof described herein.

[0053] The term "effective amount" in reference to a compound means an amount capable of treating or preventing a disorder, disease or condition, or a symptom thereof, as disclosed herein.

[0054] As used herein, the terms "subject" and "patient" include animals, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals, and in another embodiment are humans. In one embodiment, the subject is a human having or at risk of having an androgen receptor-mediated disease or a symptom thereof.

[0055] As used herein, the term "androgen receptor," or "AR," or "NR3C4," refers to a nuclear hormone receptor that is activated by the binding of male hormones, including testosterone or dihydrotestosterone. The term "androgen receptor" can refer to the nucleotide sequence or protein sequence of the human androgen receptor (e.g., Entrez 367, Uniprot P10275, RefSeq NM_000044, or RefSeq NP_000035).

[0056] As used herein, the term "AR-full length" (AR-FL) refers to an AR protein containing all four functional domains, including the N-terminal transactivation domain (NTD, exon 1), the DNA-binding domain (DBD, exons 2-3), the hinge domain (exon 4), and the C-terminal ligand-binding domain (LBD, exons 4-8).

[0057] The term "castration-resistant prostate cancer" (CRPC) refers to advanced prostate cancer that worsens or progresses while a patient is receiving androgen deprivation therapy or other testosterone-reducing therapy, or prostate cancer that is considered hormone-refractory, hormone-naive, androgen-independent, or resistant to chemical or surgical castration. Castration-resistant prostate cancer (CRPC) is advanced prostate cancer that develops despite ongoing ADT and / or surgical castration. Castration-resistant prostate cancer can be caused by prior surgical castration, gonadotropin-releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®)), or chemotherapeutic agents (e.g., cyclophosphamide, docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide). Prostate cancer is defined as prostate cancer that progresses or worsens or continues to adversely affect the patient's health despite continued treatment with bozantinib (Cometriq®, also known as XL184)) or other prostate cancer therapies (e.g., vaccines (sipuleucel-T (Provenge®), GVAX, etc.), botanicals (PC-SPES) and lyase inhibitors (abiraterone)), as evidenced by increased or higher serum levels of prostate-specific antigen (PSA), metastasis, bone metastasis, pain, lymph node involvement, increased size or serum markers of tumor growth, worsening of prognostic markers or patient condition.

[0058] compound Formula (I): [ka] (In the formula, R N is H; n is 0 to 4; Each R 1 are halogens, CN and C 1~3 independently selected from alkyl; a is 1 or 2; R 2 and R 3 is H and C 1~3 alkyl, or R 2 and R 3 and the carbon to which they are attached may be substituted or unsubstituted C 3~6 Forming a cycloalkyl; m is 0 to 8; Each R 4 are independently substituted or unsubstituted C 1~3 alkyl or two R 4 The groups may be substituted or unsubstituted C 3~6 Form a cycloalkyl or two R 4 groups, together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4- to 7-membered heterocyclyl; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 It's Alki L is a substituted or unsubstituted -O(C 1~6 alkyl)-, (C 1~6 alkyl)O-, -O(C 1~6 alkyl)O- or -(C 1~9 alkyl)-; V is [ka] where: B is N, CH or CR B and; Each R B is a halogen and a substituted or unsubstituted C 1~6 independently selected from alkyl; R C is a halogen, CF3 or SF5; R 5 and R 6 is C 1~3 alkyl or R 5 and R 6 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; and b is 0 to 2) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0059] Formula (I): [ka] (In the formula, R N is H; n is 0 to 4; Each R 1 are halogens, CN and C 1~3 independently selected from alkyl; a is 1 or 2; R 2 and R 3 is H and C 1~3 alkyl, or R 2 and R 3 and the carbon to which they are attached may be substituted or unsubstituted C 3~6 Forming a cycloalkyl; m is 0 to 8; Each R 4 are independently substituted or unsubstituted C 1~3 alkyl or two R 4The groups may be substituted or unsubstituted C 3~6 Form a cycloalkyl or two R 4 groups, together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4- to 7-membered heterocyclyl; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 It's Alki L is a substituted or unsubstituted -O(C 1~6 alkyl)-, (C 1~6 alkyl)O- or -(C 1~9 alkyl)-; V is [ka] where: B is N, CH or CR B and; Each R B is a halogen and a substituted or unsubstituted C 1~6 independently selected from alkyl; R C is a halogen, CF3 or SF5; R 5 and R 6 is C 1~3 alkyl or R 5 and R 6 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; and b is 0 to 2) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0060] In some embodiments of the compounds of Formula (I), n is 0. In some embodiments of the compounds of Formula (I), a is 1 and R 2and R 3 are both H. In some embodiments of compounds of Formula (I), each R 4 is substituted or unsubstituted methyl. In some embodiments of the compound of Formula (I), each R 4 is independently selected from methyl and CF3. In some embodiments of the compound of Formula (I), m is 0, 1, 2, 3, or 4. In some embodiments of the compound of Formula (I), m is 1 or 2. In some embodiments of the compound of Formula (I), X is N. In some embodiments of the compound of Formula (I), X is CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl).

[0061] In some embodiments of the compound of Formula (I), L is substituted or unsubstituted -O(CH) p -, -O(CH2) p O- or -(CH2) p - and p is 1 to 4. In some embodiments of the compound of Formula (I), L is substituted or unsubstituted -O(CH2) p -or-(CH2) p - and p is 1 to 4. In some embodiments of the compound of Formula (I), L is substituted or unsubstituted -O(CH2) p -, -O(CH2) p O- or -(CH2) p - and p is 2 or 3. In some embodiments of the compound of Formula (I), L is substituted or unsubstituted -O(CH) p - and p is 2 or 3. In some embodiments of the compound of Formula (I), L is substituted or unsubstituted -(CH) p - and p is 3 or 4.

[0062] In some embodiments of a compound of Formula (I), L is -O(CH)(CH)-, -O(CH)(CH)(CH)-, -O(CH)(CH)(CH)O-, -(CH)(CH)-, -(CH)(CH)(CH)(CH)-, or -(CH)(CH)(CH)(CH)(CH)-. In some embodiments of a compound of Formula (I), L is -O(CH)(CH)-, -O(CH)(CH)(CH)-, -(CH)(CH)(CH)-, -(CH)(CH)(CH)(CH)-, or -(CH)(CH)(CH)(CH)(CH)-. In some embodiments of a compound of Formula (I), L is -O(CH)(CH)- or -(CH)(CH)(CH)(CH)-.

[0063] In some embodiments of the compounds of Formula (I), B is CH. In some embodiments of the compounds of Formula (I), B is N. In some embodiments of the compounds of Formula (I), b is 0. In some embodiments of the compounds of Formula (I), R C is CF3, Cl, or SF5. In some embodiments of the compound of Formula (I), R C is CF3. In some embodiments of the compounds of Formula (I), R 5 and R 6 is methyl.

[0064] In some embodiments of the compound of Formula (I), the compound is [ka] (In the formula, R N is H; Each R 4m is independently hydrogen or substituted or unsubstituted methyl, the substituents, if present, being selected from 1 to 5 halo; X is N or CR X and; R x is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0065] In some embodiments of the compound of Formula (I), the compound is [ka] (In the formula, R N is H; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(C 1~3 alkyl)-, O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0066] In some embodiments of the compound of Formula (I), the compound is [ka] (In the formula, R N is H; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(C 1~3 alkyl)-, O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0067] In some embodiments of compounds of Formula (I), (II), (III), and (IV), n is 0; and X is N or CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(CH) p -or-(CH2) p-, p is 1 to 4; B is CH or N; b is 0; R C is CF3, Cl or SF5; R C is CF3; and R 5 and R 6 is methyl.

[0068] In some embodiments of compounds of Formula (I), (II), (III), and (IV), L is -O(CH)(CH)-, -O(CH)(CH)(CH)-, -O(CH)(CH)(CH)O-, -(CH)(CH)-, -(CH)(CH)(CH)(CH)-, or -(CH)(CH)(CH)(CH)(CH)-. In some embodiments of compounds of Formula (I), (II), (III), and (IV), L is -O(CH)(CH)-, -O(CH)(CH)(CH)-, -(CH)(CH)(CH)-, -(CH)(CH)(CH)(CH)-, or -(CH)(CH)(CH)(CH)(CH)-.

[0069] Further embodiments provided herein include any combination of one or more of the specific embodiments set forth above.

[0070] In some embodiments of the compound of Formula (I), the compound is a compound of Table 1.

[0071] The compounds shown in Table 1 were tested and found to have activity in the AR-mediated assays described herein. In one embodiment, the compounds described herein cause AR protein degradation by at least about 50% or more at a concentration of 1 μM.

[0072] Method for producing piperidinedione compounds The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. By way of example and not limitation, R N , R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R B , R C Compounds of formula (I), wherein L, V, X, n, m, a, and b are as defined herein, can be prepared as outlined in the schemes shown below and in the examples set forth herein. It should be noted that one of ordinary skill in the art would know how to modify the procedures set forth in the illustrative schemes and examples to arrive at the desired product. [ka]

[0073] As shown in Scheme 1, X is N or CR X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4Compounds of formula (I) where LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu, can be prepared by reacting piperidine derivative a with ester intermediate b (where LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperatures (e.g., about 40 °C to about 100 °C) to give intermediate c. In some cases, an iodide salt is used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the ester protecting group from intermediate c (e.g., by treatment with a hydroxide base in a solvent such as LiOH in THF and water when alk is Me, Et, or other alkyl, or by treatment with an acid in a solvent such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane when alk is tert-butyl) gives intermediate d. Coupling of intermediate d with piperidinedione intermediate e in the presence of a coupling agent (e.g., HATU, HBTU, or EDC or TCFH optionally in combination with HOBt) and a base (e.g., N,N-diisopropylethylamine, triethylamine, or N-methylimidazole) in a solvent such as DCM, DMF, NMP, or mixtures thereof at a temperature between 0°C and about 70°C affords the formation of a compound in which X is N or CR X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 Alternatively, X is N and L is —O(C alkyl)-. 1~3 alkyl)- or -(C 1~4The intermediate c, which is an alkyl)-, can be prepared starting by reacting the derivative VL-LG (LG is a suitable leaving group such as Cl, Br, I, triflate or alkylsulfonate) with an appropriately derivatized piperidyl ester derivative f (e.g., alk is an alkyl group such as Me, Et, Bn or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at elevated temperature (e.g., about 40°C to about 80°C) to give intermediate c. [ka]

[0074] X is N and L is -O(C 1~3 alkyl)- or -(C 1~4 Compounds of formula (I) where X is N or CR can also be prepared according to the alternative sequence shown in Scheme 2 by reacting the derivative VL-LG (LG is a suitable leaving group such as Cl, Br, I, triflate, or alkylsulfonate) with an appropriately derivatized piperidyl derivative g in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperature (e.g., about 40 °C to about 100 °C). In some cases, an iodide salt is used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Alternatively, when X is N or CR X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4Compounds of formula (I) where X is N or CR can be prepared by starting with compound e and reacting an appropriately functionalized carbonyl intermediate h (where LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DCM or triethylamine in pyridine) at a temperature between 0°C and about 60°C to give intermediate i. Reaction of i (where LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) with amine intermediate a in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at elevated temperatures (e.g., about 40°C to about 80°C) gives intermediate i, where X is N or CR. X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 The compound of formula (I) is provided wherein the aryl group is aryl, ... [ka]

[0075] Intermediates such as amine g can be prepared according to Scheme 3. Starting with an appropriately functionalized piperazine j, reacting with an ester intermediate b (where LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at elevated temperatures (e.g., about 40°C to about 100°C) provides intermediate k. In some cases, an iodide salt is used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the ester protecting group from intermediate k (e.g., by treatment with a hydroxide base in a solvent, such as LiOH in THF and water, when alk=Me, Et, or other alkyl, or by treatment with an acid in a solvent, such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane, when alk=tert-butyl) provides intermediate l. Coupling of intermediate l with piperidinedione intermediate e in the presence of a coupling agent (e.g., HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt) and a base (e.g., N,N-diisopropylethylamine, triethylamine, or N-methylimidazole) in a solvent, such as DCM, DMF, NMP, or mixtures thereof, at temperatures between 0°C and about 70°C provides amine intermediate g. Intermediates such as amine f can be prepared by removing the N-protecting group P from intermediate k. N can be prepared by removal of (e.g., P N When is Boc, by treatment with an acid in a solvent such as HCl in dioxane or EtOAc at room temperature or TFA in DCM at room temperature, or by treatment with P N When is Bn or Cbz, by metal-catalyzed hydrogenation in a solvent such as palladium on carbon in methanol. [ka]

[0076] X is N and L is -O(C 1~3alkyl)- or -(C 1~4 Intermediates such as a, where V is -O(C alkyl)-, can be prepared according to Scheme 4. 1~3 alkyl)- or -(C 1~4 Treatment of amine n with an amine (wherein LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperatures (e.g., about 40°C to about 100°C) provides intermediate o. In some cases, an iodide salt is used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the N-protecting group P from intermediate o can be accomplished by the use of an amine (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperatures (e.g., about 40°C to about 100°C). N Removal of (e.g., P N When is Boc, by treatment with an acid in a solvent such as HCl in dioxane or EtOAc at room temperature or TFA in DCM at room temperature, or by treatment with P N is Bn or Cbz, by hydrogenation with a metal catalyst in a solvent such as palladium on carbon in methanol, to obtain a compound in which X is N and L is -O(C 1~3 alkyl)- or -(C 1~4 The intermediate a is given as follows: [ka]

[0077] R Z is an alcohol, a protected alcohol, a leaving group, or a heterocycle (such as a substituted piperidine or piperazine). ZIntermediates such as (e.g., intermediate r) can be prepared according to Scheme 5. Treatment of ester intermediate p (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu) with appropriately derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile q in the presence of a base such as triethylamine in a solvent such as EtOAc at elevated temperatures, for example, about 70°C to about 90°C, provides intermediate r. LG is a leaving group (such as Cl, Br, I, triflate, or alkylsulfonate) and L is -O(C 1~3 alkyl)- or -(C 1~4 The intermediates such as u, which is an alkyl)-, can be converted to intermediates s (where P O is an alcohol protecting group such as THP, TBS, acetate or benzyl. O Removal of (e.g., P O When LG is THP, activation of the alcohol functionality in t to a leaving group (e.g., when LG is Br, by treatment of t with thionyl bromide in dichloromethane) provides the alcohol intermediate t, where LG is a leaving group (such as Cl, Br, I, triflate, or alkylsulfonate) and L is -O(C 1~3 alkyl)- or -(C 1~4 alkyl)- provides intermediate u, which can be further reacted to provide compounds of formula (I). [ka]

[0078] L is -O(C 1~3 alkyl)-, and R Z But protected alcohol OP O Intermediate p, such as aa, which is (e.g., a THP ether or a TBS ether), can be prepared according to Scheme 6. Alcohol intermediate v (where P Nis an amine protecting group such as Bn or Boc), an electrophile w (where LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate), and P O is an oxygen protecting group such as THP or TBS) in the presence of a base, optionally with a catalyst, in a solvent (e.g., KOH and tetrabutylammonium bromide in xylene) at elevated temperatures, e.g., 70°C to 130°C, to give intermediate x. N Removal of (e.g., P N When is Bn, hydrogenation over palladium on carbon in methanol can be performed, or by P N is Boc), by treatment with HCl in dioxane, provides amine intermediate y. Reaction of amine y with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base, optionally with an iodide salt, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile) at elevated temperatures (e.g., about 70°C to 130°C) provides intermediate aa, which can be further reacted to give intermediate aa, where L=-O(C 1~3

[0046] This can give a compound of formula (I) wherein the aryl group is a methyl group, ... [ka]

[0079] L is -(C 1~3 alkyl)-, and R Z Intermediates p, such as hh, where P is an alcohol or a protected alcohol (e.g., a THP ether or a TBS ether), can be prepared according to Scheme 6. The aldehyde intermediate bb (where P NStarting from (where R is an amine protecting group such as Bn or Boc), reaction with an olefinating reagent in the presence of a base in a solvent (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) at temperatures between 0°C and 60°C provides the olefin intermediate cc. Reduction of cc by hydrogenation at high pressure (e.g., 10-100 psi) in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) provides the intermediate dd. Reduction of the ester functionality can be achieved by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at temperatures between -78°C and 25°C, to provide the intermediate dd. Y is H to give intermediate ee. Alternatively, intermediate ee can be prepared by treatment of intermediate cc with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at temperatures between -78°C and 25°C to give intermediate ff. Hydrogenation of ff at high pressure (e.g., 10-100 psi) in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) gives intermediate ee. The protecting group P in ee N Removal of (e.g., P N When is Bn, hydrogenation over palladium on carbon in methanol can be performed, or by P N Reaction of amine gg with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate), optionally with an iodide salt, in the presence of a base, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile) at elevated temperatures (e.g., about 70° C. to 130° C.), affords amine intermediate gg. Y is H or an alcohol protecting group (e.g., THP, TBS, or Tr) to give intermediate hh, which is further reacted to give intermediate hh, where L is -(C 1~3 This can give a compound of formula (I) in which the aryl group is (alkyl)-. [ka]

[0080] L is -(C 1~3 alkyl)O-, and R Z Intermediate p, e.g. mm, where P is a heterocycle or cycloalkyl group, can be prepared according to Scheme 8. Intermediate ii (where P N’ is an amine protecting group, e.g., Bn or Boc, and LG is a leaving group, e.g., Cl, Br, I, triflate, or alkylsulfonate, to afford an alcohol jj (where P N is an amine protecting group, e.g., Bn or Boc), in the presence of a base, optionally with a catalyst, in a solvent (e.g., KOH and tetrabutylammonium bromide in xylene) at elevated temperatures (e.g., 70°C to 130°C) to provide the ether intermediate kk. N’ Removal of (e.g., P N’ When is Bn, hydrogenation over palladium on carbon in methanol can be performed, or by P N When is Boc, treatment with HCl in dioxane) provides the amine intermediate ll.

[0081] Reaction of amine ll with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate), optionally with an iodide salt, in the presence of a base, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile) at elevated temperatures (e.g., about 70°C to 130°C), provides intermediate mm, which can be further reacted to convert L to -(C 1~3 This can give a compound of formula (I) in which the alkyl group is O-. [ka]

[0082] L is -O(C 1~3 alkyl)-, and R ZFor certain intermediates p, such as qq, where p is a protected heterocycle or cycloalkyl group, the modified sequence shown in Scheme 9 can be used. N is an amine protecting group such as Bn or Boc), to form an electrophilic intermediate nn (where LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate, and P N’ is an amine protecting group such as Bn or Boc), in the presence of a base, optionally with a catalyst, in a solvent (e.g., KOH and tetrabutylammonium bromide in xylene) at elevated temperatures (e.g., 70°C to 130°C) to provide the ether intermediate oo. N Removal of (e.g., P N’ When is Bn, hydrogenation over palladium on carbon in methanol can be performed, or by P N is Boc), treatment with HCl in dioxane provides the amine intermediate pp. Reaction of the amine pp with an ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate), optionally with an iodide salt, in the presence of a base, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile) at elevated temperatures (e.g., about 70°C to 130°C), provides intermediate qq, which can be further reacted to convert L to —O(C 1~3 This can give a compound of formula (I) in which the aryl group is (alkyl)-. [ka]

[0083] X is CR Z Specific examples of intermediates nn, such as vv, were prepared according to Scheme 10. NOlefination of the ketone intermediate rr, where R is an amine protecting group (e.g., Bn, Boc, or Cbz), with an olefinating reagent and a base in a solvent (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) at a temperature between 0°C and 60°C provides the olefin intermediate ss. Hydrogenation of ss in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at high pressure (e.g., 10-100 psi) provides intermediate tt. Reduction of the ester functionality in tt is achieved by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at a temperature between -78°C and 25°C to provide intermediate uu. Activation of alcohol uu to leaving group LG (e.g., by treatment with thionyl bromide in dichloromethane and DMF when LG is Br, or by treatment with trifluoromethanesulfonic anhydride in dichloromethane when LG is a triflate) provides intermediate vv, which can be further reacted to convert L to —O(C 1~3 alkyl)-, and X is CR X This can give a compound of formula (I) [ka]

[0084] Appropriately derivatized 3-((3-aminophenyl)amino)piperidine-2,6-dione e is prepared by the reaction of R 1 -derivatized 3-nitroaniline ww, which is prepared by adding the amine protecting group P N Protected by (P NFor example, when is Boc, intermediate xx is formed by treatment with BocO in a solvent such as THF, NMP, or DMF in the presence of a base such as TEA, DIEA, or DBU. The nitro group in intermediate xx is reduced (by treatment with a reducing agent, such as H, in the presence of a catalyst such as Pd / C in EtOH or MeOH solvent; or by treatment with Fe and NHCl in a solvent such as EtOH and HO) to provide a monoprotected derivatized dianiline intermediate yy. Coupling of intermediate yy with 3-bromopiperidine-2,6-dione in the presence of a base in a solvent (e.g., NaHCO, CsCO, or KCO in DMF or NMP at elevated temperatures, e.g., about 50°C to about 80°C; or DIEA in DMF or NMP at elevated temperatures, e.g., about 150°C) followed by removal of the protecting group P N Removal of (e.g., P N is Boc, treatment with an acid in a solvent such as TFA in DCM; or treatment with HCl in dioxane or EtOAc) provides intermediate e. Alternatively, intermediate e can be obtained by iron-catalyzed reductive coupling of intermediate xx and 3-bromopiperidine-2,6-dione (e.g., in the presence of Zn, TMSCl, FeCl*4H0, in a solvent such as NMP, at elevated temperatures, e.g., about 80°C to about 100°C), followed by the removal of the protecting group P N is removed (e.g., P N is Boc, treatment with acid in a solvent such as TFA in DCM; or treatment with HCl in dioxane or EtOAc).

[0085] How to use In one embodiment, the compounds described herein have utility as pharmaceuticals for treating, preventing, or ameliorating a condition in an animal or human. The compounds described herein have utility as pharmaceuticals for treating, preventing, or ameliorating a condition in an animal or human. Accordingly, many uses of the compounds are provided herein, including the treatment or prevention of those diseases described below. In one embodiment, the methods provided herein include administering an effective amount of the compound to a subject in need thereof.

[0086] The methods provided herein include administering to a subject in need thereof an effective amount of one or more compounds.

[0087] Provided herein are methods for treating or preventing an androgen receptor (AR)-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0088] Provided herein are methods for treating or preventing an AR-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0089] In another aspect, provided herein are compounds for use in treating or preventing an AR-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound described herein. In some embodiments, provided herein are compounds for use in treating an AR-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound described herein. In some embodiments, provided herein are compounds for use in preventing an AR-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0090] In some embodiments, the compound used in the methods herein is a compound 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 Table 1.

[0091] In some embodiments, the AR-mediated disease is an AR wild-type mediated disease. In other embodiments, the AR-mediated disease is the result of AR amplification.

[0092] 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 other embodiments, the prostate cancer is non-metastatic CRPC (nmCRPC). In some embodiments, the prostate cancer is hormone-refractory. In some embodiments, the prostate cancer is resistant to treatment with an AR antagonist. For example, the 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.

[0093] Provided herein are methods for reducing AR levels, comprising administering an effective amount of a compound to a subject. Also provided herein are compounds for use in methods for reducing AR levels in cells in vivo, ex vivo, or in vitro, comprising contacting the cells with an effective amount of a compound. In one embodiment, the cells are within a patient. In one embodiment, the cells are not within a patient. In one embodiment, provided herein are methods for reducing wild-type AR levels in tumors, comprising administering a therapeutically effective amount of a compound to reduce wild-type AR in the tumor. In one embodiment, provided herein are methods for reducing AR-full length (AR-FL) levels in tumors, comprising administering a therapeutically effective amount of a compound to reduce AR-full length (AR-FL) levels in the tumor. In some embodiments, the AR levels are reduced compared to the AR levels before administration of the compound. In some embodiments, the AR levels are reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the AR levels before administration of the compound.

[0094] Also provided herein are methods for regulating AR protein activity in a patient in need thereof, comprising administering to the patient an amount of a compound. In some such embodiments, provided herein are methods for reducing AR protein activity in a patient in need thereof, comprising administering to the patient an amount of a compound. In some embodiments, AR protein activity is reduced compared to AR protein activity before administration of the compound. In some embodiments, AR protein activity is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to AR protein activity before administration of the compound.

[0095] In some embodiments of the methods described herein, the methods further comprise administering one or more second agents selected from AR antagonists (such as cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), 5α-reductase inhibitors (such as finasteride and dutasteride), CYP17A1 inhibitors (such as abiraterone acetate), gonadotropin-releasing hormone (GnRH) analogs (such as leuprorelin and cetrorelix), and antigonadotropins (such as megestrol acetate and medroxyprogesterone acetate).

[0096] In some embodiments, the compounds provided herein can be used in any of the above methods.

[0097] In some embodiments, the compounds provided herein can be used in any of the above methods.

[0098] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0099] The compounds can be administered to a subject orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared by a commonly used method, incorporating excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., stearic acid, The pharmaceutical composition may be prepared using conventional organic or inorganic additives such as cereals such as cereals containing ...

[0100] The dosage of the compound administered to a subject can vary widely and is subject to the discretion of a medical professional. Generally, the compound can be administered 1 to 4 times per day at a dosage of about 0.001 mg / kg to about 10 mg / kg of the subject's body weight, although this dosage may be appropriately varied depending on the subject's age, body weight, and condition, as well as the type of administration. In one embodiment, the dosage is about 0.001 mg / kg to about 5 mg / kg of the subject's body weight, about 0.01 mg / kg to about 5 mg / kg of the subject's body weight, about 0.05 mg / kg to about 1 mg / kg of the subject's body weight, about 0.1 mg / kg to about 0.75 mg / kg of the subject's body weight, or about 0.25 mg / kg to about 0.5 mg / kg of the subject's body weight. In one embodiment, one dosage is given per day. In any given case, the amount of the compound administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0101] In another embodiment, provided herein is a method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof 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 to about 25 mg / day, or from about 0.1 mg / day to about 10 mg / day of a compound.

[0102] In another embodiment, provided herein is a unit dose formulation comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound.

[0103] In certain embodiments, provided herein are unit dose formulations comprising about 0.1 mg or 100 mg of the compound.

[0104] In another embodiment, provided herein is a unit dose formulation comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound.

[0105] The compound can be administered once, twice, three times, four or more times per day, hi certain embodiments, doses of 100 mg or less are administered as a single daily dose, and doses of more than 100 mg are administered twice daily in an amount equal to half the total daily dose.

[0106] The compound can be administered orally for convenience. In one embodiment, when administered orally, the compound is administered with food and water. In another embodiment, the compound is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0107] Compounds may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is left to the discretion of the health-care practitioner and may depend in part on the site of the medical condition.

[0108] In one embodiment, provided herein is a capsule containing the compound without additional carriers, excipients, or vehicles.

[0109] In another embodiment, provided herein is a composition comprising an effective amount of a compound and a pharmaceutically acceptable carrier or vehicle, which may include an excipient, diluent, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0110] The compositions may be in the form of tablets, chewable tablets, capsules, liquids, parenteral solutions, lozenges, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose or a convenient fraction of a daily dose in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the liquid is prepared from a water-soluble salt, such as a hydrochloride salt. Generally, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing the compound with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Typical 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 cellulose, sugars such as fructose, mannitol, and sucrose, grain flours, and similar edible powders.

[0111] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually incorporate diluents, binders, lubricants, and disintegrants, as well as compounds. 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 are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including gum arabic, alginate, methylcellulose, polyvinylpyrrolidine, and the like, are also convenient. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0112] Lubricants may be necessary in tablet formulations to prevent the tablet and punch from sticking in the die. Lubricants can 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 up the tablet and releasing the compound. These include starch, clay, cellulose, algin, and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, and sodium lauryl sulfate can be used. Tablets can be coated with sugar as a flavoring and sealant, or with a film-forming protective agent to control the dissolution properties of the tablet. The composition can also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0113] When it is desired to administer the compound as a suppository, typical bases can be used. Cocoa butter is a conventional suppository base, and its melting point can be adjusted by adding wax to slightly raise it. In particular, water-miscible suppository bases, including polyethylene glycols of various molecular weights, are widely used.

[0114] The effect of the compound can be delayed or prolonged by appropriate formulation. For example, slowly dissolving pellets of the compound can be prepared and incorporated into tablets or capsules or as slow-release implantation devices. Techniques also include producing pellets with several different dissolution rates and filling capsules with a mixture of pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral formulations can be made long-acting by dissolving or suspending the compound in an oily or emulsified vehicle that allows the compound to slowly disperse in serum.

[0115] Enumerated Embodiments The invention can be defined with reference to the following enumerated illustrative embodiments.

[0116] 1. Formula I [ka] (In the formula, R N is H; n is 0 to 4; Each R 1 are halogens, CN and C 1~3 independently selected from alkyl; a is 1 or 2; R 2 and R 3 is H and C 1~3 alkyl, or R 2 and R 3 and the carbon to which they are attached may be substituted or unsubstituted C 3~6 Forming a cycloalkyl; m is 0 to 8; Each R 4 are independently substituted or unsubstituted C 1~3 alkyl or two R 4 The groups may be substituted or unsubstituted C 3~6 Form a cycloalkyl or two R 4 groups, together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4- to 7-membered heterocyclyl; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(C 1~6 alkyl)-, -(C 1~6 alkyl)O-, -O(C 1~6 alkyl)O- or -(C 1~9 alkyl)-; V is [ka] where: B is N, CH or CR B and; Each R B is a halogen and a substituted or unsubstituted C 1~6 independently selected from alkyl; R C is a halogen, CF3 or SF5; R 5 and R 6 is C 1~3 alkyl or R 5 and R 6 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; and b is 0 to 2) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0117] 2. The compound of embodiment 1, wherein n is 0.

[0118] 3. a is 1 and R 2 and R 3 and R are both H.

[0119] 4.Each R 4 The compound of any one of embodiments 1-3, wherein is substituted or unsubstituted methyl.

[0120] 5.Each R 4 The compound of any one of embodiments 1-4, wherein is independently selected from methyl and CF3.

[0121] 6. The compound of any one of embodiments 1-5, wherein m is 0, 1, 2, 3, or 4.

[0122] 7. The compound of any one of embodiments 1 to 5, wherein m is 1 or 2.

[0123] 8. The compound of any one of embodiments 1-7, wherein X is N.

[0124] 9.X is CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 The compound of any one of embodiments 1-7, wherein R is 1 or 2;

[0125] 10. L is a substituted or unsubstituted -O(CH2) p -, -O(CH2) p O- or -(CH2) p - and p is 1-4.

[0126] 11. L is a substituted or unsubstituted -O(CH2) p - and p is 2 or 3.

[0127] 12. L is a substituted or unsubstituted -(CH2) p - and p is 3 or 4.

[0128] 13. The compound of any one of embodiments 1-9, wherein L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0129] 14. The compound of any one of embodiments 1-9, wherein L is —O(CH 2 )(CH 2 )— or —(CH 2 )(CH 2 )(CH 2 )—.

[0130] 15. The compound of any one of embodiments 1-14, wherein B is CH.

[0131] 16. The compound of any one of embodiments 1-14, wherein B is N.

[0132] 17. The compound of any one of embodiments 1-16, wherein b is 0.

[0133] 18.R C The compound of any one of embodiments 1-17, wherein is CF3, Cl, or SF5.

[0134] 19.R C The compound of any one of embodiments 1-17, wherein is CF3.

[0135] 20.R 5 and R 6 The compound of any one of embodiments 1-19, wherein is methyl.

[0136] 21.Formula II [ka] (In the formula, R N is H; Each R 4m is independently hydrogen or substituted or unsubstituted methyl, the substituents, if present, being selected from 1 to 5 halo; X is N or CR X and; R x is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, of embodiment 1, having the formula:

[0137] 22.Formula III [ka] (In the formula, R N is H; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, of embodiment 1, having the formula:

[0138] 23.Formula IV [ka] (In the formula, R N is H; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, of embodiment 1, having the formula:

[0139] 24. A compound of embodiment 1 selected from Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0140] 25. A pharmaceutical composition comprising an effective amount of a compound of any one of embodiments 1-24 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0141] 26. A method of treating an androgen receptor mediated disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-24.

[0142] 27. A method for treating an androgen receptor mediated disease, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of embodiment 25.

[0143] 28. The method of embodiment 26 or 27, wherein the androgen-mediated disease is prostate cancer.

[0144] 29. The embodiment of embodiment 28, wherein the prostate cancer is castration-resistant prostate cancer (CRPC). [Example]

[0145] The following examples are presented by way of illustration, not limitation. Compounds are named using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures with support for the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art can modify the procedures described in the examples to arrive at the desired products.

[0146] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product with a solution of an acid (e.g., aqueous HCl) after chromatographic purification.

[0147] Abbreviations used

[0148] [Table 1]

[0149] Example 1: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] trans-4-(Dibenzylamino)cyclohexan-1-ol. To a mixture of trans-4-aminocyclohexan-1-ol (40 g, 347 mmol, 1.0 equiv.) and cesium carbonate (339 g, 1.04 mol, 3 equiv.) in acetonitrile (900 mL) was added benzyl bromide (119 g, 698 mmol, 2.01 equiv.) dropwise. The reaction solution was stirred at room temperature. After 48 h, the reaction mixture was filtered and concentrated. The resulting residue was diluted with DCM (300 mL), washed with water (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give trans-4-(dibenzylamino)cyclohexan-1-ol (77 g, 261 mmol, 75% yield) as a pale pink solid. The crude product was carried forward without further purification. MS (ESI) m / z 116.3 [M+1] + ; 1 H NMR 400MHz DMSO-d6δ 7.27-7.34(m,8H),7.19-7.21(m,2H),4.42(d,J=4.8Hz,1H),3.55(s,4H),2.33-2.3 6(m,1H),1.74-1.84(m,4H),1.40(dd,J=12.4Hz,2.0Hz,2H),0.98(d,J=13.2Hz,2H).

[0150] trans-N,N-Dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine. To a mixture of trans-4-(dibenzylamino)cyclohexan-1-ol (60 g, 203 mmol, 1.0 equiv.) and tetrabutylammonium hydrogen sulfate (13.8 g, 40.6 mmol, 0.2 equiv.) in THF (400 mL) and water (200 mL), 2-(2-bromoethoxy)tetrahydro-2H-pyran (84.9 g, 406 mmol, 61.5 mL, 2.0 equiv.) and sodium hydroxide (200 g, 5.00 mol, 24.6 equiv.) were added at 0 °C. The reaction solution was heated to 65 °C. After 12 h, the reaction solution was poured into ice water (1.0 L), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude material was purified by column chromatography (SiO, 2-50% ethyl acetate in petroleum ether) to give trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (60 g, 142 mmol, 70% yield) as a colorless oil. 1 H NMR 400MHz CDCl3δ 7.37-7.39(m,4H),.7.28-7.32(m,4H),7.22(m,2H),4.63-4.67(m,1H),3.57-3.89(m,9H),3.23-3.25(m,1H) ,2.55(m,1H),2.08-2.11(m,2H),1.92-1.95(m,5H),1.58-1.64(m,6H),1.54-1.56(m,2H),1.20-1.39(m,2H).

[0151] trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine. To a mixture of trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (65 g, 153 mmol, 1.0 equiv) in methanol (500 mL) was added 10% palladium on carbon (6.5 g) under N. The suspension was degassed under vacuum and purged with hydrogen gas three times. The reaction solution was stirred at room temperature under an atmosphere of hydrogen gas (15 psi). After 1 h, the reaction solution was filtered and the filtrate was concentrated to give trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (46 g) as an off-white oil. The crude material was carried forward without further purification. 1 H NMR 400MHz CDCl3δ 7.34-7.36(m,1H),.4.63-4.65(m,1H),3.82-3.91(m,3H),3.52-3.66(m,5H),3.28(m,1H),2.70-2.71(m,1H),2. 01-2.04(m,2H),1.85-1.89(m,3H),1.58-1.59(m,1H),1.45-1.56(m,8H),1.29-1.32(m,2H),1.11-1.14(m,2H).

[0152] Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate. To a mixture of trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (25 g, 103 mmol, 1.0 equiv.) in acetonitrile (175 mL) was added methyl 2-bromo-2-methylpropanoate (37.2 g, 205 mmol, 26.6 mL, 2.0 equiv.), potassium carbonate (28.4 g, 205 mmol, 2.0 equiv.), and potassium iodide (1.71 g, 10.3 mmol, 0.1 equiv.). The reaction solution was heated to 110° C. After 16 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by column chromatography (SiO, 0-50% ethyl acetate in petroleum ether) to give methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54 mmol, 53% yield) as a yellow oil. MS (ESI) m / z 344.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 4.63(t,J=3.2Hz,1H),.3.82-3.87(m,2H),3.70(s,3H),3.61-3.63(m,4H),3.51-3.60(m,2H),3.22-3.24(m,1H) ),2.36(m,1H),1.99(m,2H),1.83-1.86(m,3H),1.62(m,1H),1.53-1.60(m,6H),1.30(m,6H),1.12-1.14(m,2H).

[0153] 4-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54.2 mmol, 1.0 equiv.) in ethyl acetate (130 mL) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (24.7 g, 108 mmol, 2.0 equiv.) and N,N-diisopropylethylamine (14.0 g, 108 mmol, 2.0 equiv.). The reaction solution was heated to 90° C. with stirring. After 12 h, the reaction solution was concentrated and the resulting crude material was purified by silica gel column chromatography (0-50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (25 g, 46.3 mmol, 86% yield) as a yellow oil.

[0154] 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (42.5 g, 78.8 mmol, 1.0 equiv.) in dichloromethane (300 mL) was added dropwise 4 M hydrochloric acid in 1,4-dioxane (400 mL). The reaction solution was stirred at room temperature. After 1 h, the reaction solution was concentrated and purified by silica gel column chromatography (1-20% THF in dichloromethane) to give 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (21 g, 46.1 mmol, 59% yield) as a yellow glassy oil. MS(ESI) m / z 456.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 7.95(d,J=8.0Hz,1H),7.85(m,1H),7.72(dd,J=10.0Hz,1.6Hz,1H),3.73-3.77(m,4H),3.60-3.62(m,2H),3.37-3 .39(m,1H),2.88-2.91(m,2H),2.21-2.24(m,2H),1.97(m,1H),1.83-1.88(m,3H),1.61(s,6H),1.33-1.41(m,2H).

[0155] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a mixture of 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.500 g, 7.72 mmol, 1.0 equiv.) in dichloromethane (80 mL) was added N,N-dimethylformamide (8 mL) and thionyl bromide (3.201 g, 15.43 mmol, 2.0 equiv.) at 0° C. After 12 h, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (9-20% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (4.200 g, 8.13 mmol, crude) as a yellow solid. MS (ESI) m / z 518.1 [M+1] + .

[0156] tert-Butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. A solution of tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (5 g, 23.33 mmol, 1 equiv.), methyl bromoacetate (3.57 g, 23.33 mmol, 1 equiv.), and triethylamine (10.2 mL, 70 mmol, 3 equiv.) in THF (100 mL, 0.23 M) was stirred at 50 °C. After 18 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10-100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (6.2 g, 21.6 mmol, 92% yield) as a yellow oil. MS(ESI) m / z 287.2 [M+1] + .

[0157] Methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate. To a solution of tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (1 g, 3.49 mmol, 1 equiv.) in dichloromethane (3 mL) was added 4 M HCl in 1,4-dioxane (8.7 mL, 34.9 mmol, 10 equiv.), and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was concentrated, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate (5 × 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (510 mg, 2.72 mmol, 78% yield) as a yellow oil. MS(ESI)m / z 187.5[M+1] + .

[0158] Methyl 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate. To a solution of 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (208 mg, 0.400 mmol, 1 equiv.), methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate hydrochloride (116 mg, 0.520 mmol, 1.3 equiv.), and sodium iodide (79 mg, 0.5200 mmol, 1.3 equiv.) was added N,N-dimethylformamide (3.2 mL, 0.13 M) and N,N-diisopropylethylamine (0.17 mL, 0.960 mmol, 2.4 equiv.). The reaction was stirred at 60 °C. After 48 h, the reaction solution was concentrated and the crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give methyl 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (250 mg, 0.40 mmol, 97% yield) as a yellow solid. MS(ESI) m / z 624.0 [M+1] + .

[0159] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid. To a solution of methyl 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (250 mg, 0.400 mmol, 1 equiv) in 3:1 water / THF (5 mL) was added lithium hydroxide (100 mg, 4.17 mmol, 10 equiv) and the reaction solution was stirred at room temperature. After 1 h, the reaction solution was diluted with water and adjusted to pH 4 by the addition of 1 M hydrochloric acid. The solution was extracted with ethyl acetate (4 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (218 mg, 0.358 mmol, 90% yield) as a pale orange solid. MS (ESI) m / z 610.0 [M+1] + .

[0160] tert-Butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate. To a solution of tert-butyl N-(3-aminophenyl)carbamate (290 g, 1.39 mol, 1 equiv.) and 3-bromopiperidine-2,6-dione (294 g, 1.53 mol, 1.1 equiv.) in N,N-dimethylformamide (1500 mL, 0.93 M) was added sodium bicarbonate (117 g, 1.9 mol, 1.4 equiv.). The reaction mixture was stirred at 80° C. After 16 h, the reaction solution was cooled to 25° C. and poured into ice water (4 L). A precipitate formed, which was filtered and dried. The solid was washed with ethyl acetate / petroleum ether (1:1, 2000 mL) and dried to give tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (400 g, 1.25 mol, 90% yield) as a green solid. 1 H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),9.03(s,1H),6.95-6.83(m,2H),6.67-6.64(m,1H),6.31-6.29(m,1H),5.79(d,J=7. 6Hz,1H),4.24-4.20(m,1H),2.73-2.50(m,2H),2.11-2.09(m,1H),1.89-1.68(m,1H),1.49(s,9H).

[0161] 3-((3-Aminophenyl)amino)piperidine-2,6-dione. To a suspension of tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (200 g, 626 mmol) in dichloromethane (1500 mL, 0.42 M) was added trifluoroacetic acid (770 g, 6.75 mol, 10.8 equiv.) at 0 °C. The reaction solution was stirred at 25 °C for 16 h. The reaction solution was concentrated, and the residue was diluted with methyl tert-butyl ether (2000 mL) and stirred at room temperature for 30 min. The formed solid was filtered and dried to give approximately 420 g of crude product as the trifluoroacetate salt. The salt was dissolved in water (6 L), and the pH was adjusted to 7-8 by the addition of saturated aqueous sodium bicarbonate solution. The solution was filtered, and the filtrate was extracted with ethyl acetate (4 × 1500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 3-((3-aminophenyl)amino)piperidine-2,6-dione (172 g, 392 mmol, 62% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),6.73(t,J=8.0Hz,1H),5.91-5.86(m,3H),5.41(d,J=7.2Hz,1H),4.72 (s,2H),4.19-4.15(m,1H),2.72-2.51(m,2H),2.09-2.08(m,1H),1.20-1.85(m,1H).

[0162] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a mixture of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (2.500 g, 4.10 mmol, 1.0 equiv) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (1.079 g, 4.92 mmol, 1.2 equiv) in N,N-dimethylformamide (50 mL) was added N,N-diisopropylethylamine (1.590 g, 12.30 mmol, 3 equiv) and HATU (2.337 g, 6.15 mmol, 1.5 equiv). The reaction was stirred at 60° C. for 12 hours. The mixture was concentrated in vacuo and purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (1.150 g, 14.1 mmol, 35% yield) as a yellow solid. MS(ESI) m / z 811.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.77(s,1H),9.33(s,1H),8.33(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97 (dd,J=1.6,8.4Hz,1H),7.04-6.93(m,2H),6.81-6.75(m,1H),6.40(dd,J=1.6 ,8.4Hz,1H),5.89(d,J=8.0Hz,1H),4.33-4.23(m,1H),3.92-3.74(m,1H),3.5 3(t,J=6.0Hz,2H),3.29-3.21(m,1H),3.19(s,2H),2.88-2.55(m,8H),2.41(br t,J=6.0Hz,2H),2.12-2.02(m,3H),1.92-1.82(m,3H),1.71(br d,J=10.4Hz,2H),1.54(s,6H),1.39-1.25(m,2H),0.96(d,J=6.0Hz,6H).

[0163] Example 2: 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] tert-Butyl (trans-4-formylcyclohexyl)carbamate. To a mixture of tert-butyl (trans-4-(hydroxymethyl)cyclohexyl)carbamate (240 g, 1.05 mol, 1 equiv.) in acetonitrile (1.60 L) was added IBX (352 g, 1.26 mol, 1.2 equiv.) at 15 °C. The reaction was stirred at 65 °C for 1 h. The two batches were combined for workup and purification. The reaction mixture was filtered, and the filter was concentrated in vacuo to give tert-butyl (trans-4-formylcyclohexyl)carbamate (470 g, crude) as a white solid. The crude was used directly in the next step without further purification. 1H NMR(400MHz CDCl3)δ 9.62(s,1H),4.43(s,1H),4.41(s,1H),2.10-2.14(m,3H),2.01-2.05(m,2H),1.45(s,9H),1.38-1.41(m,2H),1.14-1.18(m,2H).

[0164] Ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate. To a mixture of sodium hydride (49.6 g, 1.24 mol, 60% purity, 1.2 equiv.) in THF (900 mL) at 0 °C was added ethyl 2-(diethoxyphosphoryl)acetate (255 g, 1.14 mol, 1.1 equiv.) dropwise. The reaction was stirred at 0 °C for 1 h. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (235 g, 1.03 mol, 1 equiv.) in THF (500 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 2 h. The reaction solution was poured into ice water (3.0 L) and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (800 mL, 500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (560 g, crude) as a pale yellow solid. The material was carried forward without further purification. 1 H NMR(400MHz CDCl3)δ 6.88(dd,J=15.6Hz,6.8Hz 1H),5.75-5.79(m,1H),4.40(s,1H),4.12-4.23(m,3H),3.39(s,1H),2.04-2.08(m,3H), 1.81-1.85(m,2H),1.44(s,9H),1.33-1.35(m,1H),1.26-1.30(m,6H),1.10-1.16(m,3H).

[0165] tert-Butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate. The reaction was set up as two parallel reactions. To a solution of the compound ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (280 g, 942 mmol, 1 equiv.) in dichloromethane (1.12 L) at −78° C. under an argon atmosphere was added diisobutylaluminum hydride (1 M, 1.88 L, 2 equiv.). The reaction was stirred at −78° C. for 1 hour. The reaction was quenched with MeOH (280 mL) at −60° C. The two reaction mixtures were combined and heated to −10° C. in saturated citric acid (4.0 L). The mixture was poured into 1.0 kg citric acid in HO. The mixture was extracted with ethyl acetate (2.0 L, 1.5 L). The combined organic layers were washed with aqueous sodium bicarbonate (2.0 L), brine (2.0 L), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 50 / 1 - 0 / 1) to give tert-butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (420 g, 1.645 mol, 87% yield) as a pale yellow solid. 1 H NMR(400MHz CDCl3)δ 5.58-5.60(m,2H),4.39(s,1H),4.06-4.07(m,2H),3.35(s,1H),1.80-2.00(m,3H),1.74-1.78(m,2H),1.42(s,9H),1.08-1.20(m,4H).

[0166] tert-Butyl ((trans-4-(3-hydroxypropyl)cyclohexyl)carbamate. Four batches of this reaction were carried out in parallel. A mixture of tert-butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (105 g, 411 mmol, 1 equiv.) and palladium on carbon (10.5 g, 10% purity) in MeOH (600 mL) was degassed and purged with H2 three times, then the mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The mixture was stirred. The four batches were combined for workup and purification. The reaction solution was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1). tert-butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (82 g, 19% yield) and tert-butyl (trans-4-(3-oxopropyl)cyclohexyl)carbamate (200 g, 48% yield) were obtained as white solids. 1 H NMR(400MHz CDCl3)δ 4.38(s,1H),3.63(t,J=6.4Hz,2H),3.37(s,1H),1.98-2.01(m,2H),1.60-1.79 (m,2H),1.55-1.59(m,2H),1.44(s,9H),1.22-1.28(m,3H),0.95-1.05(m,4H).

[0167] 3-(trans-4-Aminocyclohexyl)propan-1-ol hydrochloride. Two reactions were carried out in parallel. To a solution of tert-butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (115 g, 447 mmol, 1 equiv.) in methanol (200 mL) was added 4 M hydrochloric acid in methanol (500 mL). The reaction was stirred at 15 °C for 6 h. The two batches were combined for workup and purification. The reaction solution was filtered and concentrated to give 3-(trans-4-aminocyclohexyl)propan-1-ol hydrochloride (160 g, 92% yield) as a pale yellow solid. The material was carried forward without further purification. 1H NMR(400MHz DMSO-d6)δ 8.09(s,4H),4.62(s,2H),3.35(t,J=6.8Hz,2H),2.87(d,J=4.4Hz,1H),1.93(d,J=10.8Hz,2H),1. 73(d,J=12.8Hz,2H),1.38-1.42(m,2H),1.29-1.31(m,3H),1.13-1.17(m,3H),0.89-0.92(m,2H).

[0168] Methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate. To a mixture of 3-(trans-4-aminocyclohexyl)propan-1-ol hydrochloride (120 g, 619 mmol, 1 equiv.) in acetonitrile (750 mL) was added potassium carbonate (428 g, 3.10 mol, 5 equiv.) and methyl 2-bromo-2-methylpropanoate (449 g, 2.48 mol, 4 equiv.). The mixture was stirred at 110 °C for 12 h. The reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (5-100% ethyl acetate in petroleum ether) to give methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 34% yield) as a yellow oil. MS(ESI)m / z 258.2[M+1] + .

[0169] 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (62.2 g, 273 mmol, 1.3 equiv.) in ethyl acetate (350 mL) was added N,N-diisopropylethylamine (54.2 g, 420 mmol, 2 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (10–100% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (63 g, 139 mmol, 66% yield) as a yellow solid. 1 H NMR(400MHz CDCl3)δ 7.94-7.96(m,1H),7.85(m,1H),7.72-7.75(m,1H),3.64-3.67(m,2H),2.69(s,2H),1.95(d ,J=12.8Hz,2H),1.84(d,J=11.2Hz,2H),1.61(s,7H),1.29-1.37(m,5H),1.05-1.08(m,2H).

[0170] 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.820 g, 1.81 mmol, 1 equiv.) in N,N-dimethylformamide (0.800 mL) and dichloromethane (8 mL) was added thionyl bromide (0.752 g, 3.620 mmol, 2 equiv.) slowly at 0° C. After stirring at 0 °C for 2 h, the reaction solution was concentrated and purified by silica gel column chromatography (15-25% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.650 g, 1.259 mmol, 70% yield) as a brown solid. MS (ESI) m / z 516.1 [M+1] + .

[0171] Methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate. To a solution of 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (500 mg, 0.968 mmol, 1 equiv.) and methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (270 mg, 1.45 mmol, 1.5 equiv.) in N,N-dimethylformamide (4.8 mL, 0.2 M) was added N,N-diisopropylethylamine (0.46 mL, 4.84 mmol, 5 equiv.), and the reaction solution was stirred at 50° C. After 18 hours, the reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1-10% methanol in dichloromethane) to give methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate (487 mg, 0.784 mmol, 81% yield) as a pale yellow oil. MS(ESI) m / z 622.3 [M+1] + .

[0172] 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid. A solution of methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate (500 mg, 0.82 mmol, 1 equiv) in 5:1 THF / water (4 mL, 0.2 M) was treated with lithium hydroxide (59 mg, 2.46 mmol, 3 equiv). The reaction solution was stirred at room temperature. After 12 hours, the reaction solution was diluted with water (10 mL), adjusted to pH 5 by the addition of 2 M HCl, and extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (364 mg, 0.599 mmol, 73% yield) as an off-white solid. MS (ESI) m / z 608.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 8.33(d,J=8.0Hz,1H),8.19(s,1H),7.97(d,J=8.4Hz,1H),3.83(s,1H),3.37(s,2H),3.14(s,2H),2.89(s,2H),2.73(s,2H),2.40(s,2H),2 .00(s,2H),1.81(d,J=12.0Hz,2H),1.72(d,J=10.4Hz,2H),1.44-1.54(m,8H),1.15-1.19(m,3H),1.05-1.08(m,2H),1.01(d,J=6.4Hz,6H).

[0173] 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 2-((2S,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.200 g, 0.33 mmol, 1.0 equiv) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.108 g, 0.49 mmol, 1.5 equiv) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.128 g, 0.99 mmol, 3 equiv) and HATU (0.188 g, 0.49 mmol, 1.5 equiv). The reaction was stirred at 60° C. for 12 hours. The mixture was purified by standard procedures to give 2-((2S,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.108 g, 0.036 mmol, 40% yield) as a yellow solid. MS(ESI) m / z 809.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 12.09-11.54(m,1H),10.79(s,1H),10.63-10.40(m,1H),8.34(d,J=8.4Hz,1H),8.20( d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),7.08-7.01(m,1H),6.99(s,1H),6.86(br d,J=8.0Hz,1H),6.47(dd,J=1.2,8.4Hz,1H),4.27(dd,J=4.8,11.2Hz,4H),3.90-3.63(m,4H),3.36-3.15(m,2H),3.05(s,2H),2.82-2 .65(m,3H),2.64-2.55(m,1H),2.09(td,J=4.0,8.8Hz,1H),1.98-1.64(m,8H),1.55(s,6H),1.35(d,J=1.2Hz,6H),1.28-0.97(m,6H).

[0174] Example 3: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] (R)-3-((3-aminophenyl)amino)piperidine-2,6-dione and (S)-3-((3-aminophenyl)amino)piperidine-2,6-dione. Racemic 3-((3-aminophenyl)amino)piperidine-2,6-dione (8 g) was separated by chiral SFC to give two peaks upon concentration of fractions at temperatures below 35 °C. The absolute configuration was determined by vibrational circular dichroism spectroscopy (VCD). (R)-3-((3-aminophenyl)amino)piperidine-2,6-dione (2.80 g, 35.0% yield, 97.7% ee) and (S)-3-((3-aminophenyl)amino)piperidine-2,6-dione (2.90 g, 36.3% yield, 97.1% ee) were isolated as brown solids. SFC purification conditions (column: Chiralpak IC-H, 250 × 30 mm id 5 um; mobile phase: CO2 in A and EtOH:acetonitrile = 2:1 in B; gradient: B% = 40%; flow rate: 75 g / min).

[0175] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. A vial containing 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (250 mg, 0.41 mmol, 1 equiv.) was charged with (R)-3-((3-aminophenyl)-2-(2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (250 mg, 0.41 mmol, 1 equiv.) N,N-dimethylformamide (2.0 mL, 0.1 M), 1-methylimidazole (134 mg, 1.64 mmol, 8 equiv.), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (230 mg, 0.82 mmol, 4 equiv.) were added. The reaction mixture was stirred at 25° C. for 90 minutes. The reaction was taken up in dimethyl sulfoxide and purified by semi-preparative HPLC using 5-95% acetonitrile + 0.1% trifluoroacetic acid in water + 0.1% trifluoroacetic acid over 20 minutes. Fractions containing the desired product were combined, and the volatile organics were removed under reduced pressure to give a brown solid. The solid was taken up in acetonitrile:water (1:1), and 1.0 N HCl solution (0.80 mL) was added. The solution was frozen and lyophilized to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (139 mg, 0.157 mmol, 38% yield) as a brown solid. MS(ESI) m / z 811.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.34(d,J=8.31Hz,1H),8.20(d,J=1.71Hz,1H),7.97(dd,J=1.71,8.19Hz,1H),7.02-7.09(m,1H),6.99(br s,1H),6.87(br d,J=7.95Hz,1H),6.47(dd,J=1.47,8.19Hz,1H),4.27(dd,J=4.89,11.37Hz,1H),3.97-4.24(m,3H),3.76-3.95(m,3H),3.69(br s,2H),3.22-3.43(m,5H),2.68-2.94(m,3H),2.55-2.65(m,1H),2.05-2.17(m,3H), 1.91(dq,J=4.71,12.12Hz,1H),1.67-1.78(m,2H),1.55(s,6H),1.27-1.45(m,8H).

[0176] Example 4: 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (2.0 g, 5.82 mmol, 1 equiv.) in ethyl acetate (1.3234 mL) was added 2-chloro-4-isothiocyanatobenzonitrile (2.27 g, 11.65 mmol, 2 equiv.) and N,N-diisopropylethylamine (2.03 mL, 11.65 mmol, 2 equiv.). The reaction solution was heated to 90° C. with stirring. After 18 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (2 g, 3.9521 mmol, 68% yield) as a white solid. MS(ESI) m / z 506.2 [M+1] + .

[0177] 2-Chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (4.0 g, 7.9 mmol, 1 equiv.) in chloroform (5.7 mL) was added 4 M HCl in dioxane (39.52 mL, 158.08 mmol, 20 equiv.), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-40% ethyl acetate in hexanes) to give 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.5 g, 2.883 mmol, 36% yield) as an off-white solid. MS(ESI) m / z 422.2 [M+1] + .

[0178] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.51 g, 3.06 mmol) in dichloromethane (38 mL) and N,N-dimethylformamide (3.8 mL) was added thionyl bromide (0.59 mL, 7.64 mmol, 2.5 equiv.), and the reaction solution was stirred at room temperature. After 1 hour, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-80% ethyl acetate in hexanes) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (1.171 g, 2.42 mmol, 79% yield) as a pale yellow solid. MS(ESI) m / z 484.0 [M+1] + .

[0179] 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid. To a solution of tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.27 g, 7.93 mmol, 1 equiv.) in THF (20 mL) was added lithium hydroxide (208.8 mg, 8.7 mmol, 1.1 equiv.) in water (5 mL), and the reaction solution was stirred at room temperature. After 18 h, the reaction solution was concentrated in vacuo and azeotroped three times with chloroform to remove residual water, affording crude 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (2.19 g, 7.8 mmol, 99% yield) as an off-white glassy solid. The material was carried forward without further purification. MS(ESI) m / z 273.2[M+1] + .

[0180] tert-Butyl (3S,5R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (2.00 g, 7.34 mmol, 1 equiv.) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (1.61 g, 7.34 mmol, 1 equiv.) in N,N-dimethylformamide (20 mL), HATU (2.79 g, 7.34 mmol, 1 equiv.) and N,N-diisopropylethylamine (3.8 mL, 22.03 mmol, 3 equiv.) were added in one portion under nitrogen, and the reaction solution was stirred at 15 °C. After 12 h, the reaction solution was diluted with water (800 mL) and extracted with ethyl acetate (100 mL × 4). The combined organic layer was washed with brine (4 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude material was purified by flash silica gel chromatography (0-2% methanol in dichloromethane) to give tert-butyl (3S,5R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.45 g, 5.08 mmol, 69% yield) as a pale yellow solid. MS (ESI) m / z 474.3 [M+1] + .

[0181] 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of (3R,5S)-tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.30 g, 4.86 mmol, 1 equiv.) in dichloromethane (25 mL) was added 30% hydrogen bromide in acetic acid (2 mL, 14.57 mmol, 3 equiv.) in one portion under nitrogen, and the reaction solution was stirred at 15° C. After 12 h, the reaction solution was concentrated to give 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (3.000 g, 6.603 mmol, crude) as a brown solid, which was carried forward without further purification. MS(ESI) m / z 374.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.47(br s,1H),9.56-9.16(m,2H),7.06(t,J=8.1Hz,1H),6.96(s,1H),6.87(br d,J=7.9Hz,1H),6.53-6.46(m,1H),4.46-4.21(m,3H),3.94(br s,2H),3.58(br d,J=13.0Hz,2H),2.81-2.69(m,1H),2.81-2.69(m,1H),2.81-2.69(m,1H),2 .81-2.69(m,1H),2.65-2.54(m,1H),2.14-2.04(m,1H),1.90(s,4H),1.34(br s,6H).

[0182] 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (179.5 mg, 0.40 mmol, 1.3 equiv.) in N,N-dimethylformamide (3.1 mL, 0.1 M) were added 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (150 mg, 0.31 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.27 mL, 1.55 mmol, 5 equiv.), and the reaction solution was heated to 60° C. After 18 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were concentrated, filtered, and purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (113.2 mg, 0.13 mmol, 42% yield) as an off-white solid. MS(ESI) m / z 777.4 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 11.82(br s,1H),10.80(s,1H),10.49(br s,1H),8.14(d,1H,J=8.2Hz),7.93(d,1H,J=1.8Hz),7.61(dd,1H,J=1.8,8.3Hz),7.05(t,1H,J=7.4Hz),7.00(br s,1H),6.87(br d,1H,J=7.7Hz),6.48(dd,1H,J=1.5,8.2Hz),4.28(br dd,1H,J=4.8,11.4Hz),4.18(br s,5H),3.8-3.9(m,3H),3.71(br dd,2H,J=4.2,8.0Hz),3.37(tt,2H,J=3.7,10.8Hz),3.31(br s,2H),2.85(q,2H,J=11.6Hz),2.75(ddd,1H,J=5.2,12.1,17.6Hz),2.60(td,1H,J =4.0,17.5Hz),2.11(td,3H,J=4.2,8.4Hz),1.92(dq,1H,J=4.7,12.1Hz),1.72(br d,2H,J=10.8Hz),1.54(s,6H),1.3-1.4(m,8H).

[0183] Example 5: 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 5-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (6.70 g, 19.51 mmol, 1 equiv.), 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (8.94 g, 39.0 mmol, 2 equiv.), and N,N-diisopropylethylamine (6.8 mL, 39.0 mmol, 2 equiv.) were combined in ethyl acetate (56 mL, 0.35 M) and heated to 90° C. in a sealed tube for 16 hours. The reaction was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10%-100% ethyl acetate in hexanes) to give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.5 g, 6.4743 mmol, 33% yield) as a brown solid. MS (ESI) m / z 541.3 [M+1] + .

[0184] 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.50 g, 6.47 mmol, 1 equivalent) in dichloromethane (30 mL) was added 4 M hydrochloric acid (16.2 mL, 64.7 mmol, 10 equivalents), and the reaction solution was stirred at room temperature. After 3 h, the reaction solution was concentrated to give 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.4 mmol, 99% yield) as a reddish oil. The crude material was carried forward without further purification. MS(ESI) m / z 457.0 [M+1] + .

[0185] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.49 mmol) in dichloromethane (30 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.26 mL, 16.2 mmol, 2.5 equiv.), and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated and the crude material was purified by silica gel column chromatography (5%-80% ethyl acetate in hexanes) to give 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (2.00 g, 3.85 mmol, 59% yield) as a reddish-brown oil. MS(ESI) m / z 519.8[M+1] + .

[0186] 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (200 mg, 0.36 mmol), 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (192 mg, 0.47 mmol, 1.3 equiv), sodium iodide (108 mg, 0.72 mmol, 2 equiv), and N,N-diisopropylethylamine (0.38 mL, 2.16 mmol, 6 equiv) were combined in acetonitrile (1.8 mL, 0.2 M) and heated at 60° C. After 7 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by standard methods. The product fraction was treated with 4 mL of 3 M HCl and evaporated to give 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (90 mg, 0.11 mmol, 31% yield) as a white solid.MS(ESI)m / z 812.0[M+1]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.73-10.84(m,1H),9.15(d,J=1.96Hz,1H),8.75(d,J=1.96Hz,1H),6.94-7.11(m,2H),6.85(br d,J=7.82Hz,1H),6.46(br d,J=8.19Hz,1H),4.27(dd,J=11.31,4.83Hz,1H),3.85(br s,4H),3.47-3.75(m,2H),3.20-3.43(m,4H),2.58-2.95(m,4H),2.03-2.20(m,4H), 1.91(qd,J=12.12,4.71Hz,1H),1.70-1.79(m,2H),1.58(s,6H),1.11-1.48(m,7H).

[0187] Example 6: 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a 2-dram vial containing 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (100 mg, 0.16 mmol, 1 equiv.) and (3R)-3-(3-aminoanilino)piperidine-2,6-dione (46.9 mg, 0.21 mmol, 1.3 equiv.) was added N,N-dimethylformamide (0.55 mL, 0.3 M), and the reaction solution was stirred until all solids were dissolved. 1-Methylimidazole (0.13 mL, 1.65 mmol, 10 equiv.) followed by N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (69.25 mg, 0.2500 mmol, 1.5 equiv.) was added and the reaction solution was stirred at room temperature. After 20 min, the reaction solution was diluted with DMSO to a total volume of 4 mL, filtered, and purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (48 mg, 0.059 mmol, 36% yield) as an off-white solid.MS(ESI)m / z 808.4[M+1]+;1H NMR(500MHz,DMSO-d6)δ 10.77(s,1H),9.41(s,1H),8.33(d,J=8.4Hz,1H),8.19(s,1H),7.97(dd,J=1.2,8.4Hz,1 H),7.06-6.92(m,2H),6.79(d,J=8.0Hz,1H),6.40(d,J=7.6Hz,1H),5.89(d,J=7.6Hz,1H ),4.33-4.22(m,1H),3.83(s,1H),3.29-3.19(m,2H),2.83-2.66(m,5H),2.64-2.55(m,2 H),2.13-2.05(m,2H),1.95-1.67(m,7H),1.55(s,9H),1.30-1.05(m,7H),1.01(s,6H).

[0188] Example 7: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ 6 -sulfanail)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 4-Bromo-3-(pentafluoro-λ 6 -sulfanyl)aniline. 3-(pentafluoro-λ 6 To a solution of N-sulfanyl)aniline (2.0 g, 9.12 mmol, 1 equiv.) in dimethylformamide (15 mL) under a nitrogen atmosphere was added N-bromosuccinimide (1.9 g, 10.95 mmol, 1.2 equiv.) in one portion at 0° C. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give 4-bromo-3-(pentafluoro-λ 6-sulfanyl)aniline (1.7 g, 5.7 mmol, 59% yield). 1 H NMR(CDCl3,400MHz)δ 7.4-7.5(m,1H),7.1-7.2(m,1H),6.6-6.7(m,1H),3.8-4.0(m,2H).

[0189] 4-amino-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. 4-Bromo-3-(pentafluoro-λ)benzonitrile in N-methylpyrrolidinone (30 mL). 6 A 100 mL round-bottom flask containing 4-amino-2-(pentafluoro-λ6-sulfanyl)aniline (1.7 g, 5.7 mmol, 1 equiv.) and copper(I) cyanide (0.61 g, 6.84 mmol, 1.2 equiv.) was heated to 180 °C with stirring. After 4 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl acetate in hexanes on a 50 g column) to give 4-amino-2-(pentafluoro-λ6-sulfanyl)benzonitrile (1.0 g, 4.09 mmol, 72% yield) as a white solid. MS (ESI) m / z 244.8 [M+1] + .

[0190] 4-Isothiocyanato-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. Add thiophosgene (0.94 mL, 12.29 mmol, 1.2 equiv.) in water (10 mL) to a 100 mL round-bottom flask to give an orange solution. Add 4-amino-2-(pentafluoro-λ)benzonitrile in dichloromethane (10 mL). 6 -sulfanyl)benzonitrile (2.5 g, 10.24 mmol, 1 equiv.) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give 4-isothiocyanato-2-(pentafluoro-λ 6-sulfanyl)benzonitrile (1.3 g, 4.54 mmol, 44% yield) as a white solid, which was carried forward without further purification. MS (ESI) m / z 286.9 [M+1] + .

[0191] 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanail)benzonitrile. Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (1.0 g, 2.91 mmol, 1 equiv.) in ethyl acetate (10 mL) was added to 4-isothiocyanato-2-(pentafluoro-λ 6 N,N-sulfanyl)benzonitrile (1.67 g, 5.82 mmol, 1.2 equiv.) and N,N-diisopropylethylamine (1.02 mL, 5.82 mmol, 3 equiv.) were added. The reaction solution was stirred at 80° C. After 18 hours, the reaction solution was concentrated and purified by column chromatography (0-50% ethyl acetate / hexane) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanail)benzonitrile as a white solid. The intermediate solid was suspended in dichloromethane (1.5 mL), followed by the addition of 4 M hydrochloric acid in dioxane (4 mL, 16 mmol, 3 equiv.) and stirring at 25 °C for 12 hours. The reaction solution was concentrated, and the solid was dissolved in dichloromethane and purified by silica gel column chromatography (0-40% ethyl acetate in hexane) to give 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ)-benzonitrile. 6(-sulfanyl)benzonitrile as an off-white solid (0.80 g, 1.33 mmol, 46% yield). MS (ESI) m / z 513.8 [M+1] + .

[0192] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 To a solution of (3-(trans-sulfanail)benzonitrile (1.0 g, 1.95 mmol, 1 equiv.) in dichloromethane (30 mL) were added dimethylformamide (5 mL) and thionyl bromide (1.0 g, 4.87 mmol, 2.5 equiv.) sequentially. The reaction solution was stirred at room temperature overnight. After 16 hours, the reaction solution was diluted with brine (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile (0.59 g, 1.02 mmol, 53% yield) as a light brown solid. MS (ESI) m / z 578.8 [M+1] + .

[0193] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ 6-sulfanail)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride; 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 To a 1-dram vial containing 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.09 g, 0.23 mmol, 1.3 equiv.), and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv.), acetonitrile (2 mL) was added, followed by N,N-diisopropylethylamine (0.21 mL, 1.2 mmol, 6 equiv.). The reaction vial was heated to 60° C. with stirring. After 16 hours, the reaction solution was diluted to a total volume of 3 mL with dimethyl sulfoxide and purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ 6 -sulfanail)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.05 g, 0.06 mmol, 31% yield) as a yellow solid. MS (ESI) m / z 869.2 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 10.7-10.9(m,1H),8.4-8.5(m,1H),8.3-8.4(m,1H),7.9-8.0(m,1H),7.0-7.1(m,1H),7.0-7.0( m,1H),6.8-6.9(m,1H),6.4-6.5(m,1H),4.5-4.6(m,1H),4.2-4.3(m,4H),3.8-3.9(m,4H),3.57 (s,5H),3.4-3.5(m,1H),3.3-3.4(m,2H),2.8-2.9(m,2H),2.7-2.8(m,1H),2.5-2.7(m,1H),2.1 -2.2(m,3H),1.8-2.0(m,1H),1.7-1.8(m,2H),1.5-1.6(m,6H),1.3-1.4(m,2H),1.2-1.3(m,6H).

[0194] Example 8: 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 3-Chloro-5-isothiocyanato-pyridine-2-carbonitrile. To a solution of 5-amino-3-chloro-pyridine-2-carbonitrile (10.00 g, 65.12 mmol, 1 equiv.) in toluene (20 mL) was added thiophosgene (5.96 mL, 78.14 mmol, 1.2 equiv.). The mixture was stirred at 110 °C. After 16 h, the reaction solution was concentrated and purified by silica gel chromatography (20-50% ethyl acetate in petroleum ether) to give 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (8.000 g, 40.89 mmol, 63% yield) as a red solid. MS (ESI) m / z 196.2 [M+1] + .

[0195] 3-Chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile. To a mixture of methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (4.000 g, 20.45 mmol, 1 equiv.) and methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (7.720 g, 22.49 mmol, 1.1 equiv.) in ethyl acetate (100 mL, 0.2 M) was added triethylamine (5.7 mL, 40.89 mmol, 2 equiv.). The reaction solution was stirred at 90 °C. After 6 h, the reaction solution was concentrated and purified by silica gel column chromatography (10-50% ethyl acetate in petroleum ether) to give 3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile (4.000 g, 7.89 mmol, 39% yield) as a yellow solid. MS(ESI) m / z 507.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.92-8.72(m,1H),8.62-8.31(m,1H),4.68-4.50(m,1H),3.91-3.63(m,4H),3.62-3.52(m,3H),3.50- 3.39(m,3H),2.91-2.73(m,3H),2.10-2.03(m,2H),1.75-1.68(m,3H),1.55(s,6H),1.50-1.43(m,4H).

[0196] 3-Chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile. To a solution of 3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile (4.000 g, 7.89 mmol, 1 equiv.) in methanol (30 mL, 0.27 M) was added 2 M aqueous hydrochloric acid (3 mL, 15.78 mmol, 2 equiv.). The reaction solution was stirred at 25 °C. After 2 h, the pH of the mixture was adjusted to 8 by the addition of saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (33-100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.400 g, 0.01 mmol, 69% yield) as a yellow solid. MS (ESI) m / z 423.3 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.59(s,1H),7.43-7.33(m,2H),7.15(br d,J=7.0Hz,1H),6.57(br s,1H),4.40(t,J=6.7Hz,2H),2.98(s,3H),2.70-2.55(m,2H),1.53(s,5H), 1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H).

[0197] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile. To a solution of 3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.150 g, 5.08 mmol, 1 equiv.) in dichloromethane (5 mL, 1 M) and N,N-dimethylformamide (0.50 mL) was added thionyl bromide (0.65 mL, 10.17 mmol, 2 equiv.) at 0° C. The mixture was stirred at 25° C. for 16 hours. The pH of the mixture was adjusted to 8 with saturated sodium carbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (50-100% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (2.3 g, 4.73 mmol, 93% yield) as a red solid. MS (ESI) m / z 485.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.90-8.72(m,1H),8.60-8.44(m,1H),3.93-3.81(m,1H),3.79-3.72(m,2H),3.61-3.53(m,2H),3.34(br s,1H),2.90-2.74(m,2H),2.12-2.02(m,2H),1.76-1.67(m,2H),1.59-1.52(m,6H),1.44-1.28(m,2H).

[0198] 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a mixture of 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (0.120 g, 0.25 mmol, 1 equiv.), 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide hydrobromide (112 mg, 0.25 mmol, 1 equiv.), and sodium iodide (0.004 g, 0.02 mmol, 8 mol%) was added N,N-dimethylformamide (4 mL 0.06 M) and N,N-diisopropylethylamine (0.096 g, 0.74 mmol, 3 equiv.). The mixture was stirred at 60 °C. After 16 h, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.070 g, 0.09 mmol, 36% yield) as a yellow solid. MS(ESI) m / z 778.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.87-10.80(m,1H),10.76-10.46(m,1H),8.87-8.74(m,1H),8.58-8.47(m,1H),7.08-7.03(m,1 H),7.02-6.98(m,1H),6.91-6.86(m,1H),6.52-6.46(m,1H),4.31-4.26(m,2H),4.23-4.13(m,2H ),3.95-3.81(m,6H),3.43-3.26(m,6H),2.94-2.81(m,2H),2.79-2.70(m,1H),2.63-2.56(m,1H) ,2.17-2.06(m,3H),1.97-1.86(m,1H),1.76-1.67(m,2H),1.58-1.53(m,6H),1.43-1.27(m,8H).

[0199] Example 9: 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] trans-N,N-Dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine. To a solution of trans-4-(dibenzylamino)cyclohexanol (60.00 g, 203.1 mmol, 1 equiv.) in xylene (450 mL, 0.45 M) were added 2-(2-bromoethoxy)tetrahydro-2H-pyran (113.28 g, 507.75 mmol, 2.5 equiv.), tetra-N-butylammonium bromide (13.09 g, 40.62 mmol, 0.2 equiv.), and potassium hydroxide (52.42 g, 934.26 mmol, 4.6 equiv.), and the reaction solution was stirred at room temperature. After 24 hours, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (100% petroleum ether) to give trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (40.0 g, 91.4 mmol, 45% yield) as a pale yellow oil. MS (ESI) m / z 438.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.38-7.32(m,4H),7.31-7.28(m,4H),7.24-7.22(m,2H),4.61-4.57( m,1H),3.88-3.84(m,2H),3.63(s,4H),3.55-3.52(m,4H),3.51-3.16( m,1H),2.54-2.09(m,1H),2.08-2.07(m,2H),1.92-1.90(m,2H),1.61 -1.60(m,2H),1.59-1.57(m,6H),1.55-1.53(m,2H),1.38-1.16(m,2H)

[0200] trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine. To a solution of trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (20.0 g, 45.7 mmol, 1 equiv) in methanol (100 mL) was added 10% palladium on carbon (10.0 g, 9.39 mmol). The reaction flask was evacuated and purged with hydrogen gas three times and then stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 h, the reaction solution was filtered and the filtrate was concentrated to give trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (11.00 g, 42.74 mmol, 94% yield) as a pale yellow oil. The material was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.52(m,1H),3.79-3.61(m,2H),3.50-3.30(m,4H),3.18-3.05(m,1H),1.94-1.83( m,2H),1.77-1.65(m,6H),1.64-1.55(m,1H),1.53-1.38(m,4H),1.20-0.91(m,4H).

[0201] Methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate. To a solution of trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (7.00 g, 27.2 mmol, 1 equiv.) and methyl 2-bromo-2-methyl-propanoate (12.5 mL, 108.79 mmol, 4 equiv.) in acetonitrile (10 mL) was added potassium iodide (0.451 g, 2.72 mmol, 0.1 equiv.) and potassium carbonate (7.518 g, 54.4 mmol, 2 equiv.). The reaction vessel was sealed and heated to 110° C. with stirring. After 12 h, the reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (10-80% ethyl acetate in petroleum ether) to give methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (8.00 g, 22.4 mmol, 82% yield) as a pale yellow oil. MS(ESI) m / z 358.4 [M+1] + .

[0202] 2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (10.0 g, 28.0 mmol, 1 equiv.) in ethyl acetate (100 mL, 0.28 M) were added 2-chloro-4-isothiocyanatobenzonitrile (10.9 g, 56.0 mmol, 2 equiv.) and triethylamine (7.8 mL, 56.0 mmol, 2 equiv.), and the reaction solution was stirred at 80° C. After 8 hours, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (9-20% ethyl acetate in petroleum ether) to give 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (8.50 g, 16.3 mmol, 58% yield) as a red oil. MS (ESI) m / z 542.2 [M+23] + .

[0203] 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (6.80 g, 13.1 mmol) in methanol (50 mL) was added 1 M hydrochloric acid (5 mL, 13.07 mmol), and the reaction solution was stirred at 25 °C. After 2 hours, the reaction solution was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (petroleum ether 20-70% ethyl acetate) to give 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.60 g, 12.8 mmol, 98% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.12(d,J=8.4Hz,1H),7.92(d,J=1.6Hz,1H),7.61(dd,J=2.0,8.4Hz,1H),3.89-3.76(m,1H),3.48-3.42(m,4H),3.24-3.16(m, 1H),2.79(d,J=11.2Hz,2H),2.04(d,J=10.8Hz,2H),1.70(d,J=10.8Hz,2H),1.65-1.59(m,2H),1.53(s,6H),1.34-1.25(m,2H).

[0204] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.8 g, 13.3 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (2.1 mL, 26.6 mmol, 2 equiv.) at 0° C. After 8 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0–35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (4.8 g, 9.6 mmol, 72% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.14-8.11(m,1H),7.93(d,J=1.6Hz,1H),7.61(dd,J=1.6,8.0Hz,1H),3.84(s,1H),3.58-3.51(m,4H),3.27-3 .21(m,1H),2.81(d,J=11.6Hz,2H),2.06(m,2H),1.71(d,J=11.6Hz,2H),1.53(s,6H),1.33(d,J=13.2Hz,2H).

[0205] 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (0.150 g, 0.300 mmol, 1 equiv.) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.168 g, 0.450 mmol, 1.5 equiv.) was added N,N-diisopropylethylamine (0.16 mL, 0.900 mmol, 3 equiv.). The reaction mixture was stirred at 50° C. After 12 h, the reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.087 g, 0.110 mmol, 37% yield) as a yellow solid. MS (ESI) m / z 791.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.13(d,J=8.4Hz,1H),7.93(d,J=1.9Hz,1H),7.61(dd,J=1.8,8.3Hz,1H),7.09- 7.02(m,1H),6.99(s,1H),6.86(d,J=7.3Hz,1H),6.48(d,J=7.9Hz,1H),4.28(dd,J=4.8,11.3H z,2H),4.19-4.06(m,2H),3.98-3.63(m,4H),3.52(t,J=5.8Hz,2H),3.30-3.23(m,2H),3.12(s ,2H),2.87-2.60(m,4H),2.13-1.91(m,6H),1.75-1.68(m,2H),1.53(s,6H),1.42-1.26(m,8H).

[0206] Example 10: 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 5-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.00 g, 14.0 mmol, 1 equivalent) and 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (6.41 g, 28.0 mmol, 2 equivalents) in ethyl acetate (50 mL, 0.28 M) was added N,N-diisopropylethylamine (4.62 mL, 28.0 mmol, 2 equivalents), and the reaction solution was stirred at 90 °C. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (10–50% ethyl acetate in petroleum ether) to give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 90% yield) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 8.95(s,1H),8.23(s,1H),4.55-4.51(m,1H),3.81-3.78(m,2H),3.70-3.68(m,1H),3.57-3.54(m,2H),3.48-3.45(m, 2H),3.29-2.87(m,1H),2.85(d,J=10.8Hz,2H),1.85-1.80(m,8H),1.60(s,6H),1.56-1.52(m,4H),1.32-1.29(m,2H).

[0207] 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 1 equiv.) in methanol (50 mL) was added 1 M hydrogen chloride (5.0 mL, 5 mmol), and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 84% yield) as a brown oil. MS (ESI) m / z 471.2 [M+1] + .

[0208] 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 1 equiv.) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3 mmol, 2 equiv.) at 0° C. After stirring for 12 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. (ESI) m / z 535.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.98(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),3.76-3.65(m,1H),3.62(t,J=5.6Hz,2H),3.53(t,J=6.4Hz,2H),3.40-3. 29(m,1H),2.89(s,2H),2.30-2.18(m,2H),2.16-2.05(m,2H),1.83(d,J=12.4Hz,2H),1.63(s,6H),1.45-1.24(m,2H).

[0209] 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.150 g, 0.280 mmol, 1 equiv.) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (0.128 g, 0.280 mmol, 1 equiv.) in N,N-dimethylformamide (4 mL, 0.07 M) was added N,N-diisopropylethylamine (0.24 mL, 1.41 mmol, 5 equiv.) and sodium iodide (0.008 g, 0.060 mmol, 2 equiv.) in one portion under nitrogen. The mixture was stirred at 60° C. After 16 hours, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.089 g, 0.107 mmol, 38% yield) as a yellow solid. MS(ESI)m / z 826.4[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 12.76-11.23(m,1H),12.31-11.21(m,1H),10.80(s,1H),10.54(br s,1H),9.14(d,J=1.7Hz,1H),8.74(d,J=2.0Hz,1H),7.08-7.02(m,1H),6.99(br s,1H),6.86(br d,J=7.9Hz,1H),6.50-6.44(m,1H),4.27(br dd,J=4.8,11.4Hz,3H),4.16(br s,3H),3.92-3.69(m,3H),3.51(br t,J=5.8Hz,2H),3.26(br t,J=10.6Hz,2H),3.18-3.05(m,1H),3.12(br s,1H),2.90-2.76(m,1H),2.90-2.76(m,1H),2.90-2.76(m,1H),2.76-2.6 8(m,1H),2.64-2.55(m,1H),2.14-2.03(m,3H),2.02-1.85(m,3H),1.72(br d,J=10.3Hz,2H),1.57(s,6H),1.44-1.26(m,8H).

[0210] Example 11: 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.47 g, 5.71 mmol, 1 equiv.) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (1.44 g, 6.28 mmol, 1.1 equiv.) in ethyl acetate (15 mL, 0.38 M) was added N,N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 equiv.), and the reaction solution was stirred at 80 °C. After 16 h, the reaction solution was concentrated under reduced pressure and the crude material was purified by standard methods to give 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 69% yield) as a brown solid. MS(ESI) m / z 455.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.72(m,1H),3.65(t,J=6.4Hz,2H),2.72-2.70(m,2H),1 .97-1.94(m,2H),1.85-1.82(m,2H),1.63(s,6H),1.58-1.54(m,1H),1.42-1.29(m,4H),1.12-1.02(m,2H).

[0211] 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 1 equiv.) in dichloromethane (18 mL, 0.22 M) and N,N-dimethylformamide (1.8 mL) was added thionyl bromide (1.650 g, 7.92 mmol, 2 equiv.) slowly at 0° C. The reaction solution was stirred at 0° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with dichloromethane (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (5-80% ethyl acetate in hexanes) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.75 g, 3.38 mmol, 85% yield) as a brown solid. MS (ESI) m / z 516.9 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.71(m,1H),3.42(t,J=6.8Hz,2H),2 .74-2.72(m,2H),1.96-1.79(m,6H),1.63(s,6H),1.40-1.33(m,3H),1.13-1.04(m,2H).

[0212] 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.120 g, 0.232 mmol, 1 equiv.) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (0.158 g, 0.350 mmol, 1.5 equiv.) in N,N-dimethylformamide (1 mL, 0.23 M) was added N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 5 equiv.) in one portion under nitrogen. The mixture was stirred at 50 °C. After 12 hours, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.129 g, 0.157 mmol, 68% yield) as a yellow solid. MS (ESI) m / z 810.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 12.08(br s,1H),10.80(s,1H),10.64(br s,1H),9.15(d,J=1.9Hz,1H),8.75(d,J=2.0Hz,1H),7.12-6.96(m,2H),6.88(br d,J=7.9Hz,1H),6.53-6.44(m,1H),6.53-6.44(m,1H),4.32-4.11(m,5H),3.92-3.70(m,3H),3.29(br s,2H),3.06(br s,2H),2.74(ddd,J=5.1,12.0,17.4Hz,3H),2.64-2.55(m,1H),2.09(td,J= 4.1,8.5Hz,1H),1.98-1.88(m,1H),1.87-1.70(m,6H),1.57(s,6H),1.38(br d,J=3.0Hz,6H),1.21(br d,J=7.1Hz,4H),1.16-1.06(m,1H),1.16-1.06(m,1H).

[0213] Example 12: 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 4-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.0 g, 14.0 mmol, 1 equivalent) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (6.4 g, 28.0 mmol, 2 equivalents) in ethyl acetate (50 mL) was added N,N-diisopropylethylamine (4.6 mL, 28.0 mmol, 2 equivalents), and the reaction solution was stirred at 90 °C. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (10-50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol, 84% yield) as a brown oil. MS(ESI) m / z 554.4 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1H),4.60-4.58(m ,1H),3.84-3.82(m,2H),3.71-3.61(m,1H),3.60-3.52(m,2H),3.50-3.49(m, 2H),3.47-3.32(m,1H),2.22-2.20(m,2H),2.19(d,J=12.0Hz,2H),1.88-1.87 (m,6H),1.85-1.84(m,2H),1.60(s,6H),1.56-1.55(m,2H),1.54-1.35(m,2H).

[0214] 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol) in methanol (50 mL) was added 1 M hydrochloric acid (5.0 mL, 5 mmol), and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 91% yield) as a brown oil. MS(ESI) m / z 470.2 [M+1] + .

[0215] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 1 equiv.) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3 mmol, 4 equiv.) at 0° C., and the reaction solution was allowed to warm gradually to room temperature. After 12 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 9.4 mmol, 88% yield) as a pale yellow oil. MS (ESI) m / z 534.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1H),3.71-3.61(m,1H),3.60-3.53(m,2H),3.52(t,J=6.4 Hz,2H),3.35-3.32(m,1H),2.21(d,J=12.0Hz,2H),2.19-2.05(m,2H),1.83(d,J=12.0Hz,2H),1.65(s,2H),1.60(s,6H),1.35-1.32(m,2H).

[0216] 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.280 mmol, 1 equiv.) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.158 g, 0.420 mmol, 1.5 equiv.) in N,N-dimethylformamide (3 mL, 0.01 M) was added N,N-diisopropylethylamine (0.15 mL, 0.85 mmol, 3 equiv.). The reaction mixture was stirred at 50° C. After 12 hours, the reaction solution was diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.058 g, 0.069 mmol, 25% yield) as a yellow solid. MS (ESI) m / z 825.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.34(d,J=8.3Hz,1H),8.19(d,J=1.4Hz,1H),7.97(dd,J=1.6,8.3Hz,1H ),7.12-6.94(m,2H),6.87(d,J=6.3Hz,1H),6.48(d,J=5.3Hz,1H),4.37-4.24(m,4H), 3.96-3.61(m,4H),3.51(t,J=5.7Hz,2H),3.26(t,J=10.6Hz,2H),3.12(s,2H),2.84-2 .56(m,4H),2.09-1.84(m,6H),1.72(d,J=10.6Hz,2H),1.55(s,6H),1.41-1.23(m,8H).

[0217] Example 13: 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 3-Chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile. To a mixture of methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (1.600 g, 8.18 mmol, 1 equiv.) and methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (2.320 g, 9 mmol, 1.1 equiv.) in ethyl acetate (100 mL) was added triethylamine (2.28 mL, 16.36 mmol, 2 equiv.), and the reaction solution was stirred at 90° C. After 6 h, the reaction solution was concentrated and purified by silica gel column chromatography (10-100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.000 g, 4.75 mmol, 58% yield) as a yellow solid. MS(ESI) m / z 421.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.67-8.50(m,1H),7.98-7.83(m,1H),3.80-3.48(m,4H),2.75-2.52(m,2H), 1.93-1.60(m,6H),1.51-1.28(m,3H),1.27-1.15(m,5H),1.06-0.89(m,3H).

[0218] 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile. To a solution of 3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.000 g, 4.75 mmol, 1 equiv.) in dichloromethane (5 mL, 0.1 M) and N,N-dimethylformamide (0.50 mL) was added thionyl bromide (0.61 mL, 9.5 mmol, 2 equiv.) at 0°C. The reaction solution was stirred at 25°C. After 16 h, the pH of the reaction solution was adjusted to 8 by the addition of saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (50-100% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (1.600 g, 3.31 mmol, 70% yield) as a red solid. MS (ESI) m / z 483.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.73-8.50(m,1H),7.98-7.82(m,1H),3.78-3.65(m,1H),3.37-3.29(m ,2H),2.77-2.49(m,2H),1.93-1.80(m,4H),1.57-1.52(m,6H),1.30(br t,J=5.6Hz,3H),1.08-0.97(m,2H).

[0219] 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (0.100 g, 0.210 mmol, 1 equiv.) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (0.141 g, 0.310 mmol, 1.5 equiv.) in N,N-dimethylformamide (3 mL, 0.07 M) was added N,N-diisopropylethylamine (0.18 mL, 1.03 mmol, 5 equiv.) in one portion under nitrogen. The mixture was stirred at 50 °C. After 12 hours, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.073 g, 0.094 mmol, 45% yield) as a yellow solid. MS (ESI) m / z 776.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 12.24-11.28(m,1H),10.79(s,1H),10.43(br s,1H),8.82(d,J=2.0Hz,1H),8.53(d,J=2.0Hz,1H),7.08-7.01(m,1H),7.08-7.01(m,1H),7.08-7.01(m,1H),6.98(s,1H),6.85(br d,J=7.9Hz,1H),6.47(br d,J=9.8Hz,1H),4.27(br dd,J=4.8,11.3Hz,1H),4.23-4.14(m,2H),3.75(br s,6H),3.21(br s,2H),3.05(br s,2H),2.74(ddd,J=5.3,12.0,17.4Hz,3H),2.64-2.55(m,1H),2.09(td,J=4.3,8.7Hz,1H),1.97-1.66(m,7H),1.55(s,6H),1.34(br s,6H),1.22(br s,3H),1.09(q,J=11.0Hz,2H).

[0220] Example 14: 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 2-Chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.31 g, 5.1 mmol, 1 equiv.) and 2-chloro-4-isothiocyanatobenzonitrile (1.08 g, 5.57 mmol, 1.1 equiv.) in ethyl acetate (25 mL) was added N,N-diisopropylethylamine (2.51 mL, 15.18 mmol, 3 equiv.), and the reaction mixture was stirred at 80° C. After 18 h, the reaction solution was concentrated and purified by column chromatography (15-50% ethyl acetate in petroleum ether) to give 2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.26 g, 3.01 mmol, 59% yield) as a brown oil. MS(ESI) m / z 420.1 [M+1] + .

[0221] 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.26 g, 3.01 mmol) in N,N-dimethylformamide (0.30 mL) and dichloromethane (3 mL) was added thionyl bromide (1.88 g, 9.03 mmol, 3 equiv.) slowly at 0 °C. After 12 h, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (15–30% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (1.21 g, 2.50 mmol, 83% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.4Hz,1H),7.58(d,J=2.0Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),3.87(m,1H),3.43(t,J =6.8Hz,2H),2.70(s,2H),1.94-1.82(m,6H),1.59(s,6H),1.39-1.36(m,3H),1.12-1.03(m,2H).

[0222] 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (0.100 g, 0.210 mmol) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (0.141 g, 0.310 mmol, 1.5 equiv.) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.04 mmol, 5 equiv.) in one portion under nitrogen. The mixture was stirred at 50° C. for 6 hours. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by standard methods to give 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.083 g, 0.106 mmol, 51% yield) as a yellow solid. MS (ESI) m / z 775.6 [M+1]+ ; 1 H NMR(400MHz,DMSO-d6)δ 12.30-11.70(m,1H),10.80(s,1H),10.59(br s,1H),8.13(d,J=8.3Hz,1H),7.92(d,J=1.8Hz,1H),7.61(dd,J=1.9,8.4Hz,1H),7.09-7.02(m,1H),7.00(s,1H),6.87(br d,J=7.7Hz,1H),6.48(dd,J=1.5,8.2Hz,1H),4.28(br dd,J=4.8,11.3Hz,1H),4.01-3.58(m,7H),3.27(br s,2H),3.05(br s,2H),2.84-2.65(m,3H),2.64-2.55(m,1H),2.09(td,J=4.3,8.7Hz,1H),1.97-1.88(m,1H),1.87-1.67(m,6H),1.53(s,6H),1.37(br d,J=4.4Hz,6H),1.22(br s,3H),1.15-1.02(m,2H).

[0223] Example 15: 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one. To a solution of 3-oxopentanedioic acid (100.0 g, 684.5 mmol, 1 equiv.) in water (200 mL) was added acetaldehyde (150.8 g, 1368.9 mmol, 2 equiv.) at 20 °C. The reaction was stirred at 20 °C for 20 minutes, then cooled to 0 °C, and phenylmethanamine (74.61 mL, 684.5 mmol, 1 equiv.) was added dropwise. The reaction solution was allowed to warm to room temperature and stirred for 48 hours. The reaction solution was extracted with 3000 mL of ethyl acetate (1000 mL × 3), and the combined organic layer was washed with 500 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (27.70 g, 127.5 mmol, 19% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.42(d,J=7.2Hz,2H),7.37-7.29(m,2H),7.27-7.20(m,1H),3.86(s,2H),3 .17-3.09(qd,J=6.4,13.2Hz,2H),2.42-2.28(m,4H),1.16(d,J=6.4Hz,6H).

[0224] Ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate. To a solution of sodium hydride (8.283 g, 207.1 mmol, 1.5 equiv.) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (40.23 g, 179.5 mmol, 1.3 equiv.) in THF (100 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 minutes. (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (30.00 g, 138.1 mmol, 1 equiv.) in THF (200 mL) was added dropwise to the above solution, and the reaction solution was allowed to warm to room temperature. After 12 hours, the reaction solution was neutralized by the addition of saturated ammonium chloride solution and poured into ice water (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel chromatography (2.0% ethyl acetate in petroleum ether) (petroleum ether:ethyl acetate = 3:1, Rf: 0.65) and then repurified by semi-preparative reverse-phase HPLC (55-85% acetonitrile in water + 0.05% ammonium hydroxide, over 20 min). The collected fractions were concentrated, and the aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate (11.7 g, 40.7 mmol, 30% yield) as a yellow oil. MS(ESI)m / z 288.2[M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.45-7.35(m,2H),7.30(t,J=7.6Hz,2H),7.26-7.16(m,1H),5.63(s,1H),4.15(q,J=7.2Hz,2H),3.82(s,2H),3.5 7(dd,J=2.8,14.0Hz,1H),2.84-2.62(m,2H),2.29-2.08(m,3H),1.33-1.23(m,3H),1.14(dd,J=6.4,16.4Hz,6H).

[0225] tert-Butyl (2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate (5.300 g, 18.44 mmol, 1 equiv.) and di-tert-butyl dicarbonate (6.037 g, 27.66 mmol, 1.5 equiv.) in THF (80 mL, 0.23 M) was added 10% palladium on carbon (1.500 g, 1.84 mmol, 10 mol%) under nitrogen. The reaction mixture was stirred at room temperature under hydrogen (50 psi) for 12 hours. The reaction mixture was filtered and concentrated to give a residue, which was purified by flash silica gel chromatography (1% ethyl acetate in petroleum ether, petroleum ether:ethyl acetate=5:1) to give tert-butyl (2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.630 g, 8.784 mmol, 48% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.26(s,1H),4.21(m,1H),4.17-4.10(m,2H),2.26-2.18(m,2H),2.13-2.05(m,1H),1.99-1.84(m,1H),1. 66-1.55(m,1H),1.47(s,9H),1.36-1.29(m,1H),1.29-1.25(m,3H),1.24-1.19(m,6H),1.15-1.02(m,2H).

[0226] tert-Butyl (2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate. A solution of tert-butyl (2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.630 g, 8.780 mmol, 1 equiv.) in THF (40 mL) was added to a solution of lithium aluminum hydride (0.500 g, 13.18 mmol, 1.5 equiv.) in THF (10 mL) at 0 °C. The reaction solution was slowly warmed to room temperature over 1 hour. The reaction solution was quenched by the addition of 0.5 mL of water, 1 mL of 15% sodium hydroxide solution, and 1.5 mL of water. The slurry was stirred for 0.5 hours, filtered, and concentrated in vacuo. The crude material was diluted with 100 mL of water and extracted with 100 mL of ethyl acetate three times. The combined organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give tert-butyl (2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 96% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 4.40-4.25(m,1H),4.24-4.07(m,1H),3.77-3.65(m,2H),2.12-2.03(m,1H),1.68-1.56(m,2 H),1.55-1.49(m,2H),1.49-1.42(m,9H),1.33-1.26(m,1H),1.25-1.17(m,6H),1.05(m,1H).

[0227] tert-Butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate. tert-Butyl (2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 1 equiv.) and triphenylphosphine (3.332 g, 12.71 mmol, 1.5 equiv.) in dichloromethane (40 mL, 0.21 M). Carbon tetrabromide (4.214 g, 12.71 mmol, 1.5 equiv.) was added to the reaction solution at 0 °C. The reaction mixture was allowed to warm slowly to room temperature. After 2 h, the reaction solution was poured into saturated sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to give tert-butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.160 g, 6.744 mmol, 80% yield) as a clear, colorless oil. 1 H NMR(400MHz,CDCl3)δ 4.45-4.27(m,1H),4.26-4.06(m,1H),3.51-3.29(m,2H),2.18-1.96(m,2H),1.89-1.75(m,2H), 1.73-1.53(m,2H),1.48-1.39(m,9H),1.33-1.25(m,1H),1.24-1.19(m,6H),1.13-0.97(m,1H).

[0228] tert-Butyl (2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of trans-4-(dibenzylamino)cyclohexanol (12.18 g, 41.22 mmol, 2 equiv) and tert-butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (6.600 g, 20.61 mmol, 1 equiv) in xylenes (120 mL, 0.17 M) was added potassium hydroxide (5.318 g, 94.80 mmol, 4.6 equiv) and tetrabutylammonium bromide (1.328 g, 4.120 mmol, 0.2 equiv). The reaction was stirred at 30 °C. After 24 hours, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (3 × 250 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel column chromatography (2.5-3% ethyl acetate in petroleum ether) to give tert-butyl (2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 5.236 mmol, 25% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.42-7.33(m,4H),7.33-7.27(m,4H),7.24-7.17(m,2H),4.36-4.23(m,2H),4.22-4.15(m,1H),3 .62(s,4H),3.48(t,J=6.4Hz,1H),3.45-3.37(m,1H),3.19-3.06(m,1H),2.53(m,1H),2.09-2.04( m,3H),2.01-1.86(m,3H),1.63-1.59(m,1H),1.57-1.51(m,2H),1.47-1.46(m,9H),1.43-1.33(m, 2H),1.28-1.24(m,2H),1.21(s,2H),1.17(d,J=7.0Hz,6H),1.14-1.08(m,1H),1.07-0.92(m,1H).

[0229] tert-Butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 5.240 mmol, 1 equiv) in methanol (60 mL) was added palladium on carbon (2.000 g) under nitrogen. The reaction was stirred at room temperature under hydrogen (15 psi) for 12 hours. The reaction mixture was filtered and concentrated to give tert-butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 98% yield) as a yellow oil, which was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.23-4.08(m,2H),4.08-3.93(m,1H),3.50-3.40(m,2H),3.40-3.33(m,1H),3.18-3.04(m,1H),2.55-2.51(m,2H),2.49(br s,1H),2.05-1.83(m,4H),1.82-1.68(m,2H),1.67-1.47(m,2H),1.46- 1.32(m,16H),1.29-1.15(m,2H),1.15-1.07(m,9H),1.07-0.87(m,3H).

[0230] tert-Butyl (2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 1 equiv) in acetonitrile (10 mL, 0.5 M) was added potassium iodide (0.086 g, 0.520 mmol, 10 mol%), potassium carbonate (2.148 g, 15.54 mmol, 3 equiv), and methyl 2-bromo-2-methylpropanoate (3.75 mL, 25.91 mmol, 5 equiv). The reaction was stirred at 110° C. After 48 h, the reaction solution was filtered and concentrated to give tert-butyl (2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 5.279 mmol, crude) as a yellow oil, which was carried forward without further purification. MS(ESI) m / z 455.5 [M+1] + .

[0231] tert-Butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate and tert-butyl (2R,4r,6S)-4-(2-(((1r,4R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.160 g, 4.750 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.084 g, 4.750 mmol, 1 equiv.) in ethyl acetate (10 mL, 0.47 M) was added N,N-diisopropylethylamine (1.660 mL, 9.500 mmol, 2 equiv.). The reaction was stirred at 90° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.The crude material was purified by flash silica gel column chromatography to give a mixture of diastereomers, which was separated by SFC (DAICEL CHIRAL PAK IG: 250 mm × 30 mm, 10 μm, 20% methanol + 0.1% NH H O) to give tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1. This gave tert-butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.553 mmol, 12% yield). tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1H NMR(400MHz,CDCl3)δ 7.95(d,J=8.0Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.0Hz,1H),4.38-4.22(m,2H ),3.72-3.59(m,1H),3.54(t,J=6.4Hz,2H),3.37-3.24(m,1H),3.03-2.75(m,2H),2.21(br d, J = 12.4 Hz, 2H), 2.03-1.90 (m, 1H), 1.89-1.77 (m, 2H), 1.61 (s, 6H), 1.58 (m, 2H), 1.54-1.48 (m, 2H), 1.47 (s, 9H), 1.40-1.26 (m, 4H), 1.19 (d, J = 7.2 Hz, 6H). tert-Butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1 H NMR(400MHz,CDCl3)δ 7.95(d,J=8.4Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),4.28-4.10(m ,2H),3.76-3.58(m,1H),3.49(t,J=6.0Hz,2H),3.30(m,1H),3.03-2.76(m,2H),2.19(br d,J=12.0Hz,2H),2.12-1.98(m,2H),1.89-1.76(m,2H),1.61(s,6H),1.52(br t,J=6.4Hz,2H),1.47(s,9H),1.40-1.25(m,3H),1.22(d,J=6.8Hz,6H),1.03(m,2H).

[0232] 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.060 g, 1.630 mmol, 1 equiv.) in dichloromethane (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (20 mL, 80.00 mmol), and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated. The resulting yellow solid was taken up in saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.920 g, 1.67 mmol, 99% yield) as a yellow solid, which was carried forward without further purification. MS(ESI) m / z 551.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.95(d,J=8.0Hz,1H),7.84(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.0Hz,1H),3 .74-3.59(m,1H),3.51(t,J=6.8Hz,2H),3.31(m,1H),2.92(m,4H),2.20(br d,J=12.0Hz,2H),2.02-1.92(m,1H),1.82(br d,J=12.0Hz,2H),1.70(q,J=6.8Hz,2H),1.64-1.56(s,6H),1.51(br d,J=12.8Hz,2H),1.40-1.27(m,4H),1.09(br d,J=6.0Hz,6H).

[0233] 2-Chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To a solution of 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (1.000 g, 3.870 mmol, 1 equiv.) in dichloromethane (20 mL, 0.2 M) was added triethylamine (1.62 mL, 11.62 mmol, 3 equiv.) and 2-chloroacetyl chloride (0.46 mL, 5.810 mmol, 1.5 equiv.) in one portion at 0° C. under nitrogen. After 2 hours, the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (4×40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel column chromatography (0-100% ethyl acetate in dichloromethane) to give 2-chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.750 g, 2.240 mmol, 58% yield) as a gray solid. MS (ESI) m / z 335.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.91(s,1H),10.27(s,1H),7.65(d,J=7.6Hz,1H),7.18-7.08(m,2H),4.39(s,2H), 4.21(m,1H),4.06(s,3H),2.71-2.61(m,2H),2.43-2.32(m,1H),2.21-2.14(m,1H).

[0234] 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(2-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.100 g, 0.180 mmol, 1 equiv.) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.081 g, 0.270 mmol, 1.5 equiv.) in N,N-dimethylformamide (2 mL, 0.1 M) was added N,N-diisopropylethylamine (0.16 mL, 0.910 mmol, 5 equiv.) and sodium iodide (0.027 g, 0.180 mmol, 1 equiv.). The reaction was stirred at 80° C. After 13 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.081 g, 0.099 mmol, 55% yield) as a yellow solid. MS (ESI) m / z 810.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.91(s,1H),10.80(d,J=4.0Hz,1H),10.60(s,1H),10.17-9.89(m,1H),9.04(br s,1H),8.33(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.96(dd,J=1.6,8.0Hz,1H),7.12-6.95(m,2H) ,6.86(t,J=6.8Hz,1H),6.56-6.39(m,1H),4.27(dd,J=5.2,11.6Hz,1H),4.23-4.18(m,1H),4.15(br d,J=3.6Hz,1H),3.81-3.68(m,3H),3.62-3.54(m,1H),3.48(br t,J=6.0Hz,2H),3.22(m,1H),2.94-2.75(m,2H),2.75-2.68(m,1H),2.65-2.54(m,1H),2.15-2.01(m,3H),2.01-1 .84(m,3H),1.79-1.60(m,6H),1.54(d,J=1.2Hz,6H),1.39-1.33(m,3H),1.33-1.23(m,2H),1.19(d,J=6.4Hz,3H).

[0235] Example 16: 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.550 mmol, 1 equiv.) in dichloromethane (3 mL, 0.12 M) was added 4 M hydrochloric acid in 1,4-dioxane (12 mL, 48 mmol), and the reaction solution was stirred at 15 °C. After 14 h, the reaction solution was concentrated. The resulting solid was diluted with saturated bicarbonate solution (20 mL) to pH 8-9, and the aqueous solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.330 g, 0.56 mmol) as a yellow solid, which was carried forward without further purification. MS(ESI) m / z 551.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),3.73-3.59 (m,1H),3.52(t,J=6.4Hz,2H),3.30(m,1H),3.03-2.80(m,2H),2.74(m,2H),2.20(br d,J=12.4Hz,2H),1.82(br d,J=11.6Hz,2H),1.68(br d,J=13.2Hz,2H),1.61(s,6H),1.54-1.48(m,2H),1.41-1.27(m,3H),1.14(br d,J=6.4Hz,6H),0.92-0.76(m,2H).

[0236] 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.060 g, 0.110 mmol, 1 equiv.) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.048 g, 0.160 mmol, 1.5 equiv.) in N,N-dimethylformamide (1 mL, 0.11 M) was added N,N-diisopropylethylamine (0.09 mL, 0.540 mmol, 5 equiv.) and sodium iodide (0.016 g, 0.110 mmol, 1 equiv.). The reaction was stirred at 80° C. After 12 h, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.041 g, 0.0498 mmol, 46% yield). MS (ESI) m / z 810.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),10.67-10.31(m,1H),9.67-9.38(m,1H),9.06(br s,1H),8.33(d,J=8.4Hz,1H),8.18(s,1H),7.96(dd,J=1.6,8.4Hz,1H),7.10-7.00(m,1H),6.99-6.89(m,1H),6.83(br d,J=8.0Hz,1H),6.47(m,1H),4.30-4.22(m,1H),4.21-4.15(m,1H),4.0 9-4.02(m,1H),3.90-3.79(m,2H),3.53-3.42(m,4H),3.28-3.17(m,1H) ,2.90-2.68(m,3H),2.65-2.56(m,1H),2.15-2.00(m,3H),1.99-1.79(m ,3H),1.78-1.64(m,3H),1.58-1.50(m,6H),1.49-1.36(m,3H),1.34(br d,J=5.2Hz,3H),1.30-1.22(m,1H),1.20(d,J=6.4Hz,3H),1.15-1.06(m,1H).

[0237] Example 17: 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] tert-Butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate. To a solution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (2.000 g, 7.770 mmol, 1 equiv.) and N,O-dimethylhydroxylamine hydrochloride (0.830 g, 8.550 mmol, 1.1 equiv.) in N,N-dimethylformamide (20 mL, 0.38 M) was added N,N-diisopropylethylamine (6.94 mL, 38.86 mmol) and HATU (4.430 g, 11.66 mmol, 5 equiv.), and the reaction mixture was stirred at room temperature. After 12 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to give tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.200 g, 7.323 mmol, 94% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 4.41(s,1H),3.66(s,3H),3.37(s,1H),3.17(s,3H),2.31-2.29(d,J=6.4Hz ,2H),2.04-1.97(m,2H),1.85-1.79(m,3H),1.43(s,9H),1.18-1.02(m,4H).

[0238] tert-Butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate. To a solution of tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.2 g, 7.320 mmol, 1 equiv.) in dichloromethane (10 mL) was added a 70% toluene solution of bis(2-methoxyethoxy)aluminum hydride (4.08 mL, 14.65 mmol, 2 equiv.) at 0°C. After stirring for 2 hours, the reaction solution was diluted with water (20 mL) and saturated aqueous ammonium chloride solution (10 mL). The solution was extracted with dichloromethane (3 × 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude oil was purified by silica gel column chromatography (0-25% ethyl acetate in petroleum ether) to give tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.008 mmol, 82% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 9.65-9.64(t,J=2.0Hz,1H),6.69-6.64(m,1H),3.19-3.13(m,1H),2.55-2.52(m,1H),2 .29-2.27(m,2H),1.75-1.64(m,5H),1.36(s,9H),1.17-1.08(m,2H),1.06-0.83(m,2H).

[0239] Ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate. To a solution of tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.010 mmol, 1 equiv) in toluene (10 mL, 0.6 M) was added ethyl 2-(triphenylphosphoranylidene)acetate (2.300 g, 6.610 mmol, 1.1 equiv), and the reaction mixture was stirred at 80 °C. After 12 h, the reaction solution was concentrated and the resulting crude material was purified by silica gel column chromatography (0-20% ethyl acetate in hexanes) to give ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.858 mmol, 48% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 6.95-6.88(m,1H),5.82-5.78(m,1H),4.36(s,1H),4.24-4.14(m,2H),3.37(s,1H),2.12-2.08(m,2H),2 .05-1.99(m,2H),1.79-1.76(m,2H),1.46-1.36(m,10H),1.31-1.27(t,J=7.2Hz,3H),1.13-0.99(m,4H).

[0240] tert-Butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate. To a solution of sodium borohydride (0.811 g, 21.43 mmol, 7.5 equiv.) in ethanol (16 mL) and THF (16 mL) was added anhydrous lithium chloride (0.900 g, 21.43 mmol, 7.5 equiv.) at 0 °C, and the solution was stirred for 10 min. To the reaction solution was added a solution of ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.860 mmol, 1 equiv.) in THF (8 mL), and the reaction solution was stirred at 15 °C. After 12 h, the reaction was quenched by the slow addition of 1 M hydrochloric acid (10 mL), and the solution was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0-25% ethyl acetate in hexanes) to give tert-butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.763 mmol, 96% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 4.37(s,1H),3.66-3.62(t,J=6.8Hz,2H),3.36(s,1H),2.00-1.98(m,2H),1.78-1.75(m,2H ),1.58-1.51(m,2H),1.44(s,9H),1.40-1.32(m,2H),1.28-1.14(m,4H),1.08-0.94(m,4H).

[0241] 4-(trans-4-Aminocyclohexyl)butan-1-ol. To a solution of tert-butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.760 mmol, 1 equiv.) in dichloromethane (2 mL) was added 4 M hydrochloric acid in 1,4-dioxane (4 mL, 16 mmol, 5.8 equiv.), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated to remove the organic solvent, then diluted with saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(trans-4-aminocyclohexyl)butan-1-ol (0.410 g, 2.394 mmol, 87% yield) as a white solid, which was carried forward without further purification. 1 H NMR(400MHz,CDCl3)δ 3.62-3.59(t,J=6.4Hz,2H),2.61-2.54(m,1H),1.85-1.81(m,2H),1.75-1.72(m,2H),1.56 -1.49(m,4H),1.39-1.31(m,2H),1.25-1.12(m,3H),1.10-1.00(m,2H),0.97-0.87(m,2H).

[0242] Methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate. To a solution of methyl 2-bromo-2-methylpropanoate (1.733 g, 9.570 mmol, 4 equiv.) and 4-(trans-4-aminocyclohexyl)butan-1-ol (0.410 g, 2.390 mmol, 1 equiv.) in acetonitrile (3 mL), potassium carbonate (0.993 g, 7.180 mmol, 3 equiv.) and sodium iodide (0.072 g, 0.480 mmol, 0.2 equiv.) were added, and the reaction solution was stirred at 80 °C. After 12 h, the reaction solution was diluted with ethyl acetate, filtered, and concentrated to give crude methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, crude) as a brown oil. MS(ESI)m / z 272.3[M+1] + .

[0243] 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, 2.320 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.556 g, 2.440 mmol, 1.1 equiv.) in ethyl acetate (12 mL) was added N,N-diisopropylethylamine (1.15 mL, 6.960 mmol, 3 equiv.), and the reaction mixture was stirred at 80 °C. After 3 h, the reaction solution was diluted with ethyl acetate (20 mL) and concentrated. The resulting crude oil was purified by silica gel column chromatography (0-35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.736 mmol, 32% yield) as a brown solid. MS(ESI) m / z 468.1 [M+1] + .

[0244] 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.770 mmol, 1 equivalent) in dichloromethane (3 mL) was added N,N-dimethylformamide (0.30 mL) and thionyl bromide (0.400 g, 1.920 mmol, 2.5 equivalents), and the reaction solution was stirred at 15 °C. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.280 g, 0.517 mmol, 67% yield) as a brown solid. MS(ESI) m / z 530.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.96-7.94(d,J=8.4Hz,1H),7.86-7.85(d,J=1.6Hz,1H),7.75-7.72(d,J=8.4,1.6Hz,1H),3.85(s,1H),3.45-3.41(t,J=6.8Hz,2H),2.6 9(s,2H),1.95-1.92(m,2H),1.88-1.83(m,4H),1.61(s,6H),1.50-1.44(m,2H),1.36-1.34(m,1H),1.27-1.25(m,2H),1.11-1.01(m,2H).

[0245] 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.075 g, 0.140 mmol, 1 equivalent) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrobromide (0.084 g, 0.180 mmol, 1.3 equivalents) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.12 mL, 0.710 mmol, 5 equivalents) was added, and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (20 mL) and extracted with 20:1 dichloromethane / methanol (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by standard methods to give 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.034 g, 0.041 mmol, 29% yield) as a white solid. MS (ESI) m / z 823.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.35-8.33(d,J=8.4Hz,1H),8.20(s,1H),7.99-7.97(d,J=8.0Hz,1H),7.06-7.02 (m,1H),6.98(s,1H),6.84-6.82(d,J=8.0Hz,1H),6.46-6.44(m,1H),4.29-4.25(m,1H),3.95-3 .72(m,8H),3.04(m,4H),2.79-1.71(m,2H),2.62-2.58(m,1H),2.12-2.08(m,1H),1.95-1.89(m ,1H),1.84-1.81(m,2H),1.74-1.71(m,4H),1.55(s,6H),1.33-1.24(m,11H),1.13-1.07(m,2H).

[0246] Example 18: 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a 2-dram vial containing 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (200 mg, 0.33 mmol) and (S)-3-((3-aminophenyl)amino)piperidine-2,6-dione (93.8 mg, 0.43 mmol, 1.3 equiv) was added N,N-dimethylformamide (1.65 mL, 0.2 M) and stirred until all solids were dissolved. 1-Methylimidazole (0.26 mL, 3.29 mmol, 10 equiv) was added, followed by N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (138.5 mg, 0.49 mmol, 1.5 equiv) and the reaction solution was stirred at room temperature. After 20 min, the reaction solution was diluted to a total volume of 4 mL with DMSO, filtered, and purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (62 mg, 0.076 mmol, 23% yield).MS(ESI)m / z 809.4[M+1]+;1H NMR(400MHz,DMSO-d6)δ=10.77(s,1H),9.34(s,1H),8.34(d,J=8.3Hz,1H),8.20(d,J=1.7Hz,1H),7 .98(dd,J=1.7,8.3Hz,1H),7.08-6.95(m,2H),6.81-6.77(m,1H),6.40(dd,J=1.7,8.1Hz,1H),5.90( d,J=7.9Hz,1H),4.35-4.22(m,1H),3.90-3.72(m,1H),3.20(s,2H),2.82-2.54(m,8H),2.26-2.17( m,2H),1.96-1.68(m,7H),1.55(s,6H),1.51-1.38(m,2H),1.30-1.03(m,5H),0.98(d,J=6.1Hz,6H).

[0247] Example 19: 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] tert-Butyl (R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a 40 mL vial was added tert-butyl (R)-3-(trifluoromethyl)piperazine-1-carboxylate (0.5 g, 1.97 mmol), N,N-diisopropylethylamine (0.69 mL, 3.93 mmol, 2 equiv.), methyl bromoacetate (1.09 mL, 11.8 mmol, 6 equiv.), and THF (20 mL, 0.1 M). The reaction solution was stirred at room temperature. After 18 minutes, the solution was diluted with 100 mL of ethyl acetate and 100 mL of water. The organic layer was removed, and the aqueous layer was extracted with 2 x 50 mL of ethyl acetate. The combined organic layers were then dried over magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1-50% ethyl acetate in hexanes) to give tert-butyl (R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.557 g, 1.71 mmol, 88% yield) as a yellow oil. MS(ESI) m / z 227 [M-99] + .

[0248] Methyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate. tert-Butyl (R)-3-(trifluoromethyl)piperazine-1-carboxylate (250 mg, 0.7 mmol) and trifluoroacetic acid (0.58 mL, 7.6 mmol, 10 equiv.) were combined in dichloromethane (7.6 mL, 1 M) and stirred at room temperature in a screw-cap scintillation vial. After 1 h, the solution was concentrated to give methyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (255 mg, 0.75 mmol, 98% yield) as a yellow oil, which was carried forward without further purification. MS(ESI) m / z 227 [M+1] + .

[0249] Methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate. To a 1-dram vial containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.5 g, 0.96 mmol, 1 equiv.), methyl (S)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (0.33 g, 0.96 mmol, 1 equiv.), and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv.) was added acetonitrile (5 mL), followed by N,N-diisopropylethylamine (0.8 mL, 4.82 mmol, 5 equiv.). The reaction vial was heated to 60° C. with stirring. After 16 hours, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (0.6 g, 0.89 mmol, 91% yield). MS(ESI) m / z 664.2 [M+1] + .

[0250] 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid. To a cooled solution of methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (0.6 g, 0.9 mmol, 1 equiv.) in a mixture of tetrahydrofuran / methanol / water (3:1:1, 5 mL) was added lithium hydroxide monohydrate (0.58 g, 1.3 mmol, 1.5 equiv.) in one portion at 0° C. The resulting solution was stirred at room temperature. After 3 h, the reaction solution was diluted with water (20 mL) and extracted with 10% methanol in dichloromethane (4×50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.33 g, 0.46 mmol, 51% yield), which was carried forward without further purification. MS(ESI) m / z 650.2 [M+1] + .

[0251] 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. Acetonitrile (1.5 mL) and N,N-dimethylformamide (1.5 mL) were added to a 2-dram vial containing 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.12 g, 0.19 mmol, 1 equivalent) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.05 g, 0.22 mmol, 1.2 equivalents), and the reaction solution was stirred until all solids were dissolved. To the reaction solution was added 1-methylimidazole (0.07 mL, 0.84 mmol, 5 equivalents), followed by N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (0.12 g, 0.41 mmol, 2.2 equivalents), and the reaction solution was stirred at room temperature. After 1 h, the reaction solution was diluted to a total volume of 3 mL with dimethyl sulfoxide, filtered, and purified by standard methods to give 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.09 g, 0.11 mmol, 58% yield). MS(ESI) m / z 851.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.73(s,1H),9.68(s,1H),8.27(d,J=8.2Hz,1H),8.13(d,J=1.5Hz,1H),7.90(dd,J=1.6,8.2Hz,1H),7.04-6.89(m,2H),6.77(br d,J=6.5Hz,1H),6.36(br d,J=8.2Hz,1H),4.20(br dd,J=4.5,10.9Hz,2H),3.87-3.44(m,8H),3.30(br d,J=11.2Hz,4H),3.06(br d,J=9.7Hz,3H),2.89-2.51(m,4H),2.10-1.97(m,3H),1.84(dq,J=4.7,12.1Hz,1H),1.72-1.61(m,2H),1.48(s,6H),1.38-1.19(m,2H).

[0252] Example 20: 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] Methyl 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate. To a 1-dram vial containing 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (375 mg, 0.72 mmol, 1 equiv.) and methyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate trifluoroacetate (491.3 mg, 1.44 mmol, 2 equiv.) was added N,N-dimethylformamide (3.6101 mL, 0.2 M) and N,N-diisopropylethylamine (0.75 mL, 4.33 mmol, 6 equiv.). The reaction solution was heated to 55° C. with stirring. After 16 h, the reaction solution was diluted with 75 mL of ethyl acetate and washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was separated and dried over magnesium sulfate to give a yellowish oil. The crude material was purified by reverse phase HPLC to give the title compound as the formate salt. The material was taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to give methyl 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (310 mg, 0.4664 mmol, 65% yield). MS(ESI) m / z 655.2 [M+1] + ; 1H NMR(400MHz,chloroform-d)δ 1.62(s,6H)1.81(br d,J=11.86Hz,2H)2.20(br d,J=10.76Hz,2H)2.48(ddd,J=11.03,7.92,3.30Hz,1H)2.52-2.69(m,4H)2.81-2.94(m,4H)2.94-3.03(m,1H)3.27-3 .38(m,1H)3.46(dd,J=17.85,0.98Hz,1H)3.56-3.70(m,5H)3.71(s,3H)8.23(d,J=2.20Hz,1H)8.97(d,J=2.20Hz,1H)

[0253] 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate. To a 2-dram vial containing methyl 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (200 mg, 0.30 mmol) was added 1,4-dioxane (1 mL, 0.3 M) followed by 1 M aqueous lithium hydroxide solution (0.36 mL, 0.36 mmol, 1.2 equiv). The reaction was stirred at room temperature for 2 hours, at which point no starting material remained by LCMS. The reaction solution was concentrated and the resulting material dried by azeotropic removal with dioxane to give 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (193 mg, 0.29 mmol, 98% yield) as a glassy yellow oil. The material was carried forward without further purification. MS(ESI) m / z 651.2 [M+1] + .

[0254] 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. A 1-dram vial containing N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (112.2 mg, 0.40 mmol, 2 equiv.) was charged with 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl) A solution of (oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (131.31 mg, 0.20 mmol, 1 equiv.) in N,N-dimethylformamide (1.0 mL, 0.2 M) was added, followed by the addition of 3-((3-aminophenyl)amino)piperidine-2,6-dione (66 mg, 0.30 mmol, 1.5 equiv.) and 1-methylimidazole (98.5 mg, 1.2 mmol, 6 equiv.). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted to a total volume of 2 mL with DMSO, filtered, and purified by standard methods to give 2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (98 mg, 0.11 mmol, 53% yield) as an off-white solid. MS(ESI) m / z 852.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ=10.80(s,1H),10.72(br s,1H),9.72(s,1H),9.15(d,J=1.8Hz,1H),8.75(d,J=2.0Hz,1H),7.06-6.94(m,2H),6.89-6.77(m,1H),6.42(br d,J=7.6Hz,1H),4.16-4.14(m,1H),3.86(br s,4H),3.62(br s,5H),3.45-3.29(m,4H),3.21-3.03(m,3H),2.95-2.66(m,3H),2.19-2.07( m,3H),1.98-1.84(m,1H),1.80-1.69(m,2H),1.58(s,6H),1.44-1.29(m,2H).

[0255] Example 21: 2-((2S,4r,6R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 5-(3-((trans)4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of (2S,4r,6R)-tert-butyl 4-(2-(((1r,4R)-4-(3-(6-cyano-5-(1,1-difluoroethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.000 g, 3.070 mmol) in DCM (5 mL) was added 45 M HCl in dioxane (30.0 mL, 120 mmol). The reaction mixture was stirred at 15 °C for 3 h, and the reaction was concentrated to give a residue. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) to pH 8-9, and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 5-(3-((1R,4r)-4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.940 g, 3.517 mmol) as a yellow solid, which was carried forward without further purification. MS (ESI) m / z: 552.4 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 )δ 8.97(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),3.79-3.58(m,1H),3.56-3.46(m,2H),3.3 0(m,1H),3.03-2.83(m,2H),2.78(m,2H),2.26-2.15(m,2H),1.89-1.75(m,2H),1.69(br d,J=13.2Hz,2H),1.62(s,6H),1.52(q,J=6.8Hz,2H),1.41-1.29(m,2H),1.27-1.11(m,6H),0.88(q,J=11.2Hz,2H).

[0256] 2-((2S,4r,6R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 5-(3-((1R,4r)-4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.120 g, 0.220 mmol) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.096 g, 0.330 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.19 mL, 1.090 mmol) and sodium iodide (0.033 g, 0.220 mmol). The reaction mixture was stirred at 80° C. for 12 hours and then diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated. The resulting residue was purified by standard methods to give 2-((2S,4r,6R)-4-(2-(((1r,4R)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.075 g, 0.090 mmol, 41.2% yield) as a yellow solid. MS (ESI) m / z: 811.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.91(s,1H),10.80(s,1H),10.68-10.53(m,1H),10.24-9.95(m,1H),9.14(d,J=2.0Hz,1H),9.07(br s,1H),8.74(d,J=1.6Hz,1H),7.05(m,1H),6.99(br d,J=7.2Hz,1H),6.87(br d,J=8.0Hz,1H),6.57-6.36(m,1H),4.26(m,1H),4.21(br s,1H),4.12(br d,J=3.6Hz,1H),3.92-3.77(m,1H),3.70-3.56(m,1H),3.56-3.39(m,3H), 3.23(m,1H),2.92-2.68(m,3H),2.64-2.55(m,1H),2.14-2.00(m,3H),1.98 -1.82(m,2H),1.82-1.63(m,4H),1.56(d,J=1.6Hz,6H),1.50(m,1H),1.47 -1.38(m,2H),1.38-1.22(m,5H),1.20(d,J=6.4Hz,3H),1.17-1.07(m,1H).

[0257] Example 22: 2-((2S,4s,6R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 5-(3-((trans)-4-(2-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of (2S,4s,6R)-tert-butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.885 g, 1.360 mmol) in DCM (3 mL) was added 4 M HCl in dioxane (20 mL, 80 mmol), and the reaction solution was stirred at 15° C. After 12 h, the solution was concentrated, and the resulting residue was diluted with aqueous sodium bicarbonate. The aqueous solution was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to give 5-(3-((trans)-4-(2-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.750 g, 1.360 mmol) as a yellow solid, which was carried forward without further purification. MS (ESI) m / z: 552.5 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 )δ 8.97(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),3.78-3.59(m,1H),3.51(t,J=6.8Hz,2H),3.31(m,1H),3.02-2.72(m,4H),2.21(br d,J=12.4Hz,2H),2.01-1.95(m,1H),1.82(br d,J=12.0Hz,2H),1.70(q,J=6.8Hz,2H),1.63(s,6H),1.52(br d,J=13.6Hz,2H),1.41-1.26(m,4H),1.10(d,J=6.4Hz,6H).

[0258] 2-((2S,4s,6R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 5-(3-((trans)-4-(2-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.120 g, 0.220 mmol) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.095 g, 0.330 mmol) in DMF (0.500 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.19 mL, 1.090 mmol) and sodium iodide (0.033 g, 0.220 mmol). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated. The resulting residue was purified by standard methods to give 2-((2S,4s,6R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.064 g, 0.079 mmol, 36.1% yield) as a yellow solid. MS (ESI) m / z: 811.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.95(s,1H),10.80(br d,J=3.6Hz,1H),10.62(s,1H),10.27-9.86(m,1H),9.14(d,J=1.2Hz,1H),9.08-8.97(m,1H),8.74(d,J=1 .6Hz,1H),7.17-6.94(m,2H),6.93-6.73(t,J=6.8Hz,1H),6.57-6.37(m,1H),4.30-4.25(m,1H),4.21(br s,1H),4.17(m,1H),3.87-3.78(m,2H),3.59(br s,1H),3.48(br t,J=6.0Hz,2H),3.30-3.11(m,1H),2.93-2.67(m,3H),2.63-2.57(m,1H),2.16-1.86(m,6H),1.82-1.59(m,7H),1.56(d,J=1.2Hz,6H),1.35(br s,3H),1.33-1.25(m,2H),1.19(br d,J=6.0Hz,3H).

[0259] Example 23: 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide [ka] 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide. To a solution of 4-(3-((1R,4R)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.290 mmol) and N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.150 g, 0.350 mmol) in DMF (3 mL) was added potassium iodide (0.048 g, 0.290 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.15 mL, 0.870 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The reaction solution was diluted with water (30 mL) and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by standard methods to give 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide (0.062 g, 0.070 mmol, 24.2% yield) as a yellow solid. MS (ESI) m / z: 869.6 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),9.93(s,1H),8.34(d,J=8.4Hz,1H),8.19(d,J=1.8Hz,1H),7.97(d d,J=1.6,8.3Hz,1H),6.80-6.59(m,2H),6.22(d,J=12.1Hz,1H),4.45-4.31(m,1H ),4.30-4.24(m,1H),3.87(s,2H),3.82-3.56(m,8H),3.25-3.03(m,4H),2.92-2. 61(m,4H),2.10-1.87(m,1H),1.75-1.67(m,2H),1.54(s,6H),1.39-1.29(m,2H).

[0260] Example 24: 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide [ka] (3R)-tert-Butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a solution of (S)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.263 g, 0.840 mmol) and HATU (0.641 g, 1.69 mmol) in DMF (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.44 mL, 2.53 mmol) and 3-((3-amino-5-fluorophenyl)amino)piperidine-2,6-dione (0.200 g, 0.840 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The mixture was diluted with water (30 mL) and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (0-4% methanol in dichloromethane) to give (3S)-tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.340 g, 0.640 mmol, 75.9% yield) as a brown oil. MS (ESI) m / z: 554.4 [M+23] + .

[0261] N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide. To a solution of (3S)-tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.340 g, 0.640 mmol) in DCM (5 mL) was added 33% hydrogen bromide in acetic acid (0.5 mL), and the reaction mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.270 g, 0.626 mmol, 97.8% yield) as a brown oil, which was used in the next step without further purification. MS(ESI) m / z 432.3 [M+1] + .

[0262] 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide. To a solution of 5-(3-((1R,4R)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.100 g, 0.190 mmol) and N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.100 g, 0.230 mmol) in DMF (3 mL) was added potassium iodide (0.032 g, 0.190 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.580 mmol). The reaction mixture was stirred at 50° C. for 12 h, diluted with DMSO, and purified by standard methods to give 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide (0.062 g, 0.071 mmol, 36.8% yield) as a green solid. MS(ESI) m / z 870.6 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.53-10.98(m,1H),10.79(s,1H),9.94(br s,1H),9.14(d,J=1.9Hz,1H),8.74(d,J=1.9Hz,1H),6.85-6.57(m,2H),6.22(d ,J=11.9Hz,1H),4.40(s,1H),4.28(dd,J=4.7,11.2Hz,3H),3.74-3.50(m,6H),3 .47-3.28(m,4H),3.20-3.11(m,2H),2.94-2.79(m,2H),2.73(ddd,J=4.7,12.2 ,17.0Hz,1H),2.63-2.54(m,1H),2.14-2.03(m,3H),1.94-1.84(m,1H),1.72(br d,J=11.3Hz,2H),1.56(s,6H),1.41-1.29(m,2H).

[0263] Example 25: 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.180 g, 0.360 mmol) and 5-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.188 g, 0.360 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.32 mL, 1.820 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated. The resulting crude material was purified by standard methods to give 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.078 g, 0.090 mmol, 25% yield) as a yellow solid. MS(ESI) m / z 850.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.27-11.00(m,1H),10.79(s,1H),9.80-9.59(m,1H),9.15(d,J=2.0Hz, 1H),8.75(d,J=2.0Hz,1H),7.09-6.95(m,2H),6.90-6.75(m,1H),6.43(br d,J=8.0Hz,1H),4.38(br s,1H),4.27(br dd,J=4.8,11.2Hz,1H),3.67-3.55(m,4H),3.54-3.43(m,2H),3.22-2.94(m,5H),2.90-2.68(m,3H),2.64-2.54(m ,1H),2.16-2.03(m,1H),1.96-1.81(m,3H),1.81-1.66(m,4H),1.57(s,6H),1.33-1.15(m,3H),1.15-0.99(m,2H).

[0264] Example 26: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide [ka] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide. To a solution of N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.172 g, 0.390 mmol) in DMF (1 mL) was added 5-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.100 g, 0.190 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.026 g, 0.960 mmol). The reaction mixture was then stirred at 50° C. for 12 hours. The reaction solution was diluted with DMSO and purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.072 g, 0.075 mmol, 39% yield) as a yellow solid. MS(ESI) m / z 886.0 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ 10.83-10.77(m,1H),9.97-9.66(m,1H),9.15(d,J=1.6Hz,1H),8.74(d,J=1.6H z,1H),7.02-6.74(m,2H),6.46(s,1H),4.43-4.25(m,2H),3.87(s,3H),3.75-3 .57(m,5H),3.36-3.32(m,2H),3.27-2.99(m,4H),2.92-2.61(m,4H),2.16-2.0 2(m,3H),1.98-1.84(m,1H),1.78-1.68(m,2H),1.57(s,6H),1.44-1.31(m,2H).

[0265] Example 27: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide [ka] (3R)-tert-Butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a solution of 3-(3-amino-5-chloro-anilino)piperidine-2,6-dione (0.162 g, 0.640 mmol) and (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.200 g, 0.640 mmol) in pyridine (1 mL) was added EDCI (0.246 g, 1.28 mmol), and the reaction solution was heated to 50° C. After 12 h, the reaction solution was concentrated, diluted with water (40 mL), and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified by standard methods to give (3R)-tert-butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.250 g, 0.456 mmol, 71.2% yield) as a yellow solid. MS (ESI) m / z 548.1 [M+1] + .

[0266] (3R)-tert-butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. A solution of (3R)-tert-butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.250 g, 0.460 mmol) in 33% HBr in AcOH (0.5 mL, 0.460 mmol) was stirred at 25 °C. After 12 h, the reaction solution was concentrated to give (3R)-tert-butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.200 g, 0.447 mmol, 97.9% yield) as a green solid, which was carried forward without further purification. MS(ESI) m / z 448.1 [M+1] + .

[0267] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide. 4- [3- [4- (2-bromoethoxy) cyclohexyl] -4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl] -2- (trifluoromethyl) benzonitrile (0.100 g, 0.190 mmol) in DMF (1 mL) solution N- (3-chloro-5- ((2,6-dioxopiperidin-3-yl) amino) phenyl) -2- ((R) -2- (trifluoromethyl) piperazin-1-yl) acetamide (0.172 g, 0.390 mmol), N- ethyl-N- isopropylpropan-2-amine (0.124 g, 0.960 mmol) was added, and the reaction solution was heated to 50 ° C. After 12 h, the reaction solution was diluted with DMSO and purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.083 g, 0.089 mmol, 46.0% yield) as a yellow solid. MS(ESI) m / z 885.0 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ 10.80(s,2H),10.01-9.67(m,1H),8.34(d,J=8.4Hz,1H),8.20(d,J=1.6Hz,1H),8.01-7. 93(m,1H),7.05-6.72(m,2H),6.46(s,1H),4.47-4.23(m,2H),3.92-3.79(m,3H),3.77-3. 47(m,7H),3.20-3.06(m,3H,3.00-2.76(m,3H),2.75-2.66(m,1H),2.64-2.53(m,1H),2.1 4-2.02(m,3H),1.98-1.83(m,1H),1.74(dd,J=12Hz,2H),1.55(s,6H),1.45-1.30(m,2H).

[0268] Example 28: 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] tert-Butyl (3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a mixture of 3-(3-aminoanilino)piperidine-2,6-dione hydrochloride (0.737 g, 2.88 mmol) and 2-[(2R)-4-tert-butoxycarbonyl-2-(trifluoromethyl)piperazin-1-yl]acetic acid (0.600 g, 1.92 mmol) in pyridine (2 mL), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.737 g, 3.84 mmol) was added, and the reaction solution was heated to 50° C. After 16 hours, the reaction solution was diluted with water (25 mL), extracted with ethyl acetate (100 mL), and the organic layer was dried over sodium sulfate and concentrated. The resulting crude residue was purified by standard methods to give tert-butyl (3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.450 g, 0.88 mmol, 46% yield) as a yellow oil. MS (ESI) m / z 514.2 [M+1] + .

[0269] N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide. To a solution of tert-butyl (3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.450 g, 0.88 mmol) in dichloromethane (10 mL) was added 30% hydrogen bromide in acetic acid (0.60 mL, 8.76 mmol), and the reaction solution was stirred at room temperature. After 16 h, the reaction solution was concentrated to give crude N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.500 g, 1.01 mmol), which was carried forward without further purification. MS(ESI) m / z 414.1 [M+1]+ .

[0270] 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a mixture of 5-(3-((1r,4r)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.129 g, 0.24 mmol) and N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.120 g, 0.24 mmol) in N,N-dimethylformamide (2 mL), diisopropylethylamine (0.06 mL, 0.73 mmol) was added, and the reaction solution was stirred at 50° C. After 16 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude residue was purified by standard methods to give 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.045 g, 0.05 mmol, 20.7% yield). MS(ESI) m / z 866.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.08(br d,J=5.6Hz,1H),10.80(s,1H),9.82-9.56(m,1H),8.34(d,J=8.4Hz,1H),8.20(s,1H),7.98(dd,J=1.6,8.0Hz,1H),7.01(br t,J=8.0Hz,2H),6.92-6.72(m,1H),6.43(br d,J=8.0Hz,1H),4.44-4.23(m,2H),3.91-3.76(m,1H),3.71-3.41(m,5H),3.40-2.91(m,6H),2.85-2 .67(m,3H),2.64-2.56(m,1H),2.15-2.04(m,1H),1.92-1.70(m,7H),1.55(s,6H),1.42-0.91(m,6H).

[0271] Example 29: 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a mixture of 4-(3-((1r,4r)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.126 g, 0.24 mmol) and tert-butyl (3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate hydrobromide (0.120 g, 0.24 mmol) in N,N-dimethylformamide (2 mL) was added diisopropylethylamine (0.06 mL, 0.73 mmol), and the reaction solution was stirred at 50° C. After 16 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over sodium sulfate and concentrated. The resulting crude material was purified by standard methods to give 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.057 g, 0.06 mmol, 26.7% yield) as a yellow solid. MS (ESI) m / z 849.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.14-10.94(m,1H),10.79(br s,1H),9.82-9.50(m,1H),9.14(br s,1H),8.74(br s,1H),7.01(br s,2H),6.90-6.73(m,1H),6.50-6.34(m,1H),4.30-4.24(m,2H),3.66-3.45(m,7H), 3.29-3.00(m,7H),2.91-2.64(m,5H),2.15-1.83(m,7H),1.77-1.68(m,2H),1.57(br d,J=3.2Hz,6H),1.42-1.24(m,2H).

[0272] Example 30: 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 4-(3-((1r,4r)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.258 g, 0.480 mmol) and N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.200 g, 0.480 mmol) in DMF (3 mL), N-ethyl-N-isopropylpropan-2-amine (0.25 mL, 1.45 mmol) and potassium iodide (80.31 mg, 0.4800 mmol) were added, and the reaction solution was stirred at 50° C. After 12 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified by standard methods to give 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.059 g, 0.068 mmol, 14.1% yield) as a yellow solid. MS (ESI) m / z 865.5 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),9.71(s,1H),8.33(d,J=8.3Hz,1H),8.18(d,J=1.6Hz,1H),7 .96(dd,J=1.6,8.2Hz,1H),7.05-6.94(m,2H),6.87-6.74(m,1H),6.41(br d,J=8.5Hz,1H),4.43-4.27(m,1H),4.27-4.22(m,1H),3.91-3.74(m,2H),3.66(s,4H),3.32-3.00(m,8H),2.90-2. 61(m,4H),2.07(dd,J=2.5,6.0Hz,3H),1.99-1.82(m,3H),1.71(d,J=11.1Hz,2H),1.54(s,6H),1.36-1.25(m,2H).

[0273] Example 31: N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide [ka] (3R)-tert-Butyl 4-(2-((3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a solution of (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.128 g, 0.410 mmol) and HATU (311.34 mg, 0.8200 mmol) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.23 mmol) and 3-amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile (100 mg, 0.4100 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The mixture was diluted with water (30 mL) and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give (3R)-tert-butyl 4-(2-((3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (140 mg, 0.2600 mmol, 63% yield) as a brown oil. MS (ESI) m / z 539.3 [M+1] + .

[0274] N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide. To a solution of (3R)-tert-butyl 4-(2-((3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.470 g, 0.870 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.0 mL, 12.89 mmol), and the reaction mixture was stirred at 25° C. After 12 h, the reaction solution was concentrated to give crude N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.380 g, 0.867 mmol, 99% yield) as a yellow solid, which was carried forward without further purification. MS(ESI) m / z 439.2 [M+1] + .

[0275] N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide. To a solution of 5-(3-((1r,4r)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.213 g, 0.410 mmol) and N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.180 g, 0.410 mmol) in DMF (3 mL) was added potassium iodide (0.068 g, 0.410 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.23 mmol), and the mixture was stirred at 50° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by standard methods to give N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.059 g, 0.0675 mmol, 16% yield) as a green solid. MS (ESI) m / z 877.5 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.82(s,1H),9.76(s,1H),9.14(d,J=1.8Hz,1H),8.74(d,J=1.8Hz,1H),7.22(s,2H),6.7 7(s,1H),6.50(d,J=8.0Hz,1H),4.43-4.36(m,1H),3.94-3.81(m,1H),3.71-3.57(m,2H), 3.54(t,J=5.6Hz,2H),3.40(d,J=16.1Hz,2H),3.32-3.22(m,8H),2.90-2.75(m,4H),2.11 -2.03(m,3H),1.96-1.86(m,1H),1.71(d,J=11.4Hz,2H),1.56(s,6H),1.36-1.24(m,2H).

[0276] Example 32: 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((2R,4r,6S)-4-(3-((1r,4R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.150 g, 0.240 mmol) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.079 g, 0.360 mmol) in pyridine (2 mL) was added EDCI (0.086 g, 0.480 mmol), and the reaction solution was stirred at 50° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.068 g, 0.080 mmol, 33.4% yield) as a grey solid. MS(ESI) m / z 824.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.73-10.62(m,1H),10.50(s,1H),9.14(br s,1H),8.33(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),7.05(q,J=8.0Hz,1H),6.94(br d,J=6.0Hz,1H),6.84(d,J=8.0Hz,1H),6.53-6.38(m,1H),4.29-4.22(m,1H),4.19(br s,1H),4.12(m,1H),3.93-3.73(m,2H),3.46-3.34(m,4H),2.82-2.67(m,3H),2.64-2.55(m,1H),2.19-2.03(m,3H),1.98- 1.87(m,1H),1.81(m,2H),1.77-1.61(m,3H),1.55(s,6H),1.52-1.43(m,2H),1.36(d,J=6.0Hz,2H),1.29(m,2H),1.21(br d,J=6.4Hz,6H),1.14-0.97(m,2H).

[0277] Example 33: 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 5-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.090 g, 0.160 mmol) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.094 g, 0.320 mmol) in DMF (1 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.14 mL, 0.800 mmol) and sodium iodide (0.024 g, 0.160 mmol), and the reaction solution was stirred at 80° C. After 12 hours, the reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.059 g, 0.070 mmol, 44% yield) as a gray solid. MS (ESI) m / z 825.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.54-10.38(m,1H),9.15(m,2H),8.74(d,J=1.6Hz,1H),7.11-7.00(m ,1H),6.91(s,1H),6.85-6.77(m,1H),6.51-6.41(m,1H),4.30-4.22(m,1H),4.17(br s,1H),4.09-4.02(m,1H),3.90-3.78(m,1H),3.64-3.57(m,1H),3.50(br s,2H),3.41(m,2H),2.84-2.68(m,3H),2.64-2.56(m,1H),2.18-2.04(m,3H),1.99-1 .87(m,1H),1.86-1.76(m,2H),1.76-1.61(m,3H),1.57(s,6H),1.51(m,2H),1.35(br d,J=6.4Hz,2H),1.33-1.24(m,2H),1.21(br d,J=6.4Hz,6H),1.15-1.00(m,2H).

[0278] Example 34: 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 4-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.213 g, 0.410 mmol) and N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.180 g, 0.410 mmol) in DMF (1 mL), potassium iodide (68.16 mg, 0.4100 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.23 mmol) were added, and the reaction solution was stirred at 50 ° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.048 g, 0.054 mmol, 13% yield) as a green solid. MS (ESI) m / z 876.5 [M+1] +;1H NMR(400MHz,DMSO-d6)δ 10.89-10.79(m,1H),9.76(s,1H),8.34(d,J=8.2Hz,1H),8.20(d,J=1.8Hz,1H),7.98(dd,J=1.7,8.2Hz ,1H),7.25-7.21(m,2H),6.78(s,1H),6.51(d,J=8.2Hz,1H),4.40(ddd,J=4.7,7.6,12.3Hz,1H),3.91- 3.79(m,1H),3.71-3.58(m,2H),3.55(t,J=5.7Hz,2H),3.41(d,J=16.6Hz,2H),3.33-3.22(m,8H),2.97 -2.77(m,4H),2.10-2.01(m,3H),1.96-1.85(m,1H),1.75-1.65(m,2H),1.55(s,6H),1.34-1.24(m,2H).

[0279] Example 35: 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. N-ethyl-N-isopropylpropan-2-amine (0.19 mL, 1.090 mmol) and sodium iodide (0.033 g, 0.220 mmol) were added to a solution of 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.120 g, 0.220 mmol) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.129 g, 0.440 mmol) in DMF (2 mL), and the reaction solution was stirred at 80° C. After 12 hours, the reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.086 g, 0.104 mmol, 47% yield) as a yellow solid. MS (ESI) m / z 811.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.87(s,1H),10.80(s,1H),10.60(s,1H),10.36-10.05(m,1H),9.25-9.00(m,1H),8.74(d,J=2.0Hz,1H),7.10-7.01(m,1H),6.98(br d,J=10.4Hz,1H),6.86(d,J=8.0Hz,1H),6.52-6.39(m,1H),4.30-4.23(m,1H),4.22-4.14(m,2H),3.86-3.82(m,1H),3. 55-3.37(m,5H),2.84-2.66(m,3H),2.64-2.55(m,1H),2.22-2.12(m,1H),2.12-2.02(m,2H),1.98-1.86(m,1H),1.81(br d,J=12.0Hz,2H),1.76-1.62(m,3H),1.56(s,6H),1.47-1.27(m,7H),1.22(d,J=6.4Hz,3H),1.17-1.01(m,2H).

[0280] Example 36: 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.120 g, 0.200 mmol) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.065 g, 0.300 mmol) in pyridine (2 mL) was added EDCI (0.070 g, 0.390 mmol), and the reaction solution was stirred at 50° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.071 g, 0.087 mmol, 44% yield) as a yellow solid. MS(ESI) m / z 810.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),10.80(s,1H),10.60(s,1H),10.42-10.12(m,1H),9.13(br s,1H),8.34(d,J=8.0Hz,1H),8.20(d,J=2.0Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),7.11-7.01(m,1H),6.98(br d,J=10.0Hz,1H),6.86(d,J=7.6Hz,1H),6.57-6.36(m,1H),4.25(m,1H),4.19(m,2H),3.88-3.79(m,1H),3.71- 3.62(m,1H),3.58-3.39(m,4H),2.83-2.64(m,3H),2.63-2.55(m,1H),2.21-2.02(m,3H),1.91(m,1H),1.81(br d,J=12.4Hz,2H),1.76-1.62(m,3H),1.55(s,6H),1.47-1.28(m,7H),1.22(d,J=6.4Hz,3H),1.16-0.99(m,2H).

[0281] Example 37: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((trans)-4-(3-((1r,4S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetamide [ka] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetamide hydrochloride. 2 To a flask containing 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (100 mg, 0.1600 mmol) and 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione hydrochloride (52.52 mg, 0.1800 mmol) was added MeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (92.34 mg, 0.3300 mmol). The reaction mixture was stirred at 25° C. for 30 minutes. The reaction was diluted with DMSO (1.0 mL) and purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetamide hydrochloride (76.9 mg, 0.0858 mmol, 52% yield) as a gray solid. MS (ESI) m / z 844.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.34(d,J=8.31Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J=1.65,8.25Hz,1H),6.96(s,1H),6.90(br s,1H),6.49(s,1H),4.34(br dd,J=4.89,11.62Hz,5H),3.74-3.92(m,3H),3.52-3.65(m,2H),2.90-3.11(m,4H),2.68-2.8 3(m,3H),2.54-2.63(m,1H),2.01-2.11(m,1H),1.88-1.97(m,1H),1.80-1.88(m,2H),1.74(br d,J=9.29Hz,4H),1.49-1.61(m,6H),1.16-1.33(m,9H),1.01-1.15(m,2H).

[0282] Example 38: 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide [ka] 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide. 2 To a flask containing 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (100 mg, 0.1600 mmol) and 3-((3-amino-5-fluorophenyl)amino)piperidine-2,6-dione (42.9 mg, 0.1800 mmol) was added MeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (92.34 mg, 0.3300 mmol). The reaction mixture was stirred at 25° C. for 30 minutes. The reaction was diluted with DMSO (1.0 mL) and purified by standard methods to give 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide hydrochloride (70.4 mg, 0.08 mmol, 49% yield) as an off-white solid. MS(ESI) m / z 827.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.34(d,J=8.19Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J=1.59,8.19Hz,1H),6.67-6.81(m,2H),6.27(br d,J=11.98Hz,1H),4.31(br dd,J=4.89,11.62Hz,1H),2.93-3.11(m,4H),2.68-2.82(m,3H),2.55-2.62(m,1H),2.03-2.13(m,2H),1.87- 1.97(m,1H),1.80-1.87(m,2H),1.68-1.80(m,4H),1.51-1.59(m,6H),1.16-1.33(m,9H),1.02-1.15(m,3H).

[0283] Example 39: 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide [ka] 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride. 2 To a flask containing 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (100 mg, 0.1600 mmol) and 3-((3-amino-4-fluorophenyl)amino)piperidine-2,6-dione (42.9 mg, 0.1800 mmol) was added MeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (92.34 mg, 0.3300 mmol). The reaction mixture was stirred at 25° C. for 30 minutes. The reaction was diluted with DMSO (1.0 mL) and purified by standard methods to give 2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride hydrochloride (66 mg, 0.076 mmol, 46% yield) as a tan solid. MS(ESI) m / z 827.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),8.34(d,J=8.19Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J=1.65,8.25Hz,1H),7.21(br d,J=3.67Hz,1H),7.01(t,J=9.78Hz,1H),6.38-6.54(m,1H),4.24(br dd,J=4.77,11.25Hz,2H),3.02(br s,3H),2.68-2.82(m,3H),2.54-2.64(m,1H),2.02-2.13(m,1H),1.87-1.95(m,1H),1.84(br d,J=11.37Hz,2H),1.68-1.79(m,4H),1.50-1.59(m,6H),1.16-1.31(m,8H),1.02-1.16(m,3H).

[0284] Example 40: 2-((S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. 2-((S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (40 mg, 0.0600 mmol) was added to 3 mL of 2-((S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid. 3-((3-aminophenyl)amino)piperidine-2,6-dione (16.2 mg, 0.0700 mmol), 1-methylimidazole (0.03 mL, 0.3100 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (38.01 mg, 0.1400 mmol), MeCN (0.7738 mL) and DMF (0.7738 mL) were combined and the reaction was stirred at 25° C. After 18 h, the reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated, and the resulting crude material was purified by standard methods to give 2-((S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (9 mg, 0.01 mmol, 16% yield) as a yellow solid. MS(ESI) m / z 851.3 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 10.9-11.0(m,1H),10.6-10.8(m,1H),9.5-9.7(m,1H),8.2-8.3(m,1H),8.0-8.2(m,1H),7.8-8.0(m,1 H),6.9-7.0(m,2H),6.7-6.8(m,1H),6.2-6.4(m,1H),4.4-4.7(m,6H),4.2-4.2(m,1H),3.7-3.9(m,3H) ),3.6-3.7(m,1H),3.5-3.6(m,1H),3.4-3.5(m,1H),3.2-3.3(m,2H),3.0-3.1(m,2H),2.6-2.9(m,3H) ,2.5-2.6(m,1H),2.0-2.1(m,3H),1.8-1.9(m,1H),1.6-1.7(m,2H),1.4-1.5(m,6H),1.2-1.3(m,2H).

[0285] Example 41: 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (5.000 g, 7.68 mmol) and (S)-3-((3-aminophenyl)amino)piperidine-2,6-dione (1.850 g, 8.45 mmol) in DMF (50 mL) was added HATU (2.920 g, 7.68 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.01 mL, 23.05 mmol), and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (1539.8 mg, 1.78 mmol, 23% yield) as a yellow solid. MS (ESI) m / z 852.0 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.62-11.15(m,1H),10.80(s,1H),9.87-9.63(m,1H),9.14(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),7.14-6.97(m, 2H),6.94-6.78(m,1H),6.44(d,J=8.0Hz,1H),4.42(s,1H),4.35-4.21(m,1H),3.89(s,3H),3.71(d,J=11.2Hz,1H), 3.60(s,2H),3.51(d,J=11.2Hz,2H),3.36(d,J=10.8Hz,4H),3.25-3.08(m,3H),2.93-2.79(m,2H),2.77-2.68(m,1H) ),2.65-2.55(m,1H),2.16-2.04(m,3H),1.96-1.86(m,1H),1.72(d,J=10.0Hz,2H),1.57(s,6H),1.44-1.35(m,2H).

[0286] Example 42: 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (5.000 g, 7.685 mmol) and (R)-3-((3-aminophenyl)amino)piperidine-2,6-dione (1.853 g, 8.450 mmol) in DMF (50 mL) was added HATU (2.922 g, 7.680 mmol) and N,N-diisopropylethylamine (4 mL, 23.05 mmol), and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (4.594 g, 5.376 mmol, 70% yield) as an off-white solid. MS(ESI) m / z 852.1 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.98(br s,1H),10.80(s,1H),9.76-9.56(m,1H),9.16(d,J=1.6Hz,1H),8.76(d,J=1.6Hz,1H),7.04-6.94(m,2H),6.80(br d,J=8.0Hz,1H),6.40(br d,J=8.0Hz,1H),4.41(br s,1H),4.24(br dd,J=4.4,11.2Hz,1H),3.87(br s,3H),3.72(br d,J=11.2Hz,1H),3.61(br s,2H),3.52(br s,2H),3.45-3.26(m,1H),3.36(br s,3H),3.12(br d,J=10.4Hz,3H),2.88(br d,J=11.2Hz,2H),2.79-2.68(m,1H),2.64-2.54(m,1H),2.08(br dd,J=4.0,8.8Hz,3H),1.96-1.85(m,1H),1.72(br d,J=10.0Hz,2H),1.57(s,6H),1.42-1.31(m,2H).

[0287] Example 43: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.080 g, 0.130 mmol) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.042 g, 0.190 mmol) in pyridine (2 mL) was added EDCI (0.098 g, 0.510 mmol), and the reaction solution was stirred at 60° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.048 g, 0.0555 mmol, 43% yield) as a green solid. MS(ESI) m / z 826.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),9.48-9.39(s,1H),8.33(d,J=8.4Hz,1H),8.19(d,J=1.2Hz,1H),8.03-7 .91(m,1H),7.06-6.93(m,2H),6.85-6.77(m,1H),6.45-6.32(m,1H),5.87(d,J=8.0Hz, 1H),4.34-4.20(m,1H),3.93-3.72(m,1H),3.51(s,4H),3.15(s,2H),2.89-2.75(m,2H ),2.74-2.63(m,3H),2.62-2.54(m,1H),2.13-1.98(m,3H),1.95-1.82(m,3H),1.71(br d,J=11.2Hz,2H),1.54(s,6H),1.39-1.29(m,2H),1.28-1.18(m,2H),1.18-1.09(m,2H),1.05(d,J=6.2Hz,6H).

[0288] Example 44: 2-(4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] tert-Butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. To a solution of tert-butyl 3,3-difluoro-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate (1.81 g, 5.27 mmol) in xylene (30 mL) was added (trans 4-(dibenzylamino)cyclohexan-1-ol (3.11 g, 10.54 mmol), tetrabutylammonium bromide (0.340 g, 1.054 mmol), and potassium hydroxide (1.479 g, 26.4 mmol). The reaction mixture was heated to 30° C. for 24 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers The residue was washed with brine, dried over sodium sulfate, and filtered. The filtrate was taken and the volatile organics were removed under reduced pressure to give a pale yellow solid. The solid was taken up in ethyl acetate and purified on a silica gel column using 0-75% ethyl acetate in hexanes over 2000 mL. Fractions containing the desired product were combined and the volatile organics were removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.79 g, 3.30 mmol, 63% yield) as a colorless oil. MS (ESI) m / z 543.2 [M+1] + .

[0289] tert-Butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. To a solution of tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (2.65 g, 4.88 mmol) in methanol (50 mL) was added palladium on carbon (500 mg, 4.70 mmol). The air in the flask was evacuated and replaced with hydrogen (3×, 15 psi, balloon). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction was filtered through Celite. The filter cake was washed with additional methanol. The filtrate was taken and the volatile organics removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol, 97% yield) as a pale yellow oil. MS(ESI) m / z 363.2 [M+1] + .

[0290] tert-Butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate. To a solution of tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol) in acetonitrile (20 mL) was added methyl 2-bromo-2-methylpropanoate (1.718 g, 9.49 mmol), potassium iodide (0.079 g, 0.475 mmol), and potassium carbonate (1.312 g, 9.49 mmol). The reaction mixture was stirred at 110° C. for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was taken and the volatile organics removed under reduced pressure to give tert-butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (2.20 g, 4.76 mmol) as a yellow oil, which was carried forward without further purification. MS(ESI) m / z 463.2 [M+1] + .

[0291] tert-Butyl-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. To a solution of tert-butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (0.730 g, 1.578 mmol) in ethyl acetate (7 mL) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.360 g, 1.578 mmol) and diisopropylethylamine (0.827 mL, 4.73 mmol). The reaction vial was sealed and stirred at 90°C for 18 hours. The reaction mixture was partitioned between water and ethyl acetate. 5 mL of brine was added to reduce the emulsion. The organic layer was removed and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was saved and the volatile organics were removed under reduced pressure to give a foamy, deep orange semi-solid. The solid was absorbed in ethyl acetate and purified on a silica gel column using 0-100% ethyl acetate in hexanes over 1000 mL. Fractions containing the desired product were combined and the volatile organics removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (396 mg, 0.601 mmol, 38% yield) as a foamy orange semi-solid. MS(ESI) m / z 559.2 [M-99] + .

[0292] 4-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a solution of 4-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile, HCl (395 mg, 0.664 mmol, 110% yield) in 1,4-dioxane (3.0 mL) was added HCl (2.0 mL, 8.00 mmol) (4.0 M in dioxane). The reaction was stirred at ambient temperature for 90 minutes. The volatile organics were removed under reduced pressure to give 4-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (395 mg, 0.664 mmol) as a foamy orange semi-solid, which was carried forward without further purification. MS(ESI) m / z 559.2 [M+1] + .

[0293] 2-(4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a solution of 4-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.179 mmol) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (68.8 mg, 0.233 mmol) in N,N-dimethylformamide (2 mL, 0.09 M) was added diisopropylethylamine (0.094 mL, 0.537 mmol) and sodium iodide (0.027 g, 0.180 mmol, 1 equivalent). The reaction solution was stirred at 80 °C. After 22 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-(4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (55 mg, 0.066 mmol, 37% yield). MS (ESI) m / z 818.2 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 10.7-10.9(m,1H),10.2-10.4(m,1H),8.3-8.4(m,1H),8.2-8.2(m,1H),7.9-8.0(m,1H),7.0-7.1 (m,1H),6.9-7.0(m,1H),6.7-6.9(m,1H),6.4-6.5(m,1H),4.2-4.3(m,1H),3.9-4.2(m,2H),3.8-3 .9(m,2H),3.2-3.3(m,3H),2.7-2.9(m,3H),2.6-2.7(m,1H),2.2-2.3(m,2H),2.0-2.2(m,4H),1. 9-2.0(m,2H),1.6-1.8(m,3H),1.5-1.6(m,6H),1.4-1.5(m,1H),1.3-1.4(m,2H),1.2-1.3(m,2H).

[0294] Example 45: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide [ka] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a mixture of 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.100 g, 0.160 mmol) in pyridine (2 mL) was added 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.042 g, 0.190 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.02 mL, 0.640 mmol), and the reaction solution was heated to 50° C. After 8 hours, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.070 g, 0.083 mmol, 52% yield) as a yellow solid. MS (ESI) m / z 827.6 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.41(s,1H),9.15(d,J=2.0Hz,1H),8.75(d,J=1.6Hz,1H),7.02-6.97(m,2H),6.82(d,J=7.6Hz, 1H),6.40(d,J=7.6Hz,1H),5.89(d,J=8.0Hz,1H),4.32-4.26(m,1H),3.84(d,J=8.0Hz,1H),3.52(s,4H),3.32 -3.23(m,2H),3.16(s,2H),2.81(m,2H),2.74-2.65(m,3H),2.63-2.58(m,1H),2.10-2.02(m,3H),1.92-1.85( m,3H),1.74-1.68(m,2H),1.57(s,6H),1.34(d,J=12.0Hz,2H),1.14(q,J=11.2Hz,2H),1.05(d,J=6.4Hz,6H).

[0295] Example 46: 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] tert-Butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. To a solution of tert-butyl 3,3-difluoro-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate (1.81 g, 5.27 mmol) in xylene (30 mL) was added (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (3.11 g, 10.54 mmol), tetrabutylammonium bromide (0.340 g, 1.054 mmol), and potassium hydroxide (1.479 g, 26.4 mmol). The reaction mixture was heated to 30° C. for 24 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was taken and the volatile organics were removed under reduced pressure to give a pale yellow solid. The solid was absorbed in ethyl acetate and purified on a silica gel column using 0-75% ethyl acetate in hexanes over 2000 mL. Fractions containing the desired product were combined and the volatile organics were removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.79 g, 3.30 mmol, 63% yield) as a colorless oil. MS (ESI) m / z 543.2 [M+1] + .

[0296] tert-Butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. To a solution of tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (2.65 g, 4.88 mmol) in methanol (50 mL) was added palladium on carbon (500 mg, 4.70 mmol). The air in the flask was evacuated and replaced with hydrogen (3×, 15 psi, balloon). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction was filtered through Celite. The filter cake was washed with additional methanol. The filtrate was taken and the volatile organics removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol, 97% yield) as a pale yellow oil. MS(ESI) m / z 363.2 [M+1] + .

[0297] tert-Butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate. To a solution of tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol) in acetonitrile (20 mL) was added methyl 2-bromo-2-methylpropanoate (1.718 g, 9.49 mmol), potassium iodide (0.079 g, 0.475 mmol), and potassium carbonate (1.312 g, 9.49 mmol). The reaction mixture was stirred at 110° C. for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was taken and the volatile organics removed under reduced pressure to give tert-butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (2.20 g, 4.76 mmol) as a yellow oil, which was carried forward without further purification. MS(ESI) m / z 463.2 [M+1] + .

[0298] tert-Butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. To a solution of tert-butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (1.47 g, 3.18 mmol) in ethyl acetate (14 mL) was added 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (0.728 g, 3.18 mmol) and diisopropylethylamine (1.665 mL, 9.53 mmol). The reaction vial was sealed and stirred at 90°C for 18 hours. The reaction mixture was partitioned between water and ethyl acetate. A few mL of brine was added to reduce the emulsion. The organic layer was removed and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was saved and the volatile organics were removed under reduced pressure to give a foamy, deep orange semi-solid. The solid was absorbed into ethyl acetate and purified on a silica gel column using 0-100% ethyl acetate in hexanes over 1800 mL. Fractions containing the desired product were combined and the volatile organics removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.10 g, 1.667 mmol, 52% yield) as a foamy, pale orange semi-solid. MS(ESI) m / z 560.2 [M-99] + .

[0299] 5-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile hydrochloride. To a solution of tert-butyl 4-(2-(((1r,4r)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.10 g, 1.667 mmol) in 1,4-dioxane (5.0 mL) was added HCl (5.0 mL, 20.00 mmol) (4.0 M in dioxane). The reaction was stirred at ambient temperature for 90 minutes. The volatile organics were removed under reduced pressure to give 5-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile hydrochloride (1.08 g, 1.812 mmol) as a foamy orange semi-solid, which was carried forward without further purification. MS(ESI) m / z 560.2 [M+1] + .

[0300] 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate. To a solution of 5-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile, HCl (1.08 g, 1.812 mmol) in acetonitrile (15 mL) was added triethylamine (0.758 mL, 5.44 mmol) and tert-butyl 2-bromoacetate (1.338 mL, 9.06 mmol). The reaction vessel was sealed and stirred at 70° C. for 18 hours. The volatile organics were removed under reduced pressure to give an orange solid. The solid was taken up in dichloromethane and purified on a silica gel column using 0-100% ethyl acetate in hexanes over 2200 mL. Fractions containing the desired product were combined and the volatile organics removed under reduced pressure to give tert-butyl 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate (0.997 g, 1.480 mmol, 82% yield) as a foamy orange semi-solid. MS(ESI) m / z 674.2 [M+1] + .

[0301] 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetic acid hydrochloride. To a flask containing tert-butyl 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate (1.0 g, 1.484 mmol) was added HCl (10.0 mL, 40.0 mmol) (4.0 M in dioxane). The reaction mixture was stirred at ambient temperature for 3 hours. The volatile organics were removed under reduced pressure to give 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetic acid hydrochloride (1.14 g, 1.743 mmol) as a light brown solid, which was carried forward without further purification. MS(ESI) m / z 618.2 [M+1] + .

[0302] 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetic acid, HCl (100 mg, 0.153 mmol) in acetonitrile (1.0 mL) was added 3-((3-aminophenyl)amino)piperidine-2,6-dione (40.2 mg, 0.183 mmol), 1-methyl-1H-imidazole (0.049 mL, 0.612 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (86 mg, 0.306 mmol) and 1 mL DMF, and the reaction solution was stirred at room temperature. After 18 h, the reaction solution was diluted with DMSO and purified by standard methods to give 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (50 mg, 0.058 mmol, 38% yield) as a white solid. MS(ESI) m / z 819.2 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 10.79(s,1H),9.14(d,1H,J=2.0Hz),8.74(d,1H,J=2.0Hz),7.0-7.1(m,1H),6.95(s,1H),6.8-6.8(m,1 H),6.45(dd,1H,J=1.5,8.1Hz),4.26(dd,1H,J=4.6,11.2Hz),4.0-4.2(m,1H),3.8-3.9(m,1H),3.7-3. 8(m,1H),3.4-3.6(m,3H),3.3-3.4(m,1H),3.2-3.3(m,1H),3.0-3.2(m,1H),2.7-2.9(m,3H),2.6-2.6( m,1H),2.0-2.1(m,4H),1.8-2.0(m,2H),1.6-1.8(m,3H),1.57(s,6H),1.4-1.5(m,1H),1.3-1.4(m,2H).

[0303] アッセイ Cell ベースアッセイ VCAP AR Degradation Assay. Test compounds were pre-dispensed into Corning CellBind 96-well clear-bottom plates (Cat. No. 3300) using an acoustic dispenser to create a 10-point concentration series of 1:3 dilutions for each compound. The final highest concentration of each compound was 5 μM. DMSO at a final concentration of 0.1% was used as a control. VCaP cells cultured in DMEM with 8% fetal bovine serum (FBS) were seeded into compound plates at 50K cells per well in a volume of 200 μL and incubated at 37°C in a CO2 incubator for 24 hours. The medium was carefully removed from the cells, and the plates were placed on ice. 100 μL of Cell Signaling Technologies ice-cold 1x cell lysis buffer (Cat. No. 9803) was added to each well of cells, and the plates were incubated at 4°C on a shaker for 1 hour. 15 μL of cell lysate was used for AR ELISA detection using a PathScan Total Sandwich AR ELISA kit (Cell Signaling Technology, Cat. No. 12580). AR levels in compound-treated wells were normalized to those of the DMSO control and expressed as percent of control (PoC) (y). A four-parameter logistic model (sigmoidal dose-response model) was used to calculate the DC of the compound using the following formula: 50 and EC 50 It was decided that: y=(A+((BA) / (1+((C / x)^D)))) A=Y Min (Lowest AR levels normalized to DMSO control in response to compound treatment, determined by curve fit) B=Y Max (Maximum AR level determined by curve fitting) C=EC 50 D = Hill gradient x=compound concentration EC 50 =y=(Y Max -Y Min ) / 2, the concentration of the compound DC 50=y=Concentration of the compound in the case of 50% of the DMSO control (50% AR degradation) y=AR protein level normalized to the DMSO control

[0304] The AR degradation efficiency mediated by the compound was characterized using the lowest AR level measurement value normalized to the DMSO control in response to compound treatment, referred to as the Y value.

[0305] Each of the compounds in Table 1 was tested in the VCAP AR degradation assay and was found to be active therein. All of the compounds in Table 1 were shown to have DC 50 <1 μM and Y < 50% of the DMSO control.

[0306] Prostate cancer cell proliferation assay. VCAP or ENZR cells were seeded at 10K cells per well in a 96-well CellBind (Costar) plate using DMEM + 8% FBS medium. The cells were incubated overnight at 37 °C, and the test compounds were serially diluted and added to the wells. After 7 days of incubation, the assay medium was removed by inversion, and the plates were frozen at -80 °C overnight. The plates were thawed at room temperature, and 100 μL of deionized water (ddH2O) was added to each well. The plates were incubated at 37 °C in a non-CO2 incubator for 1 hour and then frozen at -80 °C overnight. The plates were thawed at room temperature, and 100-μL TNE buffer (NaCl, Tris, EDTA) + Hoescht dye (1.0 mg / ml, 1:400) was added to each well. The fluorescence signal was measured at 460 nm. All data were normalized as a percentage relative to the DMSO control. A four-parameter logistic model (sigmoidal dose-response model) was used to determine the GI 50 value of the compound using the following equation. y=(A+((B - A) / (1+((C / x)^D)))) A = Y Min (Lowest cell viability in luminescence units normalized to the DMSO control in response to compound treatment, determined by curve fitting) B = Y Max(Maximum cell viability measured as luminescence units normalized to DMSO control determined by curve fit) C=EC 50 D = Hill gradient GI 50 =Y=(Y Max +Y t0 ) / 2, the concentration of the compound EC 50 =y=(Y Max -Y Min ) / 2, the concentration of the compound I C 50 = Y = Compound concentration at 50% of DMSO control y = cell viability measured as luminescence units and normalized as a percentage relative to the DMSO control t0 = time when compound was added Y t0 = the value of y at t0

[0307] The compounds provided herein have been or will be tested in prostate cancer cell proliferation assays and have been or will be shown to have activity therein.

[0308] In vivo assay AR Degradation Assay. In vivo AR degradation assays were performed in NSG mice bearing VCaP prostate cancer xenograft tumors. Male NSG mice were inoculated with VCaP cells in the flank region on the right leg. After inoculation of the animals, tumors grew to approximately 500 mm 3 The animals were allowed to grow to 100°C and then randomized. Randomized animals were administered test compounds formulated in 20% Labrasol, 80% 25 mM citrate buffer, pH 3. Compounds were orally administered once daily for 3 days. After the last dose of compound administration, plasma and tumors were collected and processed for AR degradation assay. Intratumoral AR levels were measured using Western blot analysis. Statistical analysis was performed using one-way analysis of variance (ANOVA).

[0309] The compounds provided herein have been tested or are scheduled to be tested in an in vivo AR degradation assay and have been shown or will be shown to be active therein.

[0310] VCaP prostate cancer xenograft model. Xenograft studies were performed in male NSG mice bearing VCaP prostate cancer xenograft tumors. VCaP cells were subcutaneously inoculated into the flank region on the right hind limb of male NSG mice. After inoculation of the animals, the tumors were allowed to grow to approximately 200 mm 3 and then randomly assigned. During randomization, mice having VCaP tumors in the range of 75 - 250 mm 3 were pooled and randomly assigned to various treatment groups. Test compounds formulated in 20% Labrasol, 80% 25 mM citrate buffer pH 3 were administered at a dosing volume of 5 mL / kg. The compounds were orally administered once daily for the duration of the study. Tumors were measured twice weekly using calipers, and tumor volume was calculated using the formula W 2 ×L / 2. Statistical analysis was performed using one-way or two-way analysis of variance (ANOVA).

[0311] The compounds provided herein have been tested or are scheduled to be tested in the VCAP prostate cancer xenograft model and have been shown or will be shown to be effective as a treatment for prostate cancer in the model.

[0312] Activity table Each of the compounds in Table 1 was tested in one or more of the AR degradation assays shown above, e.g., the VCAP AR degradation assay, and was found to be active therein.

[0313] All of the compounds in Table 1 were shown to have DC 50 ≤ 1 μM and Y < 50% of the DMSO control, and some of the compounds had DC 50 value C: DC 50 ≤ 0.005 μM, some had DC 50 value B: 0.005 μM < DC 50 ≤ 0.010 μM, and other compounds had DC 50 value A: 0.010 μM < DC50 has ≦ 0.1 μM.

[0314] Furthermore, the compound is shown to have an AR degradation efficiency Y value < 50% of the DMSO control, a part of the compound has 0 < Y ≦ 15% (indicated by *), a part of the compound has 15% < Y ≦ 20% (indicated by **), and other compounds have 25% < Y < 50% (indicated by ***).

[0315] [Table 2]

[0316] [[ID=十六]] [[ID=十七]] [Table 3]

[0317] [Table 4]

[0318] [Table 5]

[0319] [Table 6]

[0320] [Table 7]

[0321] [Table 8]

[0322] [Table 9]

[0323] [Table 10]

[0324] Table 11

[0325] Table 12

[0326] Table 13

[0327] Table 14

[0328] Table 15

[0329] Table 16

[0330] Table 17

[0331] Table 18

[0332] Table 19

[0333] Table 20

[0334] [Table 21]

[0335] [Table 22]

[0336] [Table 23]

[0337] Several references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. Formula I 【Chemistry 1】 [In the formula, R Ｎ is H; n is 0 to 4; Each R １ is halogen, CN and C １～３ independently selected from alkyl; a is 1 or 2; R ２ and R ３ is H and C １～３ alkyl, or R ２ and R ３ and the carbon to which they are attached may be a substituted or unsubstituted C ３～６ Forming a cycloalkyl; m is 0 to 8; Each R ４ are independently substituted or unsubstituted C １～３ alkyl or two R ４ The groups may be substituted or unsubstituted C ３～６ Form a cycloalkyl, or two R ４ groups, together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4- to 7-membered heterocyclyl; X is N or CR Ｘ and R Ｘ is hydrogen, halogen, -O(C １～６ alkyl) or -(C １～９ alkyl); L is a substituted or unsubstituted —O(C １～６ alkyl)-, -(C １～６ alkyl)O—, —O(C １～６ alkyl)O- or -(C １～９ alkyl)-; V is, 【Chemistry 2】 wherein B is N, CH or CR Ｂ and Each R Ｂ represents halogen and substituted or unsubstituted C １～６ independently selected from alkyl; R Ｃ is a halogen, CF ３ or science fiction ５ and R ５ and R ６ is C １～３ alkyl or R ５ and R ６ are substituted or unsubstituted C together with the carbon atom to which they are attached. ３～６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; and b is 0 to 2. or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

2. n is 0, a is 1, and R ２ and R ３ and R are both H.

3. Each R ４ However, methyl and CF ３ 3. The compound of claim 1 or 2, independently selected from:

4. The compound according to any one of claims 1 to 3, wherein m is 0, 1, 2, 3 or 4.

5. X is N or CR Ｘ and R Ｘ is hydrogen, halogen, -O(C １～６ alkyl) or -(C １～９ The compound according to any one of claims 1 to 4, wherein the aryl group is aryl, ...

6. L is a substituted or unsubstituted —O(CH ２ ) ｐ -, -O(CH ２ ) ｐ O- or -(CH ２ ) ｐ - and p is 1 to 4.

7. The compound of any one of claims 1 to 6, wherein B is CH or N.

8. R Ｃ But CF ３ , Cl or SF ５ The compound according to any one of claims 1 to 7,

9. R ５ and R ６ The compound according to any one of claims 1 to 8, wherein is methyl.

10. Formula II 【Transformation 3】 [In the formula, R Ｎ is H; Each R ４ｍ is independently hydrogen or substituted or unsubstituted methyl, the substituents, if present, being selected from 1 to 5 halo; X is N or CR Ｘ and R ｘ is hydrogen, halogen, -O(C １～６ alkyl) or -(C １～９ alkyl); L is a substituted or unsubstituted —O(C １～３ alkyl)-, -O(C １～３ alkyl)O- or -(C １～４ alkyl)-; V is, 【Chemistry 4】 and B is N or CH; R Ｃ is a halogen, CF ３ or science fiction ５ and R ５ and R ６ is C １～３ alkyl] 10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, having the formula:

11. 2. The compound of claim 1 selected from Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

12. 12. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

13. A method for treating an androgen receptor mediated disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12.

14. 14. The method of claim 13, wherein the androgen-mediated disease is prostate cancer.

15. 15. The method of claim 14, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

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