Cereblon binding compound, composition thereof, and treatment method by the same

Abstract

A piperidine dione compound having the following structure, a composition comprising an effective amount of the piperidine dione compound, and a method for treating or preventing androgen receptor-mediated diseases are provided herein: [Chemical Formula I] (In the above formula, RN, R1, R2, R3, R4, RN, L, V, X, a, m, and n are as defined herein).

Description

Technology Field

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 043,555 filed on June 24, 2020, the disclosures of which are incorporated herein by reference in their entirety.

[0003] Technology field

[0004] Provided herein is provided a method for treating or preventing an androgen receptor-mediated disease, comprising a compound, a composition comprising an effective amount of such compound, and the step of administering an effective amount of such compound to a subject requiring treatment or prevention of an androgen receptor-mediated disease. Compounds and compositions for use in these methods are also provided herein. Background Technology

[0005] 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 (Chen Y et al., Lancet Oncol, 2009, 10:981-91; Mills IG, Nat Rev Cancer , 2014, 14:187-98; Taplin ME, Nat Clin Pract Oncol , 2007, 4:236-44; Wirth MP et al., Eur Urol , 2007, 51(2):306-13). Inhibiting androgen receptor signaling with antiandrogens that antagonize androgen receptors has been used or proposed for the treatment of prostate cancer.

[0006] Androgen receptors are typically located in the cytoplasm bound to chaperones, such as HSP90 (Brinkmann AO et al., J Steroid Biochem Mol Biol , 1999, 69:307-13). When binding to dihydrotestosterone (DHT), the androgen receptor changes its conformation and translocates to the nucleus, where it binds to the androgen-responsive element (ARE), which induces the transcription of canonical targets, such as KLK3 (prostate-specific antigen, also known as PSA) (Tran C et al., Science , 2009, 324:787-90; Murtha P et al., Biochemistry (Mosc.), 1993, 32:6459-64).

[0007] Prostate cancer (PCa) is one of the most frequently diagnosed non-cutaneous cancers among men in the United States and is the second most common cause of cancer death in the U.S., with over 200,000 new cases and over 30,000 deaths annually.

[0008] Androgen-deprivation therapy (ADT) is the standard treatment for advanced PCa. Patients with advanced PCa receive ADT via LHRH agonists, LHRH antagonists, or bilateral orchectomy. Despite an initial response to ADT, disease progression is inevitable, and the cancer emerges as castration-resistant prostate cancer (CRPC). Up to 30% of patients with prostate cancer treated with radiation or surgery will develop metastatic disease within 10 years of receiving first-line treatment. Approximately 50,000 patients develop metastatic disease annually, which is referred to as metastatic CRPC (mCRPC).

[0009] There remains a significant need for safe and effective methods to treat, prevent, and manage AR-mediated diseases, particularly those 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 therapy.

[0010] Any citation or identification of any reference in this section of the present application shall not be construed as an acknowledgment that such reference is prior art relating to the present application.

[0011] Compounds having the following chemical formula I, or pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers thereof are provided herein:

[0012] [Chemical Formula I]

[0013]

[0014] (In the above formula, R N , R 1 , R 2 , R 3 , R 4 , X, L, V, a, m and n are as defined in this specification).

[0015] Compounds of Formula I, or their pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, are useful for treating or preventing androgen receptor-mediated diseases in subjects.

[0016] In one embodiment, for example, compounds as described in Table 1 of the present disclosure are provided in this specification.

[0017] In one embodiment, a pharmaceutical composition comprising an effective amount of a compound as described herein and a pharmaceutically acceptable carrier, excipient, or vehicle is provided herein. In one embodiment, a pharmaceutical composition comprising an effective amount of a compound as described herein and a pharmaceutically acceptable carrier, excipient, or vehicle is provided herein. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration.

[0018] In one embodiment, a method for treating or preventing an androgen receptor-mediated disease in a subject is provided herein, said method comprising the step of administering to a subject in need of such a compound an effective amount as described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In one embodiment, a method for treating or preventing an androgen receptor-mediated disease in a subject is provided herein, said method comprising the step of administering to a subject in need of such a compound an effective amount as described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In another embodiment, a compound for use in a method for treating an androgen receptor-mediated disease is provided herein. In another embodiment, a compound for use in a method for treating an androgen receptor-mediated disease is provided herein.

[0019] In another embodiment, a method for preparing a compound as described herein is provided herein. In another embodiment, a method for preparing a compound as described herein is provided herein.

[0020] The present embodiment may be more fully understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. Specific details for implementing the invention

[0021] definition

[0022] As used herein, the terms “comprising” and “comprising” may be used interchangeably. The terms “comprising” and “comprising” should be interpreted as specifying the presence of the feature or component referred to, but do not exclude the presence or addition of one or more features or components, or a group thereof. Additionally, the terms “comprising” and “comprising” are intended to include examples included by the term “comprising”. Consequently, the term “comprising” may be used instead of the terms “comprising” and “comprising” to provide more specific embodiments of the invention.

[0023] The term “consisting of” means that the subject-matter has at least 90%, 95%, 97%, 98%, or 99% of the mentioned features or components constituting it. In another embodiment, the term “consisting of” excludes any other features or components from any subsequent enumeration, excluding those that are not essential to the technical effect to be achieved.

[0024] As used herein, the term "or" shall be interpreted as an inclusive "or" meaning any one or any combination. Accordingly, “A, B or C” means any of “A; B; C; A and B; A and C; B and C; A, B and C.” An exception to this definition will occur only where a combination of elements, functions, steps, or actions is inherently mutually exclusive in any way.

[0025] The "alkyl" group is a saturated, partially saturated, or unsaturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbons, or in some embodiments, 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; meanwhile, saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. In some embodiments, the alkyl group is an unsaturated alkyl group, which is also referred to as an alkenyl or alkynyl group. The “alkenyl” group is an alkyl group containing one or more carbon-carbon double bonds. The “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(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3). The alkyl group may be substituted or unsubstituted.Where the alkyl group described herein is described as "substituted," these include any substituent or substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogens; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocycliloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclilalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclilamino, heteroarylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclilalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; Hydroxylamino; alkoxyamino; ar-alkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or may be substituted with -B(OH)2.In certain embodiments, where the alkyl group described herein is described as "substituted," these include any substituent or substitutes such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (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; It can be substituted with B(OH)2 or O(alkyl)aminocarbonyl.

[0026] The “cycloalkyl” group is a saturated or partially saturated cyclic alkyl group having 3 to 10 carbon atoms having a single cyclic ring or a plurality of condensed or crosslinked rings that may be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6, or 3 to 7. In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, for example, a single ring structure, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or a plurality of or cross-linked 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, etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include, in particular, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl group may be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol.

[0027] The “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, the aryl group contains 6 to 14 carbons within the ring portion of the group, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms. Specific aryls include phenyl, biphenyl, naphthyl, etc. The aryl group may be substituted or unsubstituted. The phrase “aryl group” also includes a group containing a fused ring, such as a fused aromatic-aliphatic ring system (e.g., indanyl, tetrahydronaphthyl, etc.).

[0028] A “heteroaryl” group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms within a heteroaromatic ring system, with the remaining atoms being carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms within the ring portion of the group, and in other embodiments, 6 to 9 or even 6 to 10 atoms. 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, isooxazolyl, benzisooxazolyl (e.g., benzo[d]isooxazolyl), 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, Groups such as triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isooxazolopyridyl, thianaphthalenyl, furinyl, xanthinyl, adeninyl, guaniyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinoline-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl are included, but not limited to, groups. Heteroaryl groups may be substituted or unsubstituted.

[0029] “Heterocyclile” 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, the heterocyclile group comprises 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclile may also be bonded to another group at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). The heterocycloalkyl group may be substituted or unsubstituted. The heterocyclile group comprises unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The term heterocyclil includes fused ring species comprising fused aromatic and non-aromatic groups, such as 1- and 2-aminotetraline, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxolyl, and benzo[1,3]dioxolyl. This term also includes cross-linked polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclideyl.Representative examples of heterocyclil groups include aziridinyl, azetidinyl, azephanyl, oxetanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolill, imidazolidinyl, pyrazolill, pyrazolidinyl, triazolillyl, tetrazollyl, oxazolillyl, isooxazolillyl, benzisooxazolillyl (e.g., benzo[d]isooxazolillyl), thiazolillyl, thiazolidinyl, isothiazollyl, thiadiazolillyl, oxadiazolillyl, piperidyl, and piperazinyl (e.g., piperazine-2-onyl). Morfollinil, thiomophorinil, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranill, oxatianil, dioxyl, dithianil, pyranil, pyridyl, pyrimidyl, pyridazinil, pyrazinil, triazinil, dihydropyridyl, dihydrodithiinil, dihydrodithionyl, 1,4-dioxaspiro[4.5] Decanyl, homopiperazinyl, quinucridyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl, 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]imidazolyl-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzoditinyl, benzoxatininyl, benzothiazinyl, benzoxazolyl (i.e., Benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]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, isooxazolopyridyl, furinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinoline-1(2H)-onyl), quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naftiridinyl, pteridinyl, Tianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidine-2(1H)-one, and tetrahydroquinolinyl groups are included but not limited thereto. Representative non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups.Examples of non-aromatic heterocyclil groups include aziridinyl, azetidinyl, azephanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranill, oxatianil, dithianil, 1,4-dioxaspiro[4.5]decanil, homopiperazinyl, quinuclideyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclil groups may be unsubstituted or substituted more than once, and include pyridyl or morpholinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with various substituents such as those listed below, for example, but not limited to.

[0030] As used herein and unless otherwise specified, the “cycloalkylalkyl” group is a radical of the formula -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above. A substituted cycloalkylalkyl group may be substituted at the alkyl portion, the cycloalkyl portion, or both the alkyl portion and the cycloalkyl portion of this group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, etc.

[0031] As used herein and unless otherwise specified, the “aralkyl” group is a radical of the formula -alkyl-aryl, where alkyl and aryl are defined above. The substituted aralkyl group may be substituted in the alkyl portion, the aryl portion, or both the alkyl portion and the aryl portion of this group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and aralkyl groups in which an aryl group is fused to a cycloalkyl group, such as indan-4-yl ethyl.

[0032] As used herein and unless otherwise specified, the “heterocyclylalkyl” group is a radical of the formula -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. The “heteroarylalkyl” group is a radical of the formula -alkyl-heteroaryl, where alkyl and heteroaryl are defined above. The “heterocycloalkylalkyl” group is a radical of the formula -alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above. A substituted heterocyclylalkyl group may be substituted in the alkyl portion, the heterocyclyl portion, or both the alkyl portion and the heterocyclyl portion of this group. Representative heterocyclylalkyl groups include, but are not limited to, morpholine-4-yl ethyl, morpholine-4-yl propyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indole-2-yl propyl.

[0033] "Halogens" are fluorine, chlorine, bromine, or iodine.

[0034] The “hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxyl groups.

[0035] The “alkoxy” group is -O-(alkyl), where alkyl is defined above.

[0036] The “alkoxyalkyl” group is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0037] The “amino” group has the chemical formula -NH2, -NH(R # ), or -N(R # It is a radical of )2, where each R # is 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.

[0038] In one embodiment, the “amino” group is an “alkylamino” group that is a radical of the formula -NH-alkyl or -N(alkyl)2, wherein each alkyl is independently defined above. The terms “cycloalkylamino”, “arylamino”, “heterocyclylamino”, “heteroarylamino”, “heterocycloalkylamino”, etc., reflect the above description of “alkylamino”, wherein the term “alkyl” is replaced by “cycloalkyl”, “aryl”, “heterocyclyl”, “heteroaryl”, “heterocycloalkyl”, etc., respectively.

[0039] The “carboxy” group is a radical with the chemical formula -C(O)OH.

[0040] As used herein and unless otherwise specified, the “acyl” group is defined by the formula -C(O)(R # It is a radical of ) or -C(O)H, where R # is defined above. The “formyl” group is a radical of the chemical formula -C(O)H.

[0041] As used herein and unless otherwise specified, the “amido” group is defined by the formula -C(O)-NH2, -C(O)-NH(R # ), -C(O)-N(R # )2, -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H, or -N(R# )-C(O)-(R # It is a radical of ), where each R # is independently defined above.

[0042] In one embodiment, the “amido” group has the chemical formula -C(O)-NH2, -C(O)-NH(R # ), -C(O)-N(R # It is an “aminocarbonyl” group, which is the radical of )2, where each R # is independently defined above.

[0043] In one embodiment, the “amido” group has the chemical formula -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H, or -N(R # )-C(O)-(R # It is an “acylamino” group, which is the radical of ), where each R # is independently defined above.

[0044] The “sulfonylamino” group has the chemical formula -NHSO2(R # ) or -N(alkyl)SO2(R # It is a radical of ), where each alkyl and R # is defined above.

[0045] The “urea” group has the chemical formula -N(alkyl)C(O)N(R # )2, -N(alkyl)C(O)NH(R # ), -N(alkyl)C(O)NH2, -NHC(O)N(R # )2, -NHC(O)NH(R # ), or -NH(CO)NH2 radicals, where each alkyl and R # is independently as defined above.

[0046] Where groups described herein excluding alkyl groups are described as "substituted," they may be substituted with any suitable substituents. Exemplary examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; 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)2, O(alkyl)aminocarbonyl; cycloalkyl (which may be monocyclic or fused or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl)), or heterocyclic (which may be monocyclic or fused or unfused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl)); Monocyclic or fused or unfused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isooxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acrridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

[0047] As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base, including inorganic acids and inorganic bases, and organic acids and organic bases. Suitable pharmaceutically acceptable base-added salts of the compound of Formula I include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or metal salts prepared 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, campersulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromide, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, parmoic 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, hydrobromide, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Therefore, specific examples of salts include hydrochloride salts, formate salts, and mesylate salts. Others are well known in the art, for example, in the literature [ Remington's Pharmaceutical Sciences , 18 th eds., Mack Publishing, Easton PA (1990)] or literature[ Remington: The Science and Practice of Pharmacy , 19 th See eds., Mack Publishing, Easton PA (1995)].

[0048] As used herein and unless otherwise indicated, the terms “stereoisomer” or “stereoisomerically pure” mean one stereoisomer of a compound in which there are substantially no other stereoisomers of the compound provided herein. For example, a stereoisomerically pure compound having one chiral center will have substantially no opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will have substantially no other diastereomers of the compound. A conventionally stereoisomerically pure compound comprises one stereoisomer of the compound in greater than about 80 weight percent and another stereoisomer of the compound in less than about 20 weight percent, one stereoisomer of the compound in greater than about 90 weight percent and another stereoisomer of the compound in less than about 10 weight percent, one stereoisomer of the compound in greater than about 95 weight percent and another stereoisomer of the compound in less than about 5 weight percent, or one stereoisomer of the compound in greater than about 97 weight percent and another stereoisomer of the compound in less than about 3 weight percent. The compound may have a chiral center and may exist as a racemic mixture, individual enantiomers or diastereomers, and mixtures thereof. All such isomer forms, including mixtures thereof, are included within the embodiments disclosed herein.

[0049] The use of stereoisomerically pure forms of such compounds, as well as the use of mixtures of such forms, is included by the embodiments disclosed herein. For example, a mixture containing enantiomers of a specific compound in equal or unequal amounts may be used in the methods and compositions disclosed herein. These isomers may be synthesized or cleaved asymmetrically using standard techniques such as chiral columns or chiral cleaving agents. For example, the literature [Jacques, J., etal., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981)]; Literature[Wilen, SH, et al., Tetrahedron 33:2725 (1977)]; literature[Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962)]; literature[Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972)]; Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014)]; Literature [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)]; Literature[Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological ProductsRefer to [John Wiley & Sons, 2011].

[0050] Additionally, it should be noted that the compound may include E and Z isomers, or a mixture thereof, and cis and trans isomers, or a mixture thereof. In certain embodiments, the compound is isolated as either the E isomer or the Z isomer. In other embodiments, the compound is a mixture of E and Z isomers.

[0051] "Tautomers" refer to isomer forms of a compound that are in equilibrium with one another. The concentrations of the isomer forms will depend on the environment in which the compound is found, and may differ, for example, depending on whether the compound is a solid or in an organic or aqueous solution. For example, in an aqueous solution, pyrazole may exhibit the following isomer forms, which are referred to as tautomers with one another:

[0052] .

[0053] As is readily understood by those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compound of Formula I are within the scope of the present invention.

[0054] Additionally, it should be noted that the compounds provided herein may contain atomic isotopes in non-natural proportions at one or more atoms. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I), Hwang-35( 35 S), or carbon-14 ( 14 It can be radiolabeled with C), for example, deuterium ( 2 H), carbon-13( 13 C), or nitrogen-15( 15It can be isotopically enriched with N). As used herein, "isotopolog" is an isotopically enriched compound. The term "isotopically enriched" refers to such an atom having an isotopic composition other than the atom's natural isotopic composition. "Isotopically enriched" may also refer to a compound containing at least one such atom having an isotopic composition other than the atom's natural isotopic composition. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are therapeutic agents, e.g., cancer treatments, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo contrast agents ( in vivo It is useful as an imaging agent. Regardless of whether it is radioactive, all isotopic variants of the compound as described herein are intended to be included within the scope of the embodiments provided herein. In some embodiments, an isotopic of the compound is provided, for example, the isotopic is a compound enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, “deuterided” means that at least one hydrogen (H) is deuterium (D or 2 It refers to a compound replaced by (represented by H), that is, this compound is enriched with deuterium at at least one position.

[0055] It is understood that, regardless of stereoisomer composition or isotopic composition, each compound mentioned herein may be provided in the form of any pharmaceutically acceptable salt discussed herein. Likewise, it is understood that the isotopic composition may vary independently of the stereoisomer composition of each compound mentioned herein. Furthermore, the isotopic composition may vary independently of the choice of the pharmaceutically acceptable salt of each compound, although otherwise limited to the elements present in each compound or its salt.

[0056] It should be noted that if there is a discrepancy between the planned structure and its name, greater weight should be given to the planned structure.

[0057] As used herein, “treating” means alleviating, wholly or partially, one or more of a disorder, disease or condition, or symptoms associated with a disorder, disease, or condition, or slowing or stopping the further progression or worsening of such symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is an androgen receptor-mediated disease as described herein, or a symptom thereof.

[0058] As used herein, “preventing” means a method of delaying, and / or making impossible, the onset, recurrence, or spread of a disorder, disease, or condition, wholly or partially; preventing a subject from acquiring a disorder, disease, or condition; or reducing the risk of a subject acquiring a disorder, disease, or condition. In one embodiment, the disorder is an androgen receptor-mediated disease as described herein, or a symptom thereof.

[0059] With respect to compounds, the term "effective amount" means an amount capable of treating or preventing any disorder, disease, or condition, or symptoms thereof, disclosed herein.

[0060] As used herein, the terms “subject” and “patient” include, but are not limited to, animals such as cattle, monkeys, horses, sheep, pigs, chickens, ostriches, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment include mammals, and in another embodiment include humans. In one embodiment, the subject is a human who has or is at risk of having an androgen receptor-mediated disease or symptoms thereof.

[0061] As used herein, the terms “androgen receptor,” “AR,” or “NR3C4” refer to a nuclear hormone receptor that is activated by the binding of an androgen hormone, including testosterone or dihydrotestosterone. The term “androgen receptor” may refer to a nucleotide sequence or protein sequence of a human androgen receptor (e.g., Entrez 367, Uniprot P10275, RefSeq NM_000044, or RefSeq NP_000035).

[0062] As used herein, the term “AR-full length” (AR-FL) refers to an AR protein containing all four functional domains, including an N-terminal transcriptional activation domain (NTD, exon 1), a DNA-binding domain (DBD, exon 2 and exon 3), a hinge domain (exon 4), and a C-terminal ligand binding domain (LBD, exons 4 to 8).

[0063] The term "castration-resistant prostate cancer (CRPC)" refers to advanced prostate cancer that is worsening or progressing while the patient is continuing androgen deprivation therapy or other therapies to reduce testosterone, or prostate cancer considered to be 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 is treated with previous surgical castration, gonadotropin-releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutetamide), chemotherapy agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), and kinase inhibitors (imatinib (Gleevec)).® ) or gefitinib (Iressa ® ), Cabozantinib (Cometriq ® , also known as XL184)) or other prostate cancer therapies (e.g., vaccine (Cipuleucel-T (Provenge ® It is defined as prostate cancer that continues to progress or worsen or has an adverse effect on the patient's health, as evidenced by an increase or higher serum levels of prostate-specific antigen (PSA), metastasis, bone metastasis, pain, lymph node involvement, increase in size and serum markers for tumor growth, deterioration of diagnostic markers of prognosis, or the patient's condition, despite continued treatment with (e.g., GVAX, etc.), herbal (PC-SPES), and lyase inhibitor (abiraterone)).

[0064] compound

[0065] Compounds having the following chemical formula I, or pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers thereof are provided herein:

[0066] [Chemical Formula I]

[0067]

[0068] (In the above formula,

[0069] R N is H;

[0070] n is 0 to 4 and;

[0071] Each R 1 is independently halogen, CN, and C 1-3 Selected from alkyls;

[0072] a is 1 or 2 and;

[0073] R 2 and R 3 H and C, respectively, independently 1-3 Selected from alkyl, or R 2 and R 3 and the carbons to which they are attached are substituted or unsubstituted carbons. 3-6Forming a cycloalkyl;

[0074] m is 0 to 8 and;

[0075] Each R 4 is independently substituted or non-substituted C 1-3 It is alkyl, or two R 4 The groups are substituted or unsubstituted carbon atoms, together with the same carbon atom or adjacent carbon atoms to which they are attached. 3-6 Forming a cycloalkyl group or two Rs 4 The groups form a substituted or unsubstituted quaternary to hypnotic heterocyclile together with the non-adjacent carbon atoms to which they are attached;

[0076] X is N or CR X And;

[0077] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0078] L is substitutable or non-substitutable -O(C 1-6 alkyl)-, (C 1-6 Alkyl)O-, -O(C 1-6 alkyl)O-, or -(C 1-9 alkyl)- and;

[0079] V is

[0080] is,

[0081] Here

[0082] B is N, CH, or CR B And;

[0083] Each R B is independently a halogen, and substituted or unsubstituted C 1-6 Selected from alkyls;

[0084] R C is a halogen, CF3 or SF5;

[0085] R 5 and R 6 C 1-3 alkyl or R 5and R 6 They are substituted or unsubstituted carbon atoms, together with the carbon atoms to which they are attached. 3-6 Forming a cycloalkyl or ternary to 6-membered heterocyclile;

[0086] b is 0 to 2).

[0087] Compounds having the following chemical formula I, or pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers thereof are provided herein:

[0088] [Chemical Formula I]

[0089]

[0090] (In the above formula,

[0091] R N is H;

[0092] n is 0 to 4 and;

[0093] Each R 1 is independently halogen, CN, and C 1-3 Selected from alkyls;

[0094] a is 1 or 2 and;

[0095] R 2 and R 3 H and C, respectively, independently 1-3 Selected from alkyl, or R 2 and R 3 and the carbons to which they are attached are substituted or unsubstituted carbons. 3-6 Forming a cycloalkyl;

[0096] m is 0 to 8 and;

[0097] Each R 4 is independently substituted or non-substituted C 1-3 It is alkyl, or two R 4 The groups are substituted or unsubstituted carbon atoms, together with the same carbon atom or adjacent carbon atoms to which they are attached. 3-6 Forming a cycloalkyl group or two Rs 4The groups form a substituted or unsubstituted quaternary to hypnotic heterocyclile together with the non-adjacent carbon atoms to which they are attached;

[0098] X is N or CR X And;

[0099] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0100] L is substitutable or non-substitutable -O(C 1-6 alkyl)-, (C 1-6 alkyl)O-, or -(C 1-9 alkyl)- and;

[0101] V is

[0102] is,

[0103] Here

[0104] B is N, CH, or CR B And;

[0105] Each R B is independently a halogen, and substituted or unsubstituted C 1-6 Selected from alkyls;

[0106] R C is a halogen, CF3 or SF5;

[0107] R 5 and R 6 C 1-3 alkyl or R 5 and R 6 They are substituted or unsubstituted carbon atoms, together with the carbon atoms to which they are attached. 3-6 Forming a cycloalkyl or ternary to 6-membered heterocyclile;

[0108] b is 0 to 2).

[0109] In some embodiments of the compound of Formula I, n is 0. In some embodiments of the compound of Formula I, a is 1, and R 2 and R 3Both are H. In some embodiments of the compound of formula I, each R 4 is a 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, here R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 It is an alkyl.

[0110] In some embodiments of the compound of Formula I, L is a substituted or unsubstituted -O(CH2) 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(CH2) p - and p is 2 or 3. In some embodiments of the compound of Formula I, L is substituted or unsubstituted -(CH2) p - and p is 3 or 4.

[0111] In some embodiments of the compound of Formula I, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-. In some embodiments of the compound of Formula I, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-. In some embodiments of the compound of Formula I, L is -O(CH2)(CH2)- or -(CH2)(CH2)(CH2)-.

[0112] In some embodiments of the compound of Formula I, B is CH. In some embodiments of the compound of Formula I, B is N. In some embodiments of the compound of Formula I, b is 0. In some embodiments of the compound 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 compound of chemical formula I, R 5 and R 6 It is methyl.

[0113] In some embodiments of the compound of Formula I, the compound is the compound of Formula II below, or a pharmaceutically acceptable salt, tautomeric isomer, isotope, or stereoisomer thereof:

[0114] [Chemical Formula II]

[0115]

[0116] (In the above formula,

[0117] R N is H;

[0118] Each R 4m is independently a hydrogen, or a substituted or unsubstituted methyl, wherein the substituent (when present) is selected from 1 to 5 halos;

[0119] X is N or CR X And;

[0120] R x is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0121] L is substitutable or non-substitutable -O(C 1-3 Alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)- and;

[0122] V is

[0123] is,

[0124] B is N or CH and;

[0125] R C is a halogen, CF3 or SF5;

[0126] R 5 and R 6 is C 1-3 (It is an alkyl).

[0127] In some embodiments of the compound of Formula I, the compound is the compound of Formula III below, or a pharmaceutically acceptable salt, tautomeric isomer, isotope, or stereoisomer thereof:

[0128] [Chemical Formula III]

[0129]

[0130] (In the above formula,

[0131] R N is H;

[0132] X is N or CR X And;

[0133] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0134] L is substitutable or non-substitutable -O(C 1-3 Alkyl)-, O(C 1-3alkyl)O- or -(C 1-4 alkyl)- and;

[0135] V is

[0136] is,

[0137] B is N or CH and;

[0138] R C is a halogen, CF3 or SF5;

[0139] R 5 and R 6 is C 1-3 (It is an alkyl).

[0140] In some embodiments of the compound of Formula I, the compound is the compound of Formula IV below, or a pharmaceutically acceptable salt, tautomeric isomer, isotope, or stereoisomer thereof:

[0141] [Chemical Formula IV]

[0142]

[0143] (In the above formula,

[0144] R N is H;

[0145] X is N or CR X And;

[0146] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0147] L is substitutable or non-substitutable -O(C 1-3 Alkyl)-, O(C 1-3 alkyl)O- or -(C 1-4 alkyl)- and;

[0148] V is

[0149] is,

[0150] B is N or CH and;

[0151] R C is a halogen, CF3 or SF5;

[0152] R 5 and R 6 is C 1-3 (It is an alkyl).

[0153] In some embodiments of the compounds of Formula I, Formula II, Formula III and Formula IV, n is 0; and X is N or CR X is, R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and; L is substituted or unsubstituted -O(CH2) p - or -(CH2) p - and, p is 1 to 4; B is CH or N; b is 0; and R C is CF3, Cl, or SF5; R C is CF3 and; R 5 and R 6 It is methyl.

[0154] In some embodiments of the compounds of Formula I, Formula II, Formula III and Formula IV, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-. In some embodiments of the compounds of Formula I, Formula II, Formula III and Formula IV, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0155] Additional embodiments provided in this specification include any combination of one or more of the specific embodiments presented above.

[0156] In some embodiments of the compound of chemical formula I, the compound is the compound of Table 1.

[0157] The compounds presented in Table 1 were tested in the AR-mediated assay described herein and were confirmed to have activity. In one embodiment, a compound described herein at a concentration of 1 μM leads to the degradation of AR proteins by at least about 50% or more.

[0158] Method for preparing piperidine dione compounds

[0159] The compounds described herein may be prepared using conventional organic synthesis and commercially available starting materials, or by the methods provided herein. For example and without limitation, compounds of Formula I (wherein R N , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R B , R C , L, V, X, n, m, a and b are as defined herein) can be produced in the reaction scheme shown below, as well as as schematically described in the examples presented herein. It should be noted that those skilled in the art will know how to modify the procedures presented in the exemplary reaction schemes and examples to obtain the desired product.

[0160] [Reaction Schema 1]

[0161]

[0162] As shown in Reaction Schema 1, chemical formula I Compound of (where X is N or CR X and L is -O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 Alkyl)-() is a base in a solvent (e.g., in DMF) at elevated temperature (e.g., from about 40°C to about 100°C). N,N - Piperidine derivative in the presence of diisopropylethylamine, or K2CO3 in acetonitrilea ester intermediate b (Here, LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate, and alk is an alkyl group, e.g., Me, Et, Bn, or tert Starting from reacting with -Buim) intermediate c It can be manufactured by providing. In some cases, an iodide salt (e.g., sodium iodide or potassium iodide) is used to promote this conversion. (e.g., when alk = Me, Et or other alkyl, by treatment with a hydroxide base in a solvent, e.g., LiOH in THF and water, or alk = tert -In the case of butyl, intermediate by treatment with an acid in the solvent, e.g., trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane c intermediate by removing the ester protecting group from d Obtains the intermediate d A coupling agent (e.g., HATU, HBTU, or EDC or TCFH (optional combined with HOBt)), and a base (e.g.,) in a solvent (e.g., DCM, DMF, NMP, or a mixture thereof) at a temperature of 0°C to about 70°C. N,N - Diisopropylethylamine, triethylamine, or N piperidine dione intermediate in the presence of -methylimidazole e Chemical formula coupled with I Compound of (where X is N or CR X and L is -O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 Alkyl)-im) is obtained. Alternatively, the intermediate c (Here, X is N and L is -O(C 1-3 alkyl)- or -(C 1-4With respect to alkyl-LG, the derivative VL-LG (where LG is a suitable leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) is heated at an elevated temperature (e.g., from about 40°C to about 80°C) in a solvent base (e.g., in DMF). N,N - A piperidyl ester derivative appropriately derivatized in the presence of diisopropylethylamine or K2CO3 in acetonitrile f (For example, here alk is an alkyl group, such as Me, Et, Bn, or tert Starting from reacting with -Buim) intermediate c It can be manufactured by providing.

[0163] [Reaction Diagram 2]

[0164]

[0165] chemical formula I The compound of (where, X is N and L is -O(C 1-3 alkyl)- or -(C 1-4 Alkyl)-LG is also, according to the alternative sequence shown in Reaction Schematic 2, derivative VL-LG (where LG is a suitable leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) in a base (e.g., in DMF) in a solvent at an elevated temperature (e.g., from about 40°C to about 100°C). N,N - A piperidyl derivative appropriately derivatized in the presence of diisopropylethylamine or K2CO3 in acetonitrile. g It can be prepared by reacting with. In some cases, iodide salts (e.g., sodium iodide or potassium iodide) are used to facilitate this conversion. Alternatively, the chemical formula I Compound of (where X is N or CR X and L is -O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 Alkyl)-Im) is a compound ea base in a solvent (e.g., in DCM) at a temperature of 0°C to about 60°C N,N - A carbonyl intermediate appropriately functionalized in the presence of diisopropylethylamine, or triethylamine in pyridine h Starting from reacting with a leaving group (where LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) to produce an intermediate i It can be manufactured by providing. i (Here, LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) at an elevated temperature (e.g., from about 40°C to about 80°C) in a base in a solvent (e.g., in DMF) N,N - In the presence of diisopropylethylamine, or K2CO3 in acetonitrile, amine intermediate a By reacting with... chemical formula I Compound of (where X is N or CR X and L is -O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 Obtain alkyl-im).

[0166] [Reaction Diagram 3]

[0167]

[0168] Intermediates, e.g., amines g It can be prepared according to Reaction Schema 3. Appropriately functioned piperazine j ...at an elevated temperature (e.g., from about 40°C to about 100°C), a base in a solvent (e.g., in DMF) N,N - In the presence of diisopropylethylamine, or acetonitrile (K2CO3), ester intermediate b (Here, LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate, and alk is an alkyl group, e.g., Me, Et, Bn, or tert Starting from reacting with -Buim) intermediate k...is obtained. In some cases, iodide salts (e.g., sodium iodide or potassium iodide) are used to promote this conversion. (e.g., when alk = Me, Et or other alkyl, by treatment with a hydroxide base in a solvent, e.g., LiOH in THF and water, or alk = tert -In the case of butyl, intermediate by treatment with an acid in the solvent, e.g., trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane k intermediate by removing the ester protecting group from l Obtains the intermediate l A coupling agent (e.g., HATU, HBTU, or EDC or TCFH (optional combined with HOBt)) and a base (e.g.,) in a solvent (e.g., DCM, DMF, NMP, or a mixture thereof) at a temperature of 0°C to about 70°C. N,N - Diisopropylethylamine, triethylamine, or N - In the presence of methylimidazole, piperidine dione intermediate e amine intermediate by coupling with g Obtains an intermediate, e.g., an amine f is (for example, P N In the case of this Boc, by treatment with an acid in a solvent at room temperature, e.g., dioxane or HCl in EtOAc, or by treatment with TFA in DCM at room temperature, or P N When this is Bn or Cbz, the intermediate is produced by hydrogenation by a metal catalyst in the solvent, e.g., palladium on carbon in methanol. k From N-protector P N It can be manufactured by removing.

[0169] [Reaction Diagram 4]

[0170]

[0171] Intermediate, for example a (Here, X is N and L is -O(C 1-3alkyl)- or -(C 1-4 Alkyl)-im) can be prepared according to Reaction Schematic 4. VL-LG(where L is -O(C 1-3 alkyl)- or -(C 1-4 alkyl)-, where LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) at an elevated temperature (e.g., from about 40°C to about 100°C) in a base (e.g., in DMF) in a solvent N,N - In the presence of diisopropylethylamine, or K2CO3 in acetonitrile, amine n Process as an intermediate o ...is obtained. In some cases, iodide salts (e.g., sodium iodide or potassium iodide) are used to facilitate this conversion. (e.g., P N In the case of this Boc, by treatment with an acid in a solvent at room temperature, e.g., dioxane or HCl in EtOAc, or by treatment with TFA in DCM at room temperature, or P N When this is Bn or Cbz, the intermediate is produced by hydrogenation by a metal catalyst in the solvent, e.g., palladium on carbon in methanol. o From N-protector P N Remove the intermediate a (Here, X is N and L is -O(C 1-3 alkyl)- or -(C 1-4 Obtain alkyl-im).

[0172] [Reaction Diagram 5]

[0173]

[0174] Intermediate, e.g., VLR Z (For example, intermediate r )(here, R Z is an alcohol, protected alcohol, leaving group, or heterocycle (e.g., substituted piperidine or piperazine)) can be prepared according to Reaction Schematic 5. Ester intermediate p (Here, alk is an alkyl group, e.g., Me, Et, Bn, or tert -Buim) is appropriately derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile in the presence of a base, such as triethylamine, in a solvent, such as EtOAc, at an elevated temperature, for example, from about 70°C to about 90°C. q Process as intermediate r Obtains an intermediate, for example u (Here, LG is a leaving group (e.g., Cl, Br, I, trilate, or alkyl sulfonate), and L is -O(C 1-3 alkyl)- or -(C 1-4 Alkyl)-Im) is an intermediate s (Here, P O It can be manufactured from an alcohol protector, such as THP, TBS, acetate, or benzyl. s Internal protector P O (e.g., P O When it is THP, the alcohol intermediate is removed by treatment with a catalytic acid in the solvent (e.g., HCl in dioxane). t Obtains. t By activating the alcohol functional group within as a leaving group (e.g., when LG is Br, by thionyl bromide in dichloromethane t (by processing), intermediate u (Here, LG is a leaving group (e.g., Cl, Br, I, trilate, or alkyl sulfonate), and L is -O(C 1-3 alkyl)- or -(C 1-4 Alkyl)-im) is obtained, and this is further reacted to obtain the chemical formula I A compound of can be obtained.

[0175] [Reaction Diagram 6]

[0176]

[0177] intermediate p (Here, L is -O(C 1-3 alkyl)- and, R Z is protected alcohol OP O(e.g., THP ether or TBS ether), e.g. aa a can be prepared according to reaction scheme 6. Alcohol intermediate v (Here, P N Starting from an amine protecting group, e.g., Bn or Boc), an electrophile is formed in the presence of a base (e.g., KOH and tetrabutylammonium bromide in xylene) in a solvent, optionally with a catalyst, at an elevated temperature, e.g., 70°C to 130°C. w (Here, LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate, and P O is reacted with an oxygen protector (e.g., THP or TBS) to produce an intermediate x Obtains. x Internal protector P N ul (e.g., P N When this is Bn, by hydrogenation by palladium on carbon in methanol, or P N In the case of this Boc, the amine intermediate is removed by treatment with HCl in dioxane. y Obtains amine y ester z (Here, alk is an alkyl group, e.g., Me, Et, Bn, or tert -Bu, and LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) reacted with an intermediate aa Obtaining, and further reacting to obtain the chemical formula I The compound of (where, L is -O(C 1-3 Alkyl)-im) can be obtained.

[0178] [Reaction Schema 7]

[0179]

[0180] intermediate p(Here, L is -(C 1-3 alkyl)- and, R Z is an alcohol or protected alcohol (e.g., THP ether or TBS ether), e.g. hh α can be prepared according to Reaction Schematic 6. Aldehyde intermediate bb (Here, P N Starting from an amine protecting group, e.g., Bn or Boc), react with an olefinizing reagent (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) in the presence of a base in a solvent at a temperature of 0°C to 60°C to produce an olefin intermediate. cc [] is obtained by hydrogenation in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at boosted pressure (e.g., 10 to 100 psi). cc Reduce the intermediate dd The intermediate is obtained by achieving reduction of the ester functional group by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at a temperature of -78°C to 25°C. ee (Here, R Y (is H) can be obtained. Alternatively, the intermediate cc The intermediate is treated with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at a temperature of -78°C to 25°C. ff By obtaining the intermediate ee It can be manufactured. At boosted pressure (e.g., 10 to 100 psi) in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere). ff hydrogenate the intermediate ee Obtains. ee Internal protector P N ul (e.g., P N When this is Bn, by hydrogenation by palladium on carbon in methanol, or P NIn the case of this Boc, the amine intermediate is removed by treatment with HCl in dioxane. gg Obtains amine gg ester z (Here, alk is an alkyl group, e.g., Me, Et, Bn, or tert -Bu, and LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) reacted with an intermediate hh (Here, R Y is H or an alcohol protecting group (e.g., THP, TBS, or Tr) is obtained, and this is further reacted to obtain the chemical formula I The compound of (where, L is -(C 1-3 Alkyl)-im) can be obtained.

[0181] [Reaction Diagram 8]

[0182]

[0183] intermediate p (Here, L is -(C 1-3 Alkyl)O- and, R Z is a heterocyclic or cycloalkyl group), for example mm This can be prepared according to reaction scheme 8. Intermediate ii (Here, P N’ Starting from (where is an amine protecting group, e.g., Bn or Boc, and LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate), an alcohol is formed in the presence of a base (e.g., KOH and tetrabutylammonium bromide in xylene) in a solvent, optionally with a catalyst, at an elevated temperature (e.g., 70°C to 130°C). jj (Here, P N react with an amine protecting group (e.g., Bn or Boc) to form an ether intermediate kk Obtains. kk Internal protector P N’ ul (e.g., P N’ When this is Bn, by hydrogenation by palladium on carbon in methanol, or P N In the case of this Boc, the amine intermediate is removed by treatment with HCl in dioxane. ll Obtain.

[0184] amine ll At an elevated temperature (e.g., about 70°C to 130°C), in the presence of a base (e.g., potassium carbonate and potassium iodide in acetonitrile) with an optional iodide salt in a solvent, the ester z (Here, alk is an alkyl group, e.g., Me, Et, Bn, or tert -Bu, and LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) reacted with an intermediate mm Obtaining, and further reacting to obtain the chemical formula I The compound of (where, L is -(C 1-3 Alkyl (O-im) can be obtained.

[0185] [Reaction Schema 9]

[0186]

[0187] specific intermediate p (Here, L is -O(C 1-3 alkyl)- and, R Z is a protected heterocyclic or cycloalkyl group), for example qq In the case of alcohol, the modified order shown in Reaction Schema 9 can be used. v (Here, P N Starting from an amine protecting group, e.g., Bn or Boc), an electrophilic intermediate is formed in a solvent at an elevated temperature (e.g., 70°C to 130°C) in the presence of a base (e.g., KOH and tetrabutylammonium bromide in xylene) with a catalyst, optionally. nn(Here, LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate, and P N’ react with an amine protecting group (e.g., Bn or Boc) to form an ether intermediate oo Obtains. oo Internal protector P N ul (e.g., P N’ When this is Bn, by hydrogenation by palladium on carbon in methanol, or P N In the case of this Boc, the amine intermediate is removed by treatment with HCl in dioxane. pp Obtains amine pp ester z (Here, alk is an alkyl group, e.g., Me, Et, Bn, or tert -Bu, and LG is a leaving group, e.g., Cl, Br, I, trilate, or alkyl sulfonate) reacted with an intermediate qq Obtaining, and further reacting to obtain the chemical formula I The compound of (where, L is -O(C 1-3 Alkyl)-im) can be obtained.

[0188] [Reaction Diagram 10]

[0189]

[0190] intermediate nn (Here, X is CR Z Specific examples of (im), for instance vv was prepared according to Reaction Schematic 10. Ketone intermediate rr (Here, P N(is an amine protecting group (e.g., Bn, Boc, or Cbz)) is olefinized at a temperature of 0°C to 60°C using an olefinizing reagent and a base (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) to produce an olefin intermediate ss ...is obtained. At boosted pressure (e.g., 10 to 100 psi) in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere). ss hydrogenate the intermediate tt ...is obtained by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at a temperature of -78°C to 25°C. tt Achieves reduction of the ester functional group within the intermediate uu Obtains alcohol uu Activating the intermediate with the leaving group LG (e.g., by treatment with thionyl bromide in dichloromethane and DMF when LG is Br, or by treatment with tritric acid anhydride in dichloromethane when LG is trilate) vv Obtaining, and further reacting to obtain the chemical formula I The compound of (where, L is -O(C 1-3 alkyl)- and X is CR X Can obtain (Im).

[0191] [Reaction Diagram 11]

[0192]

[0193] R 1 - Derived 3-nitroaniline ww Starting from, amine protecting group P N as (here, P N This, for example in the case of Boc, is protected by treatment with Boc2O in the presence of a base, such as TEA, DIEA, or DBU, in a solvent, such as THF, NMP, or DMF, thereby protecting the intermediate xxBy forming, a suitably derivatized 3-((3-aminophenyl)amino)piperidine-2,6-dione e Manufactures the intermediate xx By reducing the nitro groups within (in the presence of a catalyst, e.g., Pd / C, in a solvent, e.g., EtOH or MeOH; or by treatment with a reducing agent, e.g., H2, in the presence of Fe and NH4Cl, in a solvent, e.g., EtOH and H2O), a mono-protected derivatized dianiline intermediate yy The intermediate is obtained in the presence of a base in a solvent (e.g., NaHCO3, CsCO3, or K2CO3 in DMF or NMP at an elevated temperature, e.g., from about 50°C to about 80°C; or DIEA in DMF or NMP at an elevated temperature, e.g., about 150°C). yy After coupling to 3-bromopiperidin-2,6-dione, protector P N By removing (e.g., P N In the case of this Boc, the intermediate is treated with an acid in the solvent, e.g., TFA in DCM; or treated with HCl in dioxane or EtOAc. e is obtained. Alternatively, (for example, by reacting at an elevated temperature, for example, from about 80°C to about 100°C, in the presence of Zn, TMSCl, FeCl2*4H2O in a solvent, such as NMP) the intermediate xx After performing iron-catalyzed reductive coupling of 3-bromopiperidine-2,6-dione, the protecting group P N By removing (e.g., P N In the case of this Boc, the intermediate is treated with an acid in the solvent, e.g., TFA in DCM; or treated with HCl in dioxane or EtOAc. e Obtains.

[0194] How to use

[0195] In one embodiment, the compound described herein has utility as a medicine for treating, preventing, or improving a disease in animals or humans. The compound described herein has utility as a medicine for treating, preventing, or improving a disease in animals or humans. Accordingly, many uses of the compound, including the treatment or prevention of the disease presented below, are provided in this specification. In one embodiment, the method provided in this specification includes the step of administering an effective amount of the compound to a subject in need thereof.

[0196] The method provided in this specification includes the step of administering an effective amount of one or more compounds to a subject in need of it.

[0197] A method for treating or preventing androgen receptor (AR)-mediated disease in a subject is provided herein, and the method comprises the step of administering an effective amount of a compound as described herein to a subject who requires it.

[0198] A method for treating or preventing an AR-mediated disease in a subject is provided herein, and the method comprises the step of administering an effective amount of a compound as described herein to a subject who requires it.

[0199] In another embodiment, a compound for use in the treatment or prevention of an AR-mediated disease in a subject is provided herein, and the method comprises the step of administering an effective amount of the compound as described herein to a subject who requires it. In some embodiments, a compound for use in the treatment of an AR-mediated disease in a subject is provided herein, and the method comprises the step of administering an effective amount of the compound as described herein to a subject who requires it. In some embodiments, a compound for use in the prevention of an AR-mediated disease in a subject is provided herein, and the method comprises the step of administering an effective amount of the compound as described herein to a subject who requires it.

[0200] In some embodiments, the compound used in the method of this specification is a compound as described in this specification. 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.

[0201] 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.

[0202] 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 another embodiment, the prostate cancer is non-metastatic CRPC (nmCRPC). In some embodiments, the prostate cancer is hormone-refractory. In some embodiments, the prostate cancer exhibits resistance to treatment with AR antagonists. For example, the prostate cancer exhibits resistance 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.

[0203] A method for reducing AR levels is provided herein, said method comprising the step of administering an effective amount of a compound to a subject. In vivo, in vitro ( ex vivo ) or in vitro ( in vitroCompounds for use in a method for reducing AR levels within cells are also provided herein, said method comprising the step of contacting cells with an effective amount of the compound. In one embodiment, the cells are present in a patient. In one embodiment, the cells are not present in a patient. In one embodiment, a method for reducing wild-type AR levels within a tumor is provided herein, said method comprising the step of reducing wild-type AR levels within a tumor by administering a therapeutically effective amount of the compound. In one embodiment, a method for reducing AR-full length (AR-FL) levels within a tumor is provided herein, said method comprising the step of reducing AR-full length (AR-FL) levels within a tumor by administering a therapeutically effective amount of the compound. In some embodiments, AR levels are reduced relative to AR levels prior to administration of the compound. In some embodiments, AR levels are reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% relative to AR levels prior to administration of the compound.

[0204] A method for controlling the protein activity of AR in a patient requiring control of the protein activity of AR is also provided herein, said method comprising the step of administering a predetermined amount of a compound to said patient. In some such embodiments, a method for reducing the protein activity of AR in a patient requiring reduction of the protein activity of AR is provided herein, said method comprising the step of administering a predetermined amount of a compound to said patient. In some embodiments, the protein activity of AR is reduced relative to the protein activity of AR prior to administration of the compound. In some embodiments, the protein activity of AR is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% relative to the protein activity of AR prior to administration of the compound.

[0205] In some embodiments of the method described herein, the method further comprises the step of administering one or more second agents, wherein the second agents are selected from AR antagonists (e.g., cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), 5α-reductase inhibitors (e.g., finasteride and dutasteride), CYP17A1 inhibitors (e.g., abiraterone acetate), gonadotropin-releasing hormone (GnRH) analogs (e.g., leuprorelin and cetrorelix), and antigonadotropins (e.g., megestrol acetate and medroxyprogesterone acetate).

[0206] In some embodiments, the compounds provided in this specification may be used in any of the methods mentioned above.

[0207] In some embodiments, the compounds provided in this specification may be used in any of the methods mentioned above.

[0208] Pharmaceutical composition and route of administration

[0209] The compounds provided in this specification may be administered orally, topically, or parenterally to a subject in the conventional form of formulations such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0210] The compound may be administered orally, topically, or parenterally to a subject in the conventional form of preparations such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations include conventional organic or inorganic additives, such as 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., magnesium stearate, hard anhydrous silica, talc, or sodium lauryl sulfate), flavorings (e.g., citric acid, menthol, glycine, or orange powder), and preservatives (e.g., sodium benzoate, sodium bisulfite, It may be prepared by a commonly used method using methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinylpyrroliclon or aluminum stearate), a dispersant (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and a base wax (e.g., cocoa butter, white petroleum jelly or polyethylene glycol). An effective amount of the compound in the pharmaceutical composition may be a level that produces the desired effect, and such level may be, for example, about 0.005 mg / kg (subject body weight) to about 10 mg / kg (subject body weight) per unit dose for both oral and parenteral administration.

[0211] The dose of the compound to be administered to the subject may vary significantly and may be subject to the judgment of a healthcare professional. Generally, the compound may be administered 1 to 4 times a day at a dose of about 0.001 mg / kg (subject body weight) to about 10 mg / kg (subject body weight), but the said dose may vary appropriately depending on the subject's age, weight, medical condition, and type of administration. In one embodiment, the dose is about 0.001 mg / kg (subject body weight) to about 5 mg / kg (subject body weight), about 0.01 mg / kg (subject body weight) to about 5 mg / kg (subject body weight), about 0.05 mg / kg (subject body weight) to about 1 mg / kg (subject body weight), about 0.1 mg / kg (subject body weight) to about 0.75 mg / kg (subject body weight), or about 0.25 mg / kg (subject body weight) to about 0.5 mg / kg (subject body weight). In one embodiment, a single dose is given per day. In any given case, the amount of compound administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0212] In another embodiment, a method for treating or preventing a disease or disorder is provided herein, the method comprises the step of administering a compound to a subject in need of the same amount of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0213] In another embodiment, a unit dosage formulation comprising a compound of 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 is provided herein.

[0214] In certain embodiments, unit dosage formulations comprising about 0.1 mg or 100 mg of a compound are provided herein.

[0215] In another embodiment, a unit dosage formulation comprising a compound of 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 is provided herein.

[0216] The compound may be administered once, twice, three times, four times or more daily. In a specific embodiment, a dose of 100 mg or less is administered as a once-daily dose, and a dose of more than 100 mg is administered twice daily as half of the total daily dose.

[0217] The compound may be administered orally for convenience. In one embodiment, when administered orally, the compound is administered with a meal 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 is administered orally as a solution or suspension.

[0218] The compound may also be administered to the ears, nose, eyes, or skin via intradermal, intramuscular, intraperitoneal, transdermal, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, vaginal, transdermal, rectal, mucosal, inhalation, or topically. The method of administration is at the discretion of a healthcare professional and may depend in part on the site of the medical condition.

[0219] In one embodiment, a capsule containing a compound without additional carrier, excipient, or vehicle is provided herein.

[0220] In another embodiment, a composition comprising an effective amount of a compound and a pharmaceutically acceptable carrier or vehicle is provided herein, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0221] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, and suspensions. The composition may be formulated to contain a daily dose, or a convenient amount of a daily dose, within a dosage unit which may be a single tablet or capsule or a liquid of a convenient volume. In one embodiment, the solution is prepared from a water-soluble salt, such as a hydrochloride salt. Generally, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules may be prepared by mixing the compound with a suitable carrier or diluent and filling a suitable amount of the mixture into the capsule. Conventional carriers and diluents include, but are not limited to, inert powdered materials, such as many different types of starch, powdered cellulose, particularly crystalline and microcrystalline cellulose, sugars, such as fructose, mannitol, and sucrose, grain flour, and similar edible powders.

[0222] Tablets can be manufactured by direct compression, wet granulation, or dry granulation. The formulation typically incorporates not only the compound but also diluents, binders, lubricants, and disintegrants. Conventional diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugars. Powdered cellulose derivatives are also useful. Conventional tablet binders are starch, gelatin, and sugars such as lactose, fructose, glucose, etc. Natural and synthetic gums, including acacia, alginate, methylcellulose, polyvinylpyrrolidine, etc., are also convenient. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0223] A lubricant may be required in the tablet formulation to prevent the tablets and punches from sticking together in the dye. The lubricant may be selected from slippery solids such as talc, magnesium stearate and calcium stearate, stearic acid, and hydrogenated vegetable oil. A tablet disintegrant is a substance that swells upon wetting to break down the tablet and release a compound. These include starch, clay, cellulose, algin, and gum. 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 carboxymethyl cellulose may be used, as well as sodium lauryl sulfate. The tablets may be coated with sugars as flavoring agents and sealants, or coated with film-forming protective agents to modify the dissolution properties of the tablets. The composition can also be formulated as a chewable tablet, for example, by using a substance such as mannitol in the formulation.

[0224] When a compound is required to be administered as a suppository, a conventional base may be used. Cocoa butter is a traditional suppository base, which can be modified by adding wax to slightly raise its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0225] The effect of the compound may be delayed or extended by an appropriate formulation. For example, a slowly soluble pellet of the compound may be prepared and introduced into a tablet or capsule, or introduced as a slow-release insertable device. This technique also includes the steps of preparing pellets with several different dissolution rates and filling a capsule with a mixture of pellets. The tablet or capsule may be coated with a film that resists dissolution for a predictable period. Furthermore, parenteral formulations may be prepared as long-acting formulations by dissolving or suspending the compound in an oily or emulsified vehicle that allows for slow dispersion in serum.

[0226] Listed implementation examples

[0227] The present invention can be defined by referring to the exemplary embodiments listed below.

[0228] 1. Compounds of Formula I, or pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers thereof:

[0229] [Chemical Formula I]

[0230]

[0231] (In the above formula,

[0232] R N is H;

[0233] n is 0 to 4 and;

[0234] Each R 1 is independently halogen, CN, and C 1-3 Selected from alkyls;

[0235] a is 1 or 2 and;

[0236] R 2 and R 3 H and C, respectively, independently 1-3 Selected from alkyl, or R 2 and R 3 and the carbons to which they are attached are substituted or unsubstituted carbons. 3-6 Forming a cycloalkyl;

[0237] m is 0 to 8 and;

[0238] Each R 4 is independently substituted or non-substituted C 1-3 It is alkyl, or two R 4 The groups are substituted or unsubstituted carbon atoms, together with the same carbon atom or adjacent carbon atoms to which they are attached. 3-6 Forming a cycloalkyl group or two Rs 4 The groups form a substituted or unsubstituted quaternary to hypnotic heterocyclile together with the non-adjacent carbon atoms to which they are attached;

[0239] X is N or CR X And;

[0240] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0241] L is substitutable or non-substitutable -O(C 1-6 Alkyl)-, -(C 1-6 Alkyl)O-, -O(C 1-6 alkyl)O-, or -(C 1-9 alkyl)- and;

[0242] V is

[0243] is,

[0244] Here

[0245] B is N, CH, or CR B And;

[0246] Each R Bis independently a halogen, and substituted or unsubstituted C 1-6 Selected from alkyls;

[0247] R C is a halogen, CF3 or SF5;

[0248] R 5 and R 6 C 1-3 alkyl or R 5 and R 6 They are substituted or unsubstituted carbon atoms, together with the carbon atoms to which they are attached. 3-6 Forming a cycloalkyl or ternary to 6-membered heterocyclile;

[0249] b is 0 to 2).

[0250] 2. A compound in which n is 0, in Embodiment 1.

[0251] 3. In Embodiment 1 or Embodiment 2, a is 1, and R 2 and R 3 A compound in which both are H.

[0252] 4. In any one of Embodiments 1 to 3, each R 4 is a compound that is a substituted or unsubstituted methyl.

[0253] 5. In any one of Embodiments 1 to 4, each R 4 is a compound independently selected from methyl and CF3.

[0254] 6. A compound in any one of Examples 1 to 5, wherein m is 0, 1, 2, 3, or 4.

[0255] 7. A compound in any one of Examples 1 to 5, wherein m is 1 or 2.

[0256] 8. A compound in any one of Examples 1 to 7, wherein X is N.

[0257] 9. In any one of Embodiments 1 to 7, X is CR Xand, here R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 A compound that is alkyl.

[0258] 10. In any one of Embodiments 1 to 9, L is a substituted or non-substituted -O(CH2) p -, -O(CH2) p O- or -(CH2) p - and, p is 1 to 4, a compound.

[0259] 11. In any one of Embodiments 1 to 9, L is a substituted or non-substituted -O(CH2) p - and, p is 2 or 3, a compound.

[0260] 12. In any one of Embodiments 1 to 9, L is a substituted or non-substituted -(CH2) p - and, p is 3 or 4, a compound.

[0261] 13. A compound in any one of Examples 1 to 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)-.

[0262] 14. A compound in any one of Examples 1 to 9, wherein L is -O(CH2)(CH2)- or -(CH2)(CH2)(CH2)-.

[0263] 15. A compound in any one of Examples 1 to 14, wherein B is CH.

[0264] 16. A compound in any one of Embodiments 1 to 14, wherein B is N.

[0265] 17. A compound in any one of Examples 1 to 16, wherein b is 0.

[0266] 18. In any one of Embodiments 1 to 17, R C is a compound that is CF3, Cl, or SF5.

[0267] 19. In any one of Embodiments 1 to 17, R C is a compound that is CF3.

[0268] 20. In any one of Embodiments 1 to 19, R 5 and R 6 It is methyl, a compound.

[0269] 21. In Embodiment 1, a compound having Formula II, or a pharmaceutically acceptable salt, tautomeric isomer, isotope, or stereoisomer thereof:

[0270] [Chemical Formula II]

[0271]

[0272] (In the above formula,

[0273] R N is H;

[0274] Each R 4m is independently a hydrogen, or a substituted or unsubstituted methyl, wherein the substituent (when present) is selected from 1 to 5 halos;

[0275] X is N or CR X And;

[0276] R x is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0277] L is substitutable or non-substitutable -O(C 1-3 Alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)- and;

[0278] V is

[0279] is,

[0280] B is N or CH and;

[0281] R C is a halogen, CF3 or SF5;

[0282] R 5 and R 6 is C 1-3 (It is an alkyl).

[0283] 22. In Embodiment 1, a compound having Formula III, or a pharmaceutically acceptable salt, tautomeric isomer, isotope, or stereoisomer thereof:

[0284] [Chemical Formula III]

[0285]

[0286] (In the above formula,

[0287] R N is H;

[0288] X is N or CR X And;

[0289] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0290] L is substitutable or non-substitutable -O(C 1-3 Alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)- and;

[0291] V is

[0292] is,

[0293] B is N or CH and;

[0294] R C is a halogen, CF3 or SF5;

[0295] R 5 and R 6 is C 1-3 (It is an alkyl).

[0296] 23. In Embodiment 1, a compound having Formula IV, or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof:

[0297] [Chemical Formula IV]

[0298]

[0299] (In the above formula,

[0300] R N is H;

[0301] X is N or CR X And;

[0302] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl) and;

[0303] L is substitutable or non-substitutable -O(C 1-3 Alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)- and;

[0304] V is

[0305] is,

[0306] B is N or CH and;

[0307] R C is a halogen, CF3 or SF5;

[0308] R 5 and R 6 is C 1-3 (It is an alkyl).

[0309] 24. In Embodiment 1, the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt, tautomeric, isotopic, or stereoisomer thereof.

[0310] 25. A pharmaceutical composition comprising any one of the compounds of Examples 1 to 24, or an effective amount of a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0311] 26. As a treatment method for androgen receptor-mediated diseases,

[0312] A method comprising the step of administering an effective amount of any one of the compounds in Examples 1 to 24 to a subject requiring this.

[0313] 27. As a treatment method for androgen receptor-mediated diseases,

[0314] A method comprising the step of administering an effective amount of the pharmaceutical composition of Embodiment 25 to a subject requiring this.

[0315] 28. Method in Embodiment 26 or Embodiment 27, wherein the androgen-mediated disease is prostate cancer.

[0316] 29. An embodiment of Example 28, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

[0317] Examples

[0318] The following examples are presented without limitation as examples. Compounds are named using an automatic naming tool provided by ChemBiodraw Ultra (Cambridgesoft) that generates systematic names for chemical structures based on the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art may modify the procedures presented in the exemplary examples to arrive at the desired product.

[0319] Salts of the compounds described herein may be prepared by standard methods, such as a method of including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or a method of stirring the product after chromatographic purification with a solution of acid (e.g., an aqueous solution of HCl).

[0320] Abbreviations used:

[0321]

[0322]

[0323] Examples 1: 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

[0324]

[0325] trans- 4-(dibenzylamino)cyclohexane-1-ol. In acetonitrile (900 mL) trans- Benzyl bromide (119 g, 698 mmol, 2.01 eq) was added dropwise to a mixture of 4-aminocyclohexan-1-ol (40 g, 347 mmol, 1.0 eq) and cesium carbonate (339 g, 1.04 mol, 3 eq). The reaction solution was stirred at room temperature. After 48 hours, the reaction mixture was filtered and concentrated. The resulting residue was diluted with DCM (300 mL), washed with water (100 mL x 3), dried with anhydrous sodium sulfate, and concentrated as a pale red solid trans- 4-(dibenzylamino)cyclohexane-1-ol (77 g, 261 mmol, 75% yield) was obtained. The crude product was transferred to the next step without further purification. MS (ESI) m / z 116.3 [M+1] + ; 1 1H NMR 400 MHz DMSO- d6 δ 7.27 - 7.34 (m, 8H), 7.19 - 7.21 (m, 2H), 4.42 (d, J = 4.8 Hz, 1H), 3.55 (s, 4H), 2.33 - 2.36 (m, 1H), 1.74 - 1.84 (m, 4H), 1.40 (dd, J = 12.4 Hz, 2.0 Hz, 2H), 0.98 (d, J = 13.2 Hz, 2H).

[0326] Trans-N,N -Dibenzyl-4-(2-((Tetrahydro-2 H -Pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine. in THF (400 mL) and water (200 mL) trans- 2-(2-bromoethoxy)tetrahydro-2 in a mixture of 4-(dibenzylamino)cyclohexan-1-ol (60 g, 203 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (13.8 g, 40.6 mmol, 0.2 eq) at 0°C H Pyran (84.9 g, 406 mmol, 61.5 mL, 2.0 eq) and sodium hydroxide (200 g, 5.00 mol, 24.6 eq) were added. The reaction solution was heated to 65°C. After 12 hours, the reaction solution was poured into ice water (1.0 L), and the aqueous phase was extracted with ethyl acetate (300 mL x 2). The combined organic layer was washed with brine (300 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The resulting crude material was purified by column chromatography (2 to 50% ethyl acetate in SiO2 petroleum ether) as a colorless oil Trans-N,N -Dibenzyl-4-(2-((Tetrahydro-2 H Pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (60 g, 142 mmol, 70% yield) was obtained. 1 H NMR 400 MHz CDCl3 δ 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).

[0327] trans- 4-(2-((tetrahydro-2 H -Pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine. In methanol (500 mL) Trans-N,N -Dibenzyl-4-(2-((Tetrahydro-2 H 10% palladium (6.5 g) on ​​carbon was added to a mixture of -pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (65 g, 153 mmol, 1.0 eq) under N2. The suspension was degassed under vacuum and purged three times with hydrogen gas. The reaction solution was stirred at room temperature under a hydrogen gas atmosphere (15 psi). After 1 hour, the reaction solution was filtered, and the filtrate was concentrated to produce an off-white oil. trans- 4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (46 g) was obtained. The crude material was transferred to the next step without further purification. 1 H NMR 400 MHz CDCl3 δ 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).

[0328] methyl 2-methyl-2-(( trans- 4-(2-((tetrahydro-2 H -Pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate. In acetonitrile (175 mL) trans- 4-(2-((tetrahydro-2 H Methyl 2-bromo-2-methylpropanoate (37.2 g, 205 mmol, 26.6 mL, 2.0 eq), potassium carbonate (28.4 g, 205 mmol, 2.0 eq), and potassium iodide (1.71 g, 10.3 mmol, 0.1 eq) were added to a mixture of pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (25 g, 103 mmol, 1.0 eq). The reaction solution was heated to 110°C. After 16 hours, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, and concentrated. The generated crude material is purified by column chromatography (SiO2, 0 to 50% ethyl acetate in petroleum ether) to obtain methyl 2-methyl-2-(( trans- 4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54 mmol, 53% yield) was obtained. MS (ESI) m / z 344.4 [M+1] + ; 1 H NMR ( 400 MHz CDCl3) δ 4.63 (t, J = 3.2 Hz, 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).

[0329] 4-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile . In ethyl acetate (130 mL), methyl 2-methyl-2-(( trans- 4-(2-((tetrahydro-2 H 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (24.7 g, 108 mmol, 2.0 eq) and in a solution of -pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54.2 mmol, 1.0 eq) and N,N -Diisopropylethylamine (14.0 g, 108 mmol, 2.0 eq) was added. The reaction solution was heated to 90°C while stirring. After 12 hours, the reaction solution was concentrated, and the resulting crude material was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain 4-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H -Pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (25 g, 46.3 mmol, 86% yield) was obtained.

[0330] 4-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. 4-(4,4-dimethyl-5-oxo-3-( in dichloromethane (300 mL) trans- 4-(2-((tetrahydro-2 H 400 mL of 4 M hydrochloric acid in 1,4-dioxane was added dropwise to a solution of -pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (42.5 g, 78.8 mmol, 1.0 eq). The reaction solution was stirred at room temperature. After 1 hour, the reaction solution was concentrated and purified by silica gel column chromatography (1 to 20% THF in dichloromethane) to obtain 4-(3-( trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (21 g, 46.1 mmol, 59% yield) was obtained. MS (ESI) m / z 456.4 [M+1] + ; 1 H NMR ( 400 MHz CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.85 (m, 1H), 7.72 (dd, J = 10.0 Hz, 1.6 Hz, 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).

[0331] 4-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. 4-(3-( in dichloromethane (80 mL) trans- In a mixture of 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (3.500 g, 7.72 mmol, 1.0 eq) at 0°C N,N -Dimethylformamide (8 mL) and thionyl bromide (3.201 g, 15.43 mmol, 2.0 eq) were added. After 12 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (9 to 20% ethyl acetate in petroleum ether) to obtain 4-(3-( trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (4.200 g, 8.13 mmol, crude state) was obtained. MS (ESI) m / z 518.1 [M+1] + .

[0332] tert -butyl (3 R ,5 S )-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. In THF (100 mL, 0.23 M) tert -butyl (3 S ,5 R A solution of )-3,5-dimethylpiperazine-1-carboxylate (5 g, 23.33 mmol, 1 eq), methyl bromoacetate (3.57 g, 23.33 mmol, 1 eq), and triethylamine (10.2 mL, 70 mmol, 3 eq) was stirred at 50°C. After 18 hours, the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10 to 100% ethyl acetate in hexane) to obtain a yellow oil. tert -butyl (3 R ,5 S )-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (6.2 g, 21.6 mmol, 92% yield) was obtained. MS (ESI) m / z 287.2 [M+1] + .

[0333] methyl 2-((2 R ,6 S )-2,6-dimethylpiperazine-1-yl)acetate . In dichloromethane (3 mL) tert -butyl (3 R ,5 STo a solution of )-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (1 g, 3.49 mmol, 1 eq), 4 M HCl in 1,4-dioxane (8.7 mL, 34.9 mmol, 10 eq) was added, and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated, neutralized with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate (5 x 50 mL). The combined organic layer was dried with anhydrous magnesium sulfate and concentrated to obtain methyl 2-((2) as a yellow oil. R ,6 S )-2,6-dimethylpiperazine-1-yl)acetate (510 mg, 2.72 mmol, 78% yield) was obtained. MS (ESI) m / z 187.5 [M+1] + .

[0334] methyl 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)acetate . 4-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (208 mg, 0.400 mmol, 1 eq), methyl 2-((2 R ,6 S In a solution of )-2,6-dimethylpiperazine-1-yl)acetate hydrochloride (116 mg, 0.520 mmol, 1.3 eq) and sodium iodide (79 mg, 0.5200 mmol, 1.3 eq) N,N -Dimethylformamide (3.2 mL, 0.13 M) and N,N -Diisopropylethylamine (0.17 mL, 0.960 mmol, 2.4 eq) was added. The reaction mixture was stirred at 60°C. After 48 hours, the reaction solution was concentrated, and the crude material was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexane) to obtain methyl 2-((2 as a yellow solidR ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)acetate (250 mg, 0.40 mmol, 97% yield) was obtained. MS (ESI) m / z 624.0 [M+1] + .

[0335] 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)acetic acid. Methyl 2-(2 in 3:1 water / THF (5 mL) R ,6 S )-4-(2-(( trans- Lithium hydroxide (100 mg, 4.17 mmol, 10 eq) was added to a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)acetate (250 mg, 0.400 mmol, 1 eq), and the reaction solution was stirred at room temperature. After 1 hour, the reaction solution was diluted with water, and the pH was adjusted to approximately 4 by adding 1 M hydrochloric acid. The solution was extracted with ethyl acetate (4 x 50 mL), the combined organic layer was dried with anhydrous sodium sulfate, and concentrated to obtain a pale orange solid, 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)acetic acid (218 mg, 0.358 mmol, 90% yield) was obtained. MS (ESI) m / z 610.0 [M+1] + .

[0336] tert -butyl (3-((2,6-dioxopiperidine-3-yl)amino)phenyl)carbamate. N,N - In dimethylformamide (1500 mL, 0.93 M) tert -butyl N Sodium bicarbonate (117 g, 1.9 mol, 1.4 eq) was added to a solution of -(3-aminophenyl)carbamate (290 g, 1.39 mol, 1 eq) and 3-bromopiperidin-2,6-dione (294 g, 1.53 mol, 1.1 eq). The reaction mixture was stirred at 80°C. After 16 hours, the reaction solution was cooled to 25°C and poured into ice water (4 L) to form a precipitate, which was filtered and dried. The solid was washed with ethyl acetate / petroleum ether (1:1, 2000 mL) and dried as a green solid tert -butyl (3-((2,6-dioxopiperidine-3-yl)amino)phenyl)carbamate (400 g, 1.25 mol, 90% yield) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6 ) 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 = 7.6 Hz, 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).

[0337] 3-((3-aminophenyl)amino)piperidine-2,6-dione . In dichloromethane (1500 mL, 0.42 M) tert Trifluoroacetic acid (770 g, 6.75 mol, 10.8 eq) was added to a suspension of γ-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (200 g, 626 mmol) at 0°C. The reaction solution was stirred at 25°C for 16 hours. The reaction solution was concentrated, and the residue was methyl tert-The mixture was diluted with butyl ether (2000 mL) and stirred at room temperature for 30 minutes. The resulting solid was filtered and dried to obtain a crude product (about 420 g) as a trifluoroacetate salt. The salt was dissolved in water (6 L), and the pH was adjusted to 7 to 8 by adding an aqueous solution of saturated sodium bicarbonate. The solution was filtered, and the filtrate was extracted with ethyl acetate (4 x 1500 mL). The combined organic layer was dried with anhydrous sodium sulfate and concentrated to obtain 3-((3-aminophenyl)amino)piperidine-2,6-dione (172 g, 392 mmol, 62% yield). 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.77 (s, 1H), 6.73 (t, J = 8.0 Hz, 1H), 5.91-5.86 (m, 3H), 5.41 (d, J = 7.2 Hz, 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).

[0338] 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. N,N -2-((2 in dimethylformamide (50 mL) R ,6 S )-4-(2-(( trans- In a mixture of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)acetic acid (2.500 g, 4.10 mmol, 1.0 eq) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (1.079 g, 4.92 mmol, 1.2 eq) N,N-Diisopropylethylamine (1.590 g, 12.30 mmol, 3 eq) and HATU (2.337 g, 6.15 mmol, 1.5 eq) were added. The reaction mixture was stirred at 60°C for 12 hours. The mixture was concentrated under vacuum and purified by standard methods to obtain 2-((2 as a yellow solid R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (1.150 g, 14.1 mmol, 35% yield) was obtained. MS (ESI) m / z 811.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.33 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 1.6, 8.4 Hz, 1H), 7.04 - 6.93 (m, 2H), 6.81 - 6.75 (m, 1H), 6.40 (dd, J = 1.6, 8.4 Hz, 1H), 5.89 (d, J = 8.0Hz, 1H), 4.33 - 4.23 (m, 1H), 3.92 - 3.74 (m, 1H), 3.53 (t, J = 6.0 Hz, 2H), 3.29 - 3.21 (m, 1H), 3.19 (s, 2H), 2.88 - 2.55 (m, 8H), 2.41 (br t, J = 6.0 Hz, 2H), 2.12 - 2.02 (m, 3H), 1.92 - 1.82 (m, 3H), 1.71 (br d, J= 10.4 Hz, 2H), 1.54 (s, 6H), 1.39 - 1.25 (m, 2H), 0.96 (d, J = 6.0 Hz, 6H).

[0339] Examples 2: 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

[0340]

[0341] tert -butyl ( trans- 4-Formylcyclohexyl)carbamate. In acetonitrile (1.60 L) tert -butyl ( trans- 4-(hydroxymethyl)cyclohexyl)carbamate (240 g, 1.05 mol, 1 eq) In a mixture of IBX (352 g, 1.26 mol, 1.2 eq) ...was added. The reaction mixture was stirred at 65°C for 1 hour. Two batches were combined for work-up and purification. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to form a white solid. tert -butyl ( trans- 4-formylcyclohexyl)carbamate (470 g, crude state) was obtained. The crude product was used directly in the next step without further purification. 1 ¹H NMR (400 MHz 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).

[0342] ethyl ( E )-3-( trans- 4-(( tert - Butoxycarbonyl)amino)cyclohexyl)acrylate. Sodium hydride (49.6 g, 1.24 mol, 60% purity, 1.2) in THF (900 mL) at 0℃ eq) Ethyl 2-(diethoxyphosphoryl)acetate (255 g, 1.14 mol, 1.1 eq) ...was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. In THF (500 mL) tert -butyl ( trans- 4-Formylcyclohexyl)carbamate (235 g, 1.03 mol, 1 eq) The solution was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was poured into ice water (3.0 L) and stirred for 20 minutes. The aqueous phase was extracted with ethyl acetate (800 mL, 500 mL). The combined organic phase was washed with brine (500 mL), dried with anhydrous sodium sulfate, and concentrated to obtain ethyl ( E )-3-( trans- 4-(( tert -Butoxycarbonyl)amino)cyclohexyl)acrylate (560 g, crude state) was obtained. This material was transferred to the next step without further purification. 1 ¹H NMR (400 MHz CDCl₃) δ 6.88 (dd, J = 15.6 Hz, 6.8 Hz 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).

[0343] tert-butyl (( trans- 4-(( E )-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate. The reaction was set up as two parallel reactions. Compound ethyl (1.12 L) in dichloromethane at -78°C under an argon atmosphere E )-3-( trans- 4-(( tert Diisobutylaluminum hydride (1 M, 1.88 L, 2 eq) was added to a solution of -butoxycarbonyl)amino)cyclohexyl)acrylate (280 g, 942 mmol, 1 eq). The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with MeOH (280 mL) at -60°C. The two reaction mixtures were combined and poured into saturated citric acid (1.0 kg of citric acid in 4.0 L of H2O) at less than 10°C. The mixture was extracted with ethyl acetate (2.0 L, 1.5 L). The combined organic layer was washed with an aqueous sodium bicarbonate solution (2.0 L) and brine (2.0 L), dried with anhydrous sodium sulfate, and concentrated. The crude material is purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to obtain tert-butyl as a pale yellow solid ( trans- 4-(( E )-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (420 g, 1.645 mol, 87% yield) was obtained. 1 ¹H NMR (400 MHz 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).

[0344] tert -butyl (( trans- 4-(3-hydroxypropyl)cyclohexyl)carbamate. Four batches of this reaction were carried out in parallel. tert-butyl (( trans-A mixture of 4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (105 g, 411 mmol, 1 eq) and palladium on carbon (10.5 g, 10% purity) was degassed, purged with H2 three times, and then the mixture was stirred at 25°C for 12 hours under H2 (15 psi). Four batches were combined for post-processing and purification. The reaction solution was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1). As a white solid 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). 1 ¹H NMR (400 MHz CDCl₃) δ 4.38 (s, 1H), 3.63 (t, J = 6.4 Hz, 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).

[0345] 3-( trans- 4-aminocyclohexyl)propan-1-ol Hydrochloride. Two reactions were carried out in parallel. In methanol (200 mL) tert -butyl ( trans- 4 M hydrochloric acid (500 mL) in methanol was added to a solution of 4-(3-hydroxypropyl)cyclohexyl)carbamate (115 g, 447 mmol, 1 eq). The reaction mixture was stirred at 15°C for 6 hours. Two batches were combined for post-treatment and purification. The reaction solution was filtered and concentrated to obtain 3-( trans-4-aminocyclohexyl)propan-1-ol hydrochloride (160 g, 92% yield) was obtained. This material was transferred to the next step without further purification. 1 1H NMR (400 MHz DMSO- d 6 ) δ 8.09 (s, 4H), 4.62 (s, 2H), 3.35 (t, J = 6.8 Hz, 2H), 2.87 (d, J = 4.4 Hz, 1H), 1.93 (d, J = 10.8 Hz, 2H), 1.73 (d, J = 12.8 Hz, 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).

[0346] methyl 2-(( trans- 4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate. 3- in acetonitrile (750 mL) trans- Potassium carbonate (428 g, 3.10 mol, 5 eq) and methyl 2-bromo-2-methylpropanoate (449 g, 2.48 mol, 4 eq) were added to a mixture of 4-aminocyclohexyl)propan-1-ol hydrochloride (120 g, 619 mmol, 1 eq). The mixture was stirred at 110°C for 12 hours. The reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (5 to 100% ethyl acetate in petroleum ether) to obtain methyl 2-(( trans- 4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 34% yield) was obtained. MS (ESI) m / z 258.2 [M+1] + .

[0347] 4-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile.Methyl 2-((in 350 mL of ethyl acetate trans- In a solution of 4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 1 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (62.2 g, 273 mmol, 1.3 eq) N,N -Diisopropylethylamine (54.2 g, 420 mmol, 2 eq) was added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (10 to 100% ethyl acetate in petroleum ether) to obtain 4-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (63 g, 139 mmol, 66% yield) was obtained. 1 ¹H NMR (400 MHz 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 = 12.8 Hz, 2H), 1.84 (d, J = 11.2 Hz, 2H), 1.61 (s, 7H), 1.29 - 1.37 (m, 5H), 1.05 - 1.08 (m, 2H).

[0348] 4-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. N,N - 4-(3-( in dimethylformamide (0.800 mL) and dichloromethane (8 mL) trans-Thionyl bromide (0.752 g, 3.620 mmol, 2 eq) was slowly added at 0°C to a solution of 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.820 g, 1.81 mmol, 1 eq). After stirring at 0°C for 2 hours, the reaction solution was concentrated and purified by silica gel column chromatography (15 to 25% ethyl acetate in petroleum ether) to obtain 4-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.650 g, 1.259 mmol, 70% yield) was obtained. MS (ESI) m / z 516.1 [M+1] + .

[0349] methyl 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetate. N,N -4-(3-( in dimethylformamide (4.8 mL, 0.2 M) trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (500 mg, 0.968 mmol, 1 eq) and methyl 2-((2 R ,6 S In a solution of )-2,6-dimethylpiperazine-1-yl)acetate (270 mg, 1.45 mmol, 1.5 eq). N,NDiisopropylethylamine (0.46 mL, 4.84 mmol, 5 eq) was added, 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 sodium bicarbonate aqueous solution (2 x 100 mL) and brine (100 mL). The organic layer was dried with anhydrous magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1 to 10% methanol in dichloromethane) and methyl 2-((2) as a pale yellow oil R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetate (487 mg, 0.784 mmol, 81% yield) was obtained. MS (ESI) m / z 622.3 [M+1] + .

[0350] 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid. Methyl 2-((2 in 5:1 THF / water (4 mL, 0.2 M) R ,6 S )-4-(3-( trans- Lithium hydroxide (59 mg, 2.46 mmol, 3 eq) was added to a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetate (500 mg, 0.82 mmol, 1 eq). The reaction solution was stirred at room temperature. After 12 hours, the reaction solution was diluted with water (10 mL), the pH adjusted to 5 by adding 2 M HCl, and extracted with ethyl acetate (4 x 50 mL). The combined organic layer was dried with anhydrous sodium sulfate and concentrated to obtain 2-((2 as a yellowish-white solid. R,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid (364 mg, 0.599 mmol, 73% yield) was obtained. MS (ESI) m / z 608.4 [M+1] + ; 1 ¹H NMR (400 MHz CDCl₃) δ 8.33 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 7.97 (d, J = 8.4 Hz, 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 = 12.0 Hz, 2H), 1.72 (d, J = 10.4 Hz, 2H), 1.44 - 1.54 (m, 8H), 1.15 - 1.19 (m, 3H), 1.05 - 1.08 (m, 2H), 1.01 (d, J = 6.4 Hz, 6H).

[0351] 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. N,N -2-((2 in dimethylformamide (4 mL) S ,6 R )-4-(3-( trans-In a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid (0.200 g, 0.33 mmol, 1.0 eq) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.108 g, 0.49 mmol, 1.5 eq) N,N -Diisopropylethylamine (0.128 g, 0.99 mmol, 3 eq) and HATU (0.188 g, 0.49 mmol, 1.5 eq) were added. The reaction mixture was stirred at 60°C for 12 hours. The mixture was purified by standard procedures to obtain 2-((2 as a yellow solid S ,6 R )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.108 g, 0.036 mmol, 40% yield) was obtained. MS (ESI) m / z 809.4 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.09 - 11.54 (m, 1H), 10.79 (s, 1H), 10.63 - 10.40 (m, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 1.6, 8.4 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.99 (s, 1H), 6.86 (br d, J = 8.0 Hz, 1H), 6.47 (dd, J = 1.2, 8.4 Hz, 1H), 4.27 (dd, J= 4.8, 11.2 Hz, 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, 8.8 Hz, 1H), 1.98 - 1.64 (m, 8H), 1.55 (s, 6H), 1.35 (d, J = 1.2 Hz, 6H), 1.28 - 0.97 (m, 6H).

[0352] Examples 3: 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( R )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0353]

[0354] ( 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, and the fraction was concentrated at a temperature below 35°C to obtain two peaks. The absolute configuration was determined by oscillatory 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) was isolated as a brown solid. SFC purification conditions (Column: Chiralpak IC-H, 250 x 30 mm, id 5 µm; Mobile phase: A: CO2 and B: EtOH:acetonitrile = 2:1; Gradient: B% = 40%; Flow rate: 75 g / min).

[0355] 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( R )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride . 2-((2 R ,6 S )-4-(2-(( trans- In a vial containing 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)acetic acid (250 mg, 0.41 mmol, 1 eq) R )-3-((3-aminophenyl)amino)piperidine-2,6-dione(107 mg, 0.49 mmol, 1.2 eq), N,N -Dimethylformamide (2.0 mL, 0.1 M), 1-methylimidazole (134 mg, 1.64 mmol, 8 eq), and N -(chloro(dimethylamino)methylene)- N-Methylmethaneamul hexafluorophosphate (230 mg, 0.82 mmol, 4 eq) was added. The reaction mixture was stirred at 25°C for 90 minutes. The reaction product was absorbed into dimethyl sulfoxide and purified over 20 minutes using semi-prep HPLC with 5 to 95% acetonitrile + 0.1% water and 0.1% trifluoroacetic acid. Fractions containing the desired product were combined, and volatile organic compounds were removed under reduced pressure to obtain a brown solid. The solid was absorbed into acetonitrile:water (1:1), and 1.0 N HCl solution (0.80 mL) was added. The solution was frozen and freeze-dried to obtain a brown solid of 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( R )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (139 mg, 0.157 mmol, 38% yield) was obtained. MS (ESI) m / z 811.4 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.34 (d, J = 8.31 Hz, 1H), 8.20 (d, J = 1.71 Hz, 1H), 7.97 (dd, J = 1.71, 8.19 Hz, 1H), 7.02-7.09 (m, 1H), 6.99 (br s, 1H), 6.87 (br d, J = 7.95 Hz, 1H), 6.47 (dd, J = 1.47, 8.19 Hz, 1H), 4.27 (dd, J= 4.89, 11.37 Hz, 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, 12.12 Hz, 1H), 1.67-1.78 (m, 2H), 1.55 (s, 6H), 1.27-1.45 (m, 8H).

[0356] Examples 4: 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0357]

[0358] 2-chloro-4-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H- Pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)benzonitrile. Methyl 2-methyl-2-((in ethyl acetate (1.3234 mL) trans- 4-(2-((tetrahydro-2 H- 2-chloro-4-isothiocyanato-benzonitrile (2.27 g, 11.65 mmol, 2 eq) and in a solution of pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate)2 g, 5.82 mmol, 1 eq) and N,N- Diisopropylethylamine (2.03 mL, 11.65 mmol, 2 eq) was added. The reaction solution was heated to 90°C while stirring. After 18 hours, the reaction solution was concentrated and purified by silica gel column chromatography (0 to 50% ethyl acetate in hexane) to obtain 2-chloro-4-(4,4-dimethyl-5-oxo-3-( trans-4-(2-((tetrahydro-2 H- Pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)benzonitrile (2 g, 3.9521 mmol, 68% yield) was obtained. MS (ESI) m / z 506.2 [M+1] + .

[0359] 2-chloro-4-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)benzonitrile. 2-chloro-4-(4,4-dimethyl-5-oxo-3-( in chloroform (5.7 mL) trans- 4-(2-((tetrahydro-2 H- 4 M HCl in dioxane (39.52 mL, 158.08 mmol, 20 eq) was added to a solution of pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)benzonitrile (4.0 g, 7.9 mmol, 1 eq), and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated and purified by silica gel column chromatography (0 to 40% ethyl acetate in hexane), yielding 2-chloro-4-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)benzonitrile (1.5 g, 2.883 mmol, 36% yield) was obtained. MS (ESI) m / z 422.2 [M+1] + .

[0360] 4-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile. Dichloromethane (38 mL) and N,N - 2-chloro-4-(3-( in dimethylformamide (3.8 mL) trans-Thionyl bromide (0.59 mL, 7.64 mmol, 2.5 eq) was added to a solution of 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)benzonitrile (1.51 g, 3.06 mmol), and the reaction solution was stirred at room temperature. After 1 hour, the reaction solution was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried with anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0 to 80% ethyl acetate in hexane) and 4-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile (1.171 g, 2.42 mmol, 79% yield) was obtained. MS (ESI) m / z 484.0 [M+1] + .

[0361] 2-((2 R ,6 S )-4-( tert -butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)acetic acid. In THF (20 mL) tert -butyl (3 R ,5 S Lithium hydroxide (208.8 mg, 8.7 mmol, 1.1 eq) in water (5 mL) was added to a solution of )-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.27 g, 7.93 mmol, 1 eq), and the reaction solution was stirred at room temperature. After 18 hours, the reaction solution was concentrated under vacuum and subjected to three azeotropic distillations with chloroform to remove residual water, resulting in a yellowish-white glassy solid. R ,6 S )-4-( tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)acetic acid (2.19 g, 7.8 mmol, 99% yield) was obtained. This material was passed to the next step without further purification. MS (ESI) m / z 273.2 [M+1] + .

[0362] tert -butyl (3 S ,5 R )-4-(2-((3-((2,6-dioxopiperidine-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. N , N -2-((in dimethylformamide (20 mL) 2R ,6 S )-4-( tert HATU (2.79 g, 7.34 mmol, 1 eq) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (1.61 g, 7.34 mmol, 1 eq) in a solution of butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)acetic acid (2.00 g, 7.34 mmol, 1 eq) and under nitrogen. N,N Diisopropylethylamine (3.8 mL, 22.03 mmol, 3 eq) was added all at once, and the reaction solution was stirred at 15°C. After 12 hours, the reaction solution was diluted with water (800 mL) and extracted with ethyl acetate (100 mL x 4). The combined organic layer was washed with brine (4 x 200 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The resulting crude material was purified by flash silica gel chromatography (0 to 2% methanol in dichloromethane) as a pale yellow solid tert -butyl (3 S ,5 R )-4-(2-((3-((2,6-dioxopiperidine-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.45 g, 5.08 mmol, 69% yield) was obtained. MS (ESI) m / z 474.3 [M+1] + .

[0363] 2-((2 S ,6 R )-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. In dichloromethane (25 mL) (3 R ,5 S )- tert 30% hydrogen bromide in acetic acid (2 mL, 14.57 mmol, 3 eq) was added all at once under nitrogen to a solution of 2-butyl 4-(2-((3-((2,6-dioxopiperidine-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.30 g, 4.86 mmol, 1 eq), and the reaction solution was stirred at 15°C. After 12 hours, the reaction solution was concentrated to obtain 2-((2 as a brown solid. S ,6 R )-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (3.000 g, 6.603 mmol, crude state) was obtained and transferred to the next step without further purification. MS (ESI) m / z 374.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.47 (br s, 1H), 9.56 - 9.16 (m, 2H), 7.06 (t, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.87 (br d, J = 7.9 Hz, 1H), 6.53 - 6.46 (m, 1H), 4.46 - 4.21 (m, 3H), 3.94 (br s, 2H), 3.58 (br d, J= 13.0 Hz, 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).

[0364] 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N,N -2-((2 in dimethylformamide (3.1 mL, 0.1 M) S ,6 R )-2,6-dimethylpiperazine-1-yl)- N In a solution of -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (179.5 mg, 0.40 mmol, 1.3 eq), 4-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile (150 mg, 0.31 mmol, 1 eq) and N,N -Diisopropylethylamine (0.27 mL, 1.55 mmol, 5 eq) was added, 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 x 50 mL). The combined organic layer was concentrated, filtered, and purified by standard methods to obtain a yellowish-white solid 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (113.2 mg, 0.13 mmol, 42% yield) was obtained. MS (ESI) m / z 777.4 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz) δ 11.82 (br s, 1H), 10.80 (s, 1H), 10.49 (br s, 1H), 8.14 (d, 1H, J = 8.2 Hz), 7.93 (d, 1H, J = 1.8 Hz), 7.61 (dd, 1H, J = 1.8, 8.3 Hz), 7.05 (t, 1H, J = 7.4 Hz), 7.00 (br s, 1H), 6.87 (br d, 1H, J = 7.7 Hz), 6.48 (dd, 1H, J = 1.5, 8.2 Hz), 4.28 (br dd, 1H, J = 4.8, 11.4 Hz), 4.18 (br s, 5H), 3.8-3.9 (m, 3H), 3.71 (br dd, 2H, J = 4.2, 8.0 Hz), 3.37 (tt, 2H, J = 3.7, 10.8 Hz), 3.31 (br s, 2H), 2.85 (q, 2H, J) = 11.6 Hz), 2.75 (ddd, 1H, J = 5.2, 12.1, 17.6 Hz), 2.60 (td, 1H, J = 4.0, 17.5 Hz), 2.11 (td, 3H, J = 4.2, 8.4 Hz), 1.92 (dq, 1H, J = 4.7, 12.1 Hz), 1.72 (br d, 2H, J = 10.8 Hz), 1.54 (s, 6H), 1.3-1.4 (m, 8H).

[0365] Examples 5: 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0366]

[0367] 5-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile. methyl 2-methyl-2-(( trans- 4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (6.70 g, 19.51 mmol, 1 eq), 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (8.94 g, 39.0 mmol, 2 eq), and N,N -Diisopropylethylamine (6.8 mL, 39.0 mmol, 2 eq) was mixed in ethyl acetate (56 mL, 0.35 M) and heated to 90°C for 16 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried with anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10% to 100% ethyl acetate in hexane) to form a brown solid, 5-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (3.5 g, 6.4743 mmol, 33% yield) was obtained. MS (ESI) m / z 541.3 [M+1] + .

[0368] 5-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile . 5-(4,4-dimethyl-5-oxo-3-( in dichloromethane (30 mL) trans- 4-(2-((tetrahydro-2 H4 M hydrochloric acid (16.2 mL, 64.7 mmol, 10 eq) was added to a solution of -pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (3.50 g, 6.47 mmol, 1 eq), and the reaction solution was stirred at room temperature. After 3 hours, the reaction solution was concentrated to obtain a reddish oil, 5-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.4 mmol, 99% yield) was obtained. The crude material was transferred to the next step without further purification. MS (ESI) m / z 457.0 [M+1] + .

[0369] 5-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile. Dichloromethane (30 mL) and N,N - 5-(3-( in dimethylformamide (5 mL) trans- Thionyl bromide (1.26 mL, 16.2 mmol, 2.5 eq) was added to a solution of 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.49 mmol), 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% to 80% ethyl acetate in hexane) to obtain a reddish-brown oil, 5-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (2.00 g, 3.85 mmol, 59% yield) was obtained. MS (ESI) m / z 519.8 [M+1] + .

[0370] 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-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-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile(200 mg, 0.36 mmol), 2-((2 R ,6 S )-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (192 mg, 0.47 mmol, 1.3 eq), sodium iodide (108 mg, 0.72 mmol, 2 eq), and N,N -Diisopropylethylamine (0.38 mL, 2.16 mmol, 6 eq) was mixed in acetonitrile (1.8 mL, 0.2 M) and heated at 60°C. After 7 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with 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 form a white solid, 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (90 mg, 0.11 mmol, 31% yield) was obtained. MS (ESI) m / z 812.0 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.73 - 10.84 (m, 1 H), 9.15 (d, J = 1.96 Hz, 1 H), 8.75 (d, J = 1.96 Hz, 1 H), 6.94 - 7.11 (m, 2 H), 6.85 (br d, J=7.82 Hz, 1 H), 6.46 (br d, J=8.19 Hz, 1 H), 4.27 (dd, J = 11.31, 4.83 Hz, 1 H), 3.85 (br s, 4 H), 3.47 - 3.75 (m, 2 H), 3.20 - 3.43 (m, 4) H), 2.58 - 2.95 (m, 4 H), 2.03 - 2.20 (m, 4 H), 1.91 (qd, J = 12.12, 4.71 Hz, 1 H), 1.70 - 1.79 (m, 2 H), 1.58 (s, 6 H), 1.11 - 1.48 (m, 7 H).

[0371] Examples 6: 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( R )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0372]

[0373] 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( R )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride . 2-((2 R ,6 S)-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid (100 mg, 0.16 mmol, 1 eq) and (3 R In a 2-dram vial of )-3-(3-aminoanilino)piperidine-2,6-dione (46.9 mg, 0.21 mmol, 1.3 eq). N,N -Dimethylformamide (0.55 mL, 0.3 M) was added, and the reaction solution was stirred until all solids were dissolved. 1-Methylimidazole (0.13 mL, 1.65 mmol, 10 eq), then N -(chloro(dimethylamino)methylene)- N -methylmethaneumin hexafluorophosphate(V) (69.25 mg, 0.2500 mmol, 1.5 eq), and the reaction solution were stirred at room temperature. After 20 minutes, the reaction solution was diluted with DMSO until the total volume was 4 ml, filtered, and purified by standard methods to obtain a yellowish-white solid 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (48 mg, 0.059 mmol, 36% yield) was obtained. MS (ESI) m / z 808.4 [M+1]+; 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.41 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.97 (dd, J = 1.2, 8.4 Hz, 1H), 7.06 - 6.92 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.89 (d, J = 7.6 Hz, 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, 2H), 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).

[0374] Examples 7: 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(pentafluoro -λ 6 - Sulfanyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0375]

[0376] 4-bromo-3-(pentafluoro-λ 6 - Sulfanyl) Aniline. 3-(pentafluoro-λ) in dimethylformamide (15 mL) under a nitrogen atmosphere 6N-bromosuccinimide (1.9 g, 10.95 mmol, 1.2 eq) was added all at once at 0°C to a solution of γ-sulfanyl)aniline (2.0 g, 9.12 mmol, 1 eq). 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 x 100 mL). The combined organic layer was washed with brine (100 mL), dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0 to 20% ethyl acetate in hexane) to obtain 4-bromo-3-(pentafluoro-λ 6 -sulfanyl)aniline (1.7 g, 5.7 mmol, 59% yield) was obtained. 1 H NMR (CDCl3, 400 MHz) 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).

[0377] 4-amino-2-(pentafluoro-λ 6 - Sulfanyl benzonitrile. 4-bromo-3-(pentafluoro-λ) in N-methylpyrrolidinone (30 mL) 6 A 100 mL round-bottom flask containing β-sulfanyl)aniline (1.7 g, 5.7 mmol, 1 eq) and copper(I) cyanide (0.61 g, 6.84 mmol, 1.2 eq) was heated to 180 °C while stirring. After 4 hours, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate in hexane on a 50 g column) to obtain 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]+.

[0378] 4-Isothiocyanate-2-(pentafluoro-λ 6 - Sulfanyl benzonitrile. An orange solution was obtained in a 100 mL round-bottom flask containing thiophosgene (0.94 mL, 12.29 mmol, 1.2 eq) in water (10 mL). 4-amino-2-(pentafluoro-λ) in dichloromethane (10 mL). 6 -sulfanyl)benzonitrile (2.5 g, 10.24 mmol, 1 eq) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated to obtain 4-isothiocyanato-2-(pentafluoro-λ) as a white solid. 6 -sulfanyl)benzonitrile (1.3 g, 4.54 mmol, 44% yield) was obtained and transferred to the next step without further purification. MS (ESI) m / z 286.9 [M+1]+.

[0379] 4-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(pentafluoro-λ 6 - Sulfanyl benzonitrile . In ethyl acetate (10 mL), methyl 2-methyl-2-(( trans- 4-(2-((tetrahydro-2 H -Pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (1.0 g, 2.91 mmol, 1 eq) in a solution of 4-isothiocyanato-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile (1.67 g, 5.82 mmol, 1.2 eq) and N,N -Diisopropylethylamine (1.02 mL, 5.82 mmol, 3 eq) was added. The reaction solution was stirred at 80°C. After 18 hours, the reaction solution was concentrated and purified by column chromatography (0 to 50% ethyl acetate / hexane) to obtain 4-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile was obtained. The intermediate solid was suspended in dichloromethane (1.5 mL), then 4 M hydrochloric acid in dioxane (4 mL, 16 mmol, 3 eq) was added, and the mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated, the solid was dissolved in dichloromethane, and purified by silica gel column chromatography (0 to 40% ethyl acetate in hexane) to obtain a yellowish-white solid, 4-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile (0.80 g, 1.33 mmol, 46% yield) was obtained. MS (ESI) m / z 513.8 [M+1]+.

[0380] 4-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(pentafluoro-λ 6 - Sulfanyl benzonitrile . In dichloromethane (30 mL), 4-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(pentafluoro-λ 6 Dimethylformamide (5 mL) and thionyl bromide (1.0 g, 4.87 mmol, 2.5 eq) were sequentially added to a solution of -sulfanyl)benzonitrile (1.0 g, 1.95 mmol, 1 eq). The reaction solution was stirred overnight at room temperature. 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 with anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexane) and obtained as a light brown solid, 4-(3-( trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(pentafluoro-λ 6 ε-sulfanyl)benzonitrile (0.59 g, 1.02 mmol, 53% yield) was obtained. MS (ESI) m / z 578.8 [M+1] + .

[0381] 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(pentafluoro-λ 6 -sulfanyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-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-thiooxomidazolidine-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile(0.1 g, 0.18 mmol, 1 eq), 2-((2 R ,6 S )-2,6-dimethylpiperazine-1-yl)- N After adding acetonitrile (2 mL) to a 1-dram vial containing -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.09 g, 0.23 mmol, 1.3 eq) and sodium iodide (2.7 mg, 0.02 mmol, 0.1 eq), N,N -Diisopropylethylamine (0.21 mL, 1.2 mmol, 6 eq) was added. The reaction vial was heated to 60°C while stirring. After 16 hours, the reaction solution was diluted with dimethyl sulfoxide until the total volume was 3 ml, purified by standard methods, and found to be a yellow solid 2-((2 R ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(pentafluoro-λ 6 -sulfanyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.05 g, 0.06 mmol, 31% yield) was obtained. MS (ESI) m / z 869.2 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz) 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).

[0382] Examples 8: 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0383]

[0384] 3-chloro-5-isothiocyanate-pyridine-2-carbonitrile.Thiophosgene (5.96 mL, 78.14 mmol, 1.2 eq) was added to a solution of 5-amino-3-chloro-pyridine-2-carbonitrile (10.00 g, 65.12 mmol, 1 eq) in toluene (20 mL). The mixture was stirred at 110°C. After 16 hours, the reaction solution was concentrated and purified by silica gel chromatography (20 to 50% ethyl acetate in petroleum ether) to obtain 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] + .

[0385] 3-chloro-5-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H -Pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)picolinonitrile . Methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (4.000 g, 20.45 mmol, 1 eq) and methyl 2-methyl-2-(( trans- 4-(2-((tetrahydro-2 H Triethylamine (5.7 mL, 40.89 mmol, 2 eq) was added to a mixture of -pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (7.720 g, 22.49 mmol, 1.1 eq). The reaction solution was stirred at 90°C. After 6 hours, the reaction solution was concentrated and purified by silica gel column chromatography (10 to 50% ethyl acetate in petroleum ether) to obtain 3-chloro-5-(4,4-dimethyl-5-oxo-3-( trans- 4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)picolinonitrile (4.000 g, 7.89 mmol, 39% yield) was obtained. MS (ESI) m / z 507.2 [M+1] + ; 1H NMR (400 MHz, 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).

[0386] 3-chloro-5-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)picolinonitrile. 3-chloro-5-(4,4-dimethyl-5-oxo-3-( in methanol (30 mL, 0.27 M) trans- 4-(2-((tetrahydro-2 H A 2 M aqueous hydrochloric acid solution (3 mL, 15.78 mmol, 2 eq) was added to a solution of -pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thiooxomidazolidin-1-yl)picolinonitrile (4.000 g, 7.89 mmol, 1 eq). The reaction solution was stirred at 25°C. After 2 hours, the pH of the mixture was adjusted to 8 by adding saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (250 mL). The combined organic layer was washed with brine (80 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (33 to 100% ethyl acetate in petroleum ether) to obtain 3-chloro-5-(3-( trans- 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)picolinonitrile (2.400 g, 0.01 mmol, 69% yield) was obtained. MS (ESI) m / z 423.3 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.43 - 7.33 (m, 2H), 7.15 (br d,J = 7.0 Hz, 1H), 6.57 (br s, 1H), 4.40 (t, J = 6.7 Hz, 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).

[0387] 5-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-chloropicolinonitrile. Dichloromethane (5 mL, 1 M) and N , N - 3-chloro-5-(3-( in dimethylformamide (0.50 mL) trans- Thionyl bromide (0.65 mL, 10.17 mmol, 2 eq) was added to a solution of 4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)picolinonitrile (2.150 g, 5.08 mmol, 1 eq) at 0°C. The mixture was stirred at 25°C for 16 hours. The pH of the mixture was adjusted to 8 using saturated sodium carbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography (50 to 100% ethyl acetate in petroleum ether) to obtain 5-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-chloropicolinonitrile (2.3 g, 4.73 mmol, 93% yield) was obtained. MS (ESI) m / z 485.1 [M+1] + ; 1H NMR (400 MHz, 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).

[0388] 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-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-thiooxomidazolidine-1-yl)-3-chloropicolinonitrile(0.120 g, 0.25 mmol, 1 eq), 2-((2 R ,6 S )-2,6-dimethylpiperazine-1-yl)- N -(6-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)acetamide hydrobromide (112 mg, 0.25 mmol, 1 eq) and sodium iodide (0.004 g, 0.02 mmol, 8 mol%) to N , N -Dimethylformamide (4 mL 0.06 M) and N,N -Diisopropylethylamine (0.096 g, 0.74 mmol, 3 eq) was added. The mixture was stirred at 60°C. After 16 hours, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to obtain 2-((2 as a yellow solid R ,6 S )-4-(3-( trans-4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.070 g, 0.09 mmol, 36% yield) was obtained. MS (ESI) m / z 778.3 [M+1] + ; 1 H NMR (400 MHz, 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, 1H), 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).

[0389] Examples 9: 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0390]

[0391] Trans-N,N -Dibenzyl-4-(3-((Tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexane-1-amine.In xylene (450 mL, 0.45 M) trans- 2-(2-bromoethoxy)tetrahydro-2 in a solution of 4-(dibenzylamino)cyclohexanol (60.00 g, 203.1 mmol, 1 eq). H- Piran (113.28 g, 507.75 mmol, 2.5 eq), tetra- N Butylammonium bromide (13.09 g, 40.62 mmol, 0.2 eq) and potassium hydroxide (52.42 g, 934.26 mmol, 4.6 eq) were added, 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) and brine (200 mL), dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (100% petroleum ether) as a pale yellow oil Trans-N,N -Dibenzyl-4-(3-((Tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (40.0 g, 91.4 mmol, 45% yield) was obtained. MS (ESI) m / z 438.4 [M+1] + ; 1 H NMR (400 MHz, 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)

[0392] trans- 4-(3-((tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexane-1-amine.In methanol (100 mL) Trans-N , N -Dibenzyl-4-(3-((Tetrahydro-2 H- 10% palladium on carbon (10.0 g, 9.39 mmol) was added to a solution of pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (20.0 g, 45.7 mmol, 1 eq). The reaction flask was scavenged, purged three times with hydrogen gas, and then stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 hours, the reaction solution was filtered, the filtrate was concentrated, and as a pale yellow oil trans- 4-(3-((tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (11.00 g, 42.74 mmol, 94% yield) was obtained. This material was passed to the next step without further purification. 1 H NMR (400 MHz, 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).

[0393] methyl 2-methyl-2-(( trans- 4-(3-((tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate. In acetonitrile (10 mL) trans- 4-(3-((tetrahydro-2 H-Potassium iodide (0.451 g, 2.72 mmol, 0.1 eq) and potassium carbonate (7.518 g, 54.4 mmol, 2 eq) were added to a solution of pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (7.00 g, 27.2 mmol, 1 eq) and methyl 2-bromo-2-methyl-propanoate (12.5 mL, 108.79 mmol, 4 eq). The reaction vessel was sealed and heated to 110°C while stirring. After 12 hours, the reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (10 to 80% ethyl acetate in petroleum ether) to obtain methyl 2-methyl-2-(( trans- 4-(3-((tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (8.00 g, 22.4 mmol, 82% yield) was obtained. MS (ESI) m / z 358.4 [M+1] + .

[0394] 2-chloro-4-(4,4-dimethyl-5-oxo-3-( trans- 4-(3-((tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)benzonitrile . Methyl 2-methyl-2-(( in 100 mL, 0.28 M ethyl acetate (100 mL, 0.28 M) trans- 4-(3-((tetrahydro-2 H-2-chloro-4-isothiocyanatobenzonitrile (10.9 g, 56.0 mmol, 2 eq) and triethylamine (7.8 mL, 56.0 mmol, 2 eq) were added to a solution of pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate)10.0 g, 28.0 mmol, 1 eq) and 2-chloro-4-isothiocytobenzonitrile (10.9 g, 56.0 mmol, 2 eq) 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 layer was washed with brine (40 mL), dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (9 to 20% ethyl acetate in petroleum ether) and as a red oil, 2-chloro-4-(4,4-dimethyl-5-oxo-3-( trans- 4-(3-((tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)benzonitrile (8.50 g, 16.3 mmol, 58% yield) was obtained. MS (ESI) m / z 542.2 [M+23] + .

[0395] 4-(3-( trans- 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. 2-chloro-4-(4,4-dimethyl-5-oxo-3-( in methanol (50 mL) trans- 4-(3-((tetrahydro-2 H-1 M hydrochloric acid (5 mL, 13.07 mmol) was added to a solution of pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidin-1-yl)benzonitrile (6.80 g, 13.1 mmol), and the reaction solution was stirred at 25°C. After 2 hours, the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (20 to 70% ethyl acetate in petroleum ether) and obtained as a yellow solid 4-(3-( trans- 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (5.60 g, 12.8 mmol, 98% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 2.0, 8.4 Hz, 1H), 3.89 - 3.76 (m, 1H), 3.48 - 3.42 (m, 4H), 3.24 - 3.16 (m, 1H), 2.79 (d, J = 11.2 Hz, 2H), 2.04 (d, J = 10.8 Hz, 2H), 1.70 (d, J = 10.8 Hz, 2H), 1.65 - 1.59 (m, 2H), 1.53 (s, 6H), 1.34 - 1.25 (m, 2H).

[0396] 4-(3-( trans- 4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile. Dichloromethane (50 mL) and N,N - 4-(3-( in dimethylformamide (5 mL) trans-Thionyl bromide (2.1 mL, 26.6 mmol, 2 eq) was added to a solution of 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.8 g, 13.3 mmol) at 0°C. After 8 hours, the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0 to 35% ethyl acetate in petroleum ether) to obtain 4-(3-( trans- 4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile (4.8 g, 9.6 mmol, 72% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 8.14 - 8.11 (m, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 3.84 (s, 1H), 3.58 - 3.51 (m, 4H), 3.27 - 3.21 (m, 1H), 2.81 (d, J = 11.6 Hz, 2H), 2.06 (m, 2H), 1.71 (d, J = 11.6 Hz, 2H), 1.53 (s, 6H), 1.33 (d, J = 13.2 Hz, 2H).

[0397] 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . 4-(3-( trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile (0.150 g, 0.300 mmol, 1 eq) and 2-((2 R ,6 S )-2,6-dimethylpiperazine-1-yl)- N In a solution of -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.168 g, 0.450 mmol, 1.5 eq). N,N -Diisopropylethylamine (0.16 mL, 0.900 mmol, 3 eq) was added. The reaction mixture was stirred at 50°C. After 12 hours, the reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods and found to be a yellow solid, 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.087 g, 0.110 mmol, 37% yield) was obtained. MS (ESI) m / z 791.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 1.8, 8.3 Hz, 1H), 7.09 - 7.02 (m, 1H), 6.99 (s, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.48 (d, J= 7.9 Hz, 1H), 4.28 (dd, J = 4.8, 11.3 Hz, 2H), 4.19 - 4.06 (m, 2H), 3.98 - 3.63 (m, 4H), 3.52 (t, J = 5.8 Hz, 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).

[0398] Examples 10: 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0399]

[0400] 5-(4,4-dimethyl-5-oxo-3-( trans- 4-(3-((tetrahydro-2 H- Pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile . Methyl 2-methyl-2-(( in ethyl acetate (50 mL, 0.28 M) trans- 4-(3-((tetrahydro-2 H- In a solution of pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.00 g, 14.0 mmol, 1 eq) and 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (6.41 g, 28.0 mmol, 2 eq) N,N - Diisopropylethylamine (4.62 mL, 28.0 mmol, 2 eq) was added, and the reaction solution was stirred at 90°C. After 12 hours, the reaction solution was concentrated and purified by silica gel column chromatography (10 to 50% ethyl acetate in petroleum ether) to obtain 5-(4,4-dimethyl-5-oxo-3-( trans- 4-(3-((tetrahydro-2H- Pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 90% yield) was obtained. 1 H NMR (400 MHz, 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 = 10.8 Hz, 2H), 1.85 - 1.80 (m, 8H), 1.60 (s, 6H), 1.56 - 1.52 (m, 4H), 1.32 - 1.29 (m, 2H).

[0401] 5-(3-( trans- 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile. 5-(4,4-dimethyl-5-oxo-3-( in methanol (50 mL) trans- 4-(3-((tetrahydro-2 H- 1 M hydrogen chloride (5.0 mL, 5 mmol) was added to a solution of pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 1 eq), and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, and concentrated to form a brown oil 5-(3-( trans- 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 84% yield) was obtained. MS (ESI) m / z 471.2 [M+1] + .

[0402] 5-(3-( trans- 4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile. Dichloromethane (50 mL) and N,N - 5-(3-( in dimethylformamide (5 mL) trans- Thionyl bromide (1.7 mL, 21.3 mmol, 2 eq) was added to a solution of 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 1 eq) at 0°C. After stirring for 12 hours, the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10 to 20% ethyl acetate in petroleum ether) and obtained as a pale yellow solid 5-(3-( trans- 4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile was obtained. (ESI) m / z 535.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ 8.98 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 3.76 - 3.65 (m, 1H), 3.62 (t, J = 5.6 Hz, 2H), 3.53 (t, J = 6.4 Hz, 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 = 12.4 Hz, 2H), 1.63 (s, 6H), 1.45 - 1.24 (m, 2H).

[0403] 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N , N - 5-(3-( in dimethylformamide (4 mL, 0.07 M) trans- 4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (0.150 g, 0.280 mmol, 1 eq) and 2-((2 R ,6 S )-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (0.128 g, 0.280 mmol, 1 eq) in a solution under nitrogen N,N Diisopropylethylamine (0.24 mL, 1.41 mmol, 5 eq) and sodium iodide (0.008 g, 0.060 mmol, 2 eq) were added simultaneously. 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 x 30 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods and found to be a yellow solid, 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.089 g, 0.107 mmol, 38% yield) was obtained. MS (ESI) m / z 826.4 [M+1]+ ; 1 H NMR (400 MHz, 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 = 1.7 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 7.08 - 7.02 (m, 1H), 6.99 (br s, 1H), 6.86 (br d, J = 7.9 Hz, 1H), 6.50 - 6.44 (m, 1H), 4.27 (br dd, J = 4.8, 11.4 Hz, 3H), 4.16 (br s, 3H), 3.92 - 3.69 (m, 3H), 3.51 (br t, J = 5.8 Hz, 2H), 3.26 (br t, J = 10.6 Hz, 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 - 2.68 (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 = 10.3 Hz, 2H), 1.57 (s, 6H), 1.44 - 1.26 (m, 8H).

[0404] Examples 11: 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0405]

[0406] 5-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile . Methyl 2-(( in ethyl acetate (15 mL, 0.38 M) trans- In a solution of 4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.47 g, 5.71 mmol, 1 eq) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (1.44 g, 6.28 mmol, 1.1 eq) N,N -Diisopropylethylamine (2.21 g, 17.13 mmol, 3 eq) was added, and the reaction solution was stirred at 80°C. After 16 hours, the reaction solution was concentrated under reduced pressure, and the crude material was purified by standard methods to obtain a brown solid 5-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 69% yield) was obtained. MS (ESI) m / z 455.0 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 8.99 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.65(t, J = 6.4 Hz, 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).

[0407] 5-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile. Dichloromethane (18 mL, 0.22 M) and N,N - 5-(3-( in dimethylformamide (1.8 mL) trans-Thionyl bromide (1.650 g, 7.92 mmol, 2 eq) was slowly added to a solution of 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 1 eq) 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 layer was dried with anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (5 to 80% ethyl acetate in hexane) and 5-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (1.75 g, 3.38 mmol, 85% yield) was obtained. MS (ESI) m / z 516.9 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 8.99 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.42 (t, J = 6.8 Hz, 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).

[0408] 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N , N - 5-(3-( in dimethylformamide (1 mL, 0.23 M) trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (0.120 g, 0.232 mmol, 1 eq) and 2-((2 S ,6 R )-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (0.158 g, 0.350 mmol, 1.5 eq) in a solution under nitrogen N,N Diisopropylethylamine (0.2 mL, 1.16 mmol, 5 eq) was added all at once. 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 layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods and found to be a yellow solid, 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.129 g, 0.157 mmol, 68% yield) was obtained. MS (ESI) m / z 810.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 10.80 (s, 1H), 10.64 (br s, 1H), 9.15 (d, J = 1.9 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.12 - 6.96 (m, 2H), 6.88 (br d, J= 7.9 Hz, 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, 17.4 Hz, 3H), 2.64 - 2.55 (m, 1H), 2.09 (td, J = 4.1, 8.5 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.87 - 1.70 (m, 6H), 1.57 (s, 6H), 1.38 (br d, J = 3.0 Hz, 6H), 1.21 (br d, J = 7.1 Hz, 4H), 1.16 - 1.06 (m, 1H), 1.16 - 1.06 (m, 1H).

[0409] Examples 12: 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0410]

[0411] 4-(4,4-dimethyl-5-oxo-3-( trans- 4-(3-((tetrahydro-2 H -pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile . In ethyl acetate (50 mL), methyl 2-methyl-2-(( trans- 4-(3-((tetrahydro-2 H In a solution of -pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.0 g, 14.0 mmol, 1 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (6.4 g, 28.0 mmol, 2 eq) N,N- Diisopropylethylamine (4.6 mL, 28.0 mmol, 2 eq) was added, and the reaction solution was stirred at 90°C. After 12 hours, the reaction solution was concentrated and purified by silica gel column chromatography (10 to 50% ethyl acetate in petroleum ether) to obtain 4-(4,4-dimethyl-5-oxo-3-( trans- 4-(3-((tetrahydro-2 H -pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol, 84% yield) was obtained. MS (ESI) m / z 554.4 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 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 = 12.0 Hz, 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).

[0412] 4-(3-( trans- 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. 4-(4,4-dimethyl-5-oxo-3-( trans- 4-(3-((tetrahydro-2 H1 M aqueous hydrochloric acid solution (5.0 mL, 5 mmol) was added to a solution of -pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thiooxomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol), and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated to form a brown oil 4-(3-( trans- 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 91% yield) was obtained. MS (ESI) m / z 470.2 [M+1] + .

[0413] 4-(3-( trans- 4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. Dichloromethane (50 mL) and N,N - 4-(3-( in dimethylformamide (5 mL) trans- Thionyl bromide (1.7 mL, 21.3 mmol, 4 eq) was added to a solution of 4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 1 eq) at 0°C, and the reaction solution was slowly heated to room temperature. After 12 hours, the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography and 4-(3-( trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 9.4 mmol, 88% yield) was obtained. MS (ESI) m / z 534.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 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 = 12.0 Hz, 2H), 2.19 - 2.05 (m, 2H), 1.83 (d, J = 12.0 Hz, 2H), 1.65 (s, 2H), 1.60 (s, 6H), 1.35 - 1.32 (m, 2H).

[0414] 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N,N -4-(3-( in dimethylformamide (3 mL, 0.01 M) trans- 4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.280 mmol, 1 eq) and 2-((2 R ,6 S )-2,6-dimethylpiperazine-1-yl)- N In a solution of -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.158 g, 0.420 mmol, 1.5 eq). N , N-Diisopropylethylamine (0.15 mL, 0.85 mmol, 3 eq) was added. 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 layer was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods and found to be a yellow solid, 2-((2 R ,6 S )-4-(3-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.058 g, 0.069 mmol, 25% yield) was obtained. MS (ESI) m / z 825.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.97 (dd, J = 1.6, 8.3 Hz, 1H), 7.12 - 6.94 (m, 2H), 6.87 (d, J = 6.3 Hz, 1H), 6.48 (d, J = 5.3 Hz, 1H), 4.37 - 4.24 (m, 4H), 3.96 - 3.61 (m, 4H), 3.51 (t, J = 5.7 Hz, 2H), 3.26 (t, J = 10.6 Hz, 2H), 3.12 (s, 2H), 2.84 - 2.56 (m, 4H), 2.09 - 1.84 (m, 6H), 1.72 (d, J= 10.6 Hz, 2H), 1.55 (s, 6H), 1.41 - 1.23 (m, 8H).

[0415] Examples 13: 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0416]

[0417] 3-chloro-5-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)picolinonitrile. Methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (1.600 g, 8.18 mmol, 1 eq) and methyl 2-(( trans- Triethylamine (2.28 mL, 16.36 mmol, 2 eq) was added to a mixture of 4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (2.320 g, 9 mmol, 1.1 eq), and the reaction solution was added at 90°C. After 6 hours, the reaction solution was concentrated and purified by silica gel column chromatography (10 to 100% ethyl acetate in petroleum ether) to obtain 3-chloro-5-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)picolinonitrile (2.000 g, 4.75 mmol, 58% yield) was obtained. MS (ESI) m / z 421.2 [M+1] + ; 1H NMR (400 MHz, 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).

[0418] 5-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-chloropicolinonitrile. Dichloromethane (5 mL, 1 M) and N , N - 3-chloro-5-(3-( in dimethylformamide (0.50 mL) trans- Thionyl bromide (0.61 mL, 9.5 mmol, 2 eq) was added to a solution of 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)picolinonitrile (2.000 g, 4.75 mmol, 1 eq) at 0°C. The reaction solution was stirred at 25°C. After 16 hours, the pH of the reaction solution was adjusted to 8 by adding saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (25 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (50 to 100% ethyl acetate in petroleum ether) to obtain 5-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-chloropicolinonitrile (1.600 g, 3.31 mmol, 70% yield) was obtained. MS (ESI) m / z 483.1 [M+1] + ; 1H NMR (400 MHz, 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 = 5.6 Hz, 3H), 1.08 - 0.97 (m, 2H).

[0419] 2-((2 R ,6S)-4-(3-( trans- 4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N,N - 5-(3-( in dimethylformamide (3 mL, 0.07 M) trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-chloropicolinonitrile (0.100 g, 0.210 mmol, 1 eq) and 2-((2 S ,6 R )-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (0.141 g, 0.310 mmol, 1.5 eq) in a solution under nitrogen N , N Diisopropylethylamine (0.18 mL, 1.03 mmol, 5 eq) was added all at once. 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 layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by standard methods and found to be a yellow solid, 2-((2 R ,6 S )-4-(3-( trans-4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.073 g, 0.094 mmol, 45% yield) was obtained. MS (ESI) m / z 776.4 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.24 - 11.28 (m, 1H), 10.79 (s, 1H), 10.43 (br s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 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 = 7.9 Hz, 1H), 6.47 (br d, J = 9.8 Hz, 1H), 4.27 (br dd, J = 4.8, 11.3 Hz, 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, 17.4 Hz, 3H), 2.64 - 2.55 (m, 1H), 2.09 (td, J = 4.3, 8.7 Hz, 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 = 11.0 Hz, 2H).

[0420] Examples 14: 2-((2 S ,6 R )-4-(3-( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0421]

[0422] 2-chloro-4-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)benzonitrile. Methyl 2-((in ethyl acetate (25 mL) trans- In a solution of 4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.31 g, 5.1 mmol, 1 eq) and 2-chloro-4-isothiocyanatobenzonitrile (1.08 g, 5.57 mmol, 1.1 eq) N,N - Diisopropylethylamine (2.51 mL, 15.18 mmol, 3 eq) was added, and the reaction mixture was stirred at 80°C. After 18 hours, the reaction solution was concentrated and purified by column chromatography (15 to 50% ethyl acetate in petroleum ether) to obtain 2-chloro-4-(3-( trans- 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)benzonitrile (1.26 g, 3.01 mmol, 59% yield) was obtained. MS (ESI) m / z 420.1 [M+1] + .

[0423] 4-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile. N,N - 2-chloro-4-(3-( in dimethylformamide (0.30 mL) and dichloromethane (3 mL) trans-Thionyl bromide (1.88 g, 9.03 mmol, 3 eq) was slowly added to a solution of 4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)benzonitrile (1.26 g, 3.01 mmol) at 0°C. After 12 hours, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (15 to 30% ethyl acetate in petroleum ether) to obtain 4-(3-( trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile (1.21 g, 2.50 mmol, 83% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 3.87 (m, 1H), 3.43 (t, J = 6.8 Hz, 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).

[0424] 2-((2 S ,6 R )-4-(3-( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N,N - 4-(3-( in dimethylformamide (4 mL) trans- 4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-chlorobenzonitrile (0.100 g, 0.210 mmol) and 2-((2 S ,6 R )-2,6-dimethylpiperazine-1-yl)- N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (0.141 g, 0.310 mmol, 1.5 eq) in a solution under nitrogen N , N -Diisopropylethylamine (0.18 mL, 1.04 mmol, 5 eq) was added all at once. 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 x 30 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by standard methods and found to be a yellow solid, 2-((2 S ,6 R )-4-(3-( trans- 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.083 g, 0.106 mmol, 51% yield) was obtained. MS (ESI) m / z 775.6 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.30 - 11.70 (m, 1H), 10.80 (s, 1H), 10.59 (br s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 1.9, 8.4 Hz, 1H), 7.09 - 7.02 (m, 1H), 7.00 (s, 1H), 6.87 (br d, J = 7.7 Hz, 1H), 6.48 (dd, J = 1.5, 8.2 Hz, 1H), 4.28 (br dd, J= 4.8, 11.3 Hz, 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, 8.7 Hz, 1H), 1.97 - 1.88 (m, 1H), 1.87 - 1.67 (m, 6H), 1.53 (s, 6H), 1.37 (br d, J = 4.4 Hz, 6H), 1.22 (br s, 3H), 1.15 - 1.02 (m, 2H).

[0425] Examples 15: 2-((2 R ,4 s ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0426]

[0427] (2 S ,6 R )-1-benzyl-2,6-dimethylpiperidin-4-one.Acetaldehyde (150.8 g, 1368.9 mmol, 2 eq) was added at 20°C to a solution of 3-oxopentandioic acid (100.0 g, 684.5 mmol, 1 eq) in water (200 mL). The reaction mixture was stirred at 20°C for 20 minutes, then cooled to 0°C, and phenylmethaneamine (74.61 mL, 684.5 mmol, 1 eq) was added dropwise. The reaction solution was heated 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 with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography and as a yellow oil (2 S ,6 R )-1-benzyl-2,6-dimethylpiperidin-4-one (27.70 g, 127.5 mmol, 19% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.2 Hz, 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, 13.2 Hz, 2H), 2.42 - 2.28 (m, 4H), 1.16 (d, J = 6.4 Hz, 6H).

[0428] ethyl 2-((2 R ,6 S )-1-benzyl-2,6-dimethylpiperidine-4-ylidene)acetate. Ethyl 2-(diethoxyphosphoryl)acetate (40.23 g, 179.5 mmol, 1.3 eq) in THF (100 mL) was added dropwise at 0°C to a solution of sodium hydride (8.283 g, 207.1 mmol, 1.5 eq) in THF (50 mL). The mixture was stirred at 0°C for 30 minutes. (2 in THF (200 mL) S ,6 R)-1-benzyl-2,6-dimethylpiperidin-4-one (30.00 g, 138.1 mmol, 1 eq) was added dropwise to the above solution, and the reaction solution was heated to room temperature. After 12 hours, the reaction solution was neutralized by adding a 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 layer was washed with brine (300 mL), dried with 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 subsequently re-purified by semi-preparative reverse-phase HPLC (55 to 85% acetonitrile + 0.05% ammonium hydroxide in water, over 20 minutes). The collected fractions were concentrated, and the aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with brine (300 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 2-((2) as a yellow oil. R ,6 S )-1-benzyl-2,6-dimethylpiperidine-4-ylidene)acetate (11.7 g, 40.7 mmol, 30% yield) was obtained. MS (ESI) m / z 288.2 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.45 - 7.35 (m, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.26 - 7.16 (m, 1H), 5.63 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.82 (s, 2H), 3.57 (dd, J = 2.8, 14.0 Hz, 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, 16.4 Hz, 6H).

[0429] tert -butyl (2 S ,6 R )-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate. Ethyl 2-((2 in THF (80 mL, 0.23 M) R ,6 S )-1-benzyl-2,6-dimethylpiperidine-4-ylidene)acetate (5.300 g, 18.44 mmol, 1 eq) and di- tert 10% palladium carbonate (1,500 g, 1.84 mmol, 10 mol%) was added to a solution of butyl dicarbonate (6.037 g, 27.66 mmol, 1.5 eq) 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 obtain the residue, which was purified by flash silica gel chromatography (1% ethyl acetate in petroleum ether, petroleum ether:ethyl acetate = 5:1) as a yellow oil tert -butyl (2 S ,6 R )-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.630 g, 8.784 mmol, 48% yield) was obtained. 1 H NMR (400 MHz, 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).

[0430] tert -butyl (2 S ,6 R )-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate.In a solution of lithium aluminum hydride (0.500 g, 13.18 mmol, 1.5 eq) in THF (10 mL) at 0°C in THF (40 mL) tert -butyl (2 S ,6 R A solution of )-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.630 g, 8.780 mmol, 1 eq) was added. The reaction solution was slowly heated to room temperature over 1 hour. The reaction solution was quenched by adding water (0.5 mL), 15% sodium hydroxide solution (1 mL), and water (1.5 mL). The slurry was stirred for 0.5 hours, filtered, and concentrated under vacuum. The crude material was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) as a yellow solid tert -butyl (2 S ,6 R )-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 96% yield) was obtained. 1 H NMR (400 MHz, 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, 2H), 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).

[0431] tert -butyl (2 S ,6 R )-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate.In dichloromethane (40 mL, 0.21 M) tert -butyl (2 S ,6 R To a solution of )-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 1 eq) and triphenylphosphine (3.332 g, 12.71 mmol, 1.5 eq). Carbon tetrabromide (4.214 g, 12.71 mmol, 1.5 eq) was added to the reaction solution at 0°C. The reaction mixture was slowly heated to room temperature. After 2 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with dichloromethane (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) as a transparent colorless oil tert -butyl (2 S ,6 R )-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.160 g, 6.744 mmol, 80% yield) was obtained. 1 H NMR (400 MHz, 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).

[0432] tert -butyl (2 R ,6 S )-4-(2-(( trans- 4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. In xylene (120 mL, 0.17 M) trans-4-(dibenzylamino)cyclohexanol (12.18 g, 41.22 mmol, 2 eq) and tert -butyl (2 S ,6 R Potassium hydroxide (5.318 g, 94.80 mmol, 4.6 eq) and tetrabutylammonium bromide (1.328 g, 4.120 mmol, 0.2 eq) were added to a solution of )-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (6.600 g, 20.61 mmol, 1 eq). The reaction mixture was stirred at 30°C. After 24 hours, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layer was washed with brine (150 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel column chromatography (2.5 to 3% ethyl acetate in petroleum ether) to obtain a yellow oil. tert -butyl (2 R ,6 S )-4-(2-(( trans- 4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 5.236 mmol, 25% yield) was obtained. 1 H NMR (400 MHz, 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= 6.4 Hz, 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 = 7.0 Hz, 6H), 1.14 - 1.08 (m, 1H), 1.07 - 0.92 (m, 1H).

[0433] tert -butyl (2 R ,6 S )-4-(2-(( trans- 4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. In methanol (60 mL) tert -butyl (2 R ,6 S )-4-(2-(( trans- Palladium carbon (2,000 g) was added to a solution of 4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2,800 g, 5.240 mmol, 1 eq) under nitrogen. The reaction mixture was stirred at room temperature under hydrogen (15 psi) for 12 hours. The reaction mixture was filtered and concentrated to form a yellow oil tert -butyl (2 R ,6 S )-4-(2-(( trans- 4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 98% yield) was obtained and passed to the next step without further purification. 1H NMR (400 MHz, 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).

[0434] tert -butyl (2 S ,6 R )-4-(2-(( trans- 4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate In acetonitrile (10 mL, 0.5 M) tert -butyl (2 R ,6 S )-4-(2-(( trans- Potassium iodide (0.086 g, 0.520 mmol, 10 mol%), potassium carbonate (2.148 g, 15.54 mmol, 3 eq), and methyl 2-bromo-2-methylpropanoate (3.75 mL, 25.91 mmol, 5 eq) were added to a solution of 4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 1 eq). The reaction mixture was stirred at 110°C. After 48 hours, the reaction solution was filtered and concentrated to form a yellow oil. tert -butyl (2 S ,6 R )-4-(2-(( trans-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 5.279 mmol, crude state) was obtained and transferred to the next step without further purification. MS (ESI) m / z 455.5 [M+1] + .

[0435] tert -butyl (2 R ,4 s ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-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-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate . In ethyl acetate (10 mL, 0.47 M) tert -butyl (2 S ,6 R )-4-(2-(( trans- In a solution of 4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.160 g, 4.750 mmol, 1 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.084 g, 4.750 mmol, 1 eq) N,N - Diisopropylethylamine (1.660 mL, 9.500 mmol, 2 eq) was added. The reaction mixture was stirred at 90°C. After 12 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel column chromatography to obtain a mixture of diastereomers, which were separated using SFC (DAICEL chiral PAK IG: 250 mm * 30 mm, 10 µm, 20% methanol + 0.1% NH3·H2O). tert -butyl (2R ,4 s ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.060 g, 1.629 mmol, 34% yield) and tert -butyl (2 R ,4 r ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.553 mmol, 12% yield) was obtained. tert -butyl (2 R ,4 s ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.0, 8.0 Hz, 1H), 4.38 - 4.22 (m, 2H), 3.72 - 3.59 (m, 1H), 3.54 (t, J = 6.4 Hz, 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 (2 R ,4 r ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.0, 8.4 Hz, 1H), 4.28 - 4.10 (m, 2H), 3.76 - 3.58 (m, 1H), 3.49 (t, J = 6.0 Hz, 2H), 3.30 (m, 1H), 3.03 - 2.76 (m, 2H), 2.19 (br d, J = 12.0 Hz, 2H), 2.12 - 1.98 (m, 2H), 1.89 - 1.76 (m, 2H), 1.61 (s, 6H), 1.52 (br t, J = 6.4 Hz, 2H), 1.47 (s, 9H), 1.40 - 1.25 (m, 3H), 1.22 (d, J = 6.8 Hz, 6H), 1.03 (m, 2H).

[0436] 4-(3-( trans- 4-(2-((2 R ,4 s ,6 S )-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile . In dichloromethane (5 mL) tert -butyl (2 R ,4 s ,6 S )-4-(2-(( trans- To a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.060 g, 1.630 mmol, 1 eq), 4 M hydrochloric acid (20 mL, 80.00 mmol) in 1,4-dioxane was added, and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated. The resulting yellow solid was absorbed into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, and concentrated to obtain a yellow solid, 4-(3-( trans- 4-(2-((2 R ,4 s ,6 S )-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.920 g, 1.67 mmol, 99% yield) was obtained and transferred to the next step without further purification. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.0, 8.0 Hz, 1H), 3.74 - 3.59 (m, 1H), 3.51 (t, J = 6.8 Hz, 2H), 3.31 (m, 1H), 2.92 (m, 4H), 2.20 (br d, J = 12.0 Hz, 2H), 2.02 - 1.92 (m, 1H), 1.82 (br d, J= 12.0 Hz, 2H), 1.70 (q, J = 6.8 Hz, 2H), 1.64 - 1.56 (s, 6H), 1.51 (br d, J = 12.8 Hz, 2H), 1.40 - 1.27 (m, 4H), 1.09 (br d, J = 6.0 Hz, 6H).

[0437] 2-chloro- N -(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H -Indazole-7-yl)acetamide. 3-(7-amino-1-methyl-1 in dichloromethane (20 mL, 0.2 M) H Triethylamine (1.62 mL, 11.62 mmol, 3 eq) and 2-chloroacetyl chloride (0.46 mL, 5.810 mmol, 1.5 eq) were added simultaneously to a solution of -indazole-3-yl)piperidine-2,6-dione (1.000 g, 3.870 mmol, 1 eq) under nitrogen at 0°C. After 2 hours, the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (4 x 40 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel column chromatography (0 to 100% ethyl acetate in dichloromethane) and 2-chloro- as a gray solid N -(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H -Indazole-7-yl)acetamide (0.750 g, 2.240 mmol, 58% yield) was obtained. 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= 7.6 Hz, 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).

[0438] 2-((2 R ,4 s ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N,N -4-(3-( in dimethylformamide (2 mL, 0.1 M) trans- 4-(2-((2S,4s,6R)-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.100 g, 0.180 mmol, 1 eq) and 2-chloro- N In a solution of -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.081 g, 0.270 mmol, 1.5 eq). N,N -Diisopropylethylamine (0.16 mL, 0.910 mmol, 5 eq) and sodium iodide (0.027 g, 0.180 mmol, 1 eq) were added. The reaction mixture 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 layer was washed with brine (30 mL), dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods and found to be a yellow solid, 2-((2 R ,4 s ,6 S )-4-(2-(( trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.081 g, 0.099 mmol, 55% yield) was obtained. MS (ESI) m / z 810.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.80 (d, J = 4.0 Hz, 1H), 10.60 (s, 1H), 10.17 - 9.89 (m, 1H), 9.04 (br s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 1.6, 8.0 Hz, 1H), 7.12 - 6.95 (m, 2H), 6.86 (t, J = 6.8 Hz, 1H), 6.56 - 6.39 (m, 1H), 4.27 (dd, J = 5.2, 11.6 Hz, 1H), 4.23 - 4.18 (m, 1H), 4.15 (br d, J = 3.6 Hz, 1H), 3.81 - 3.68 (m, 3H), 3.62 - 3.54 (m, 1H), 3.48 (br t, J = 6.0 Hz, 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 = 1.2 Hz, 6H), 1.39 - 1.33 (m, 3H), 1.33 - 1.23 (m, 2H), 1.19 (d, J= 6.4 Hz, 3H).

[0439] Examples 16: 2-((2 R ,4 r ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0440]

[0441] 4-(3-( trans- 4-(2-((2 R ,4 r ,6 S )-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile . tert-butyl (2 in dichloromethane (3 mL, 0.12 M) R ,4 r ,6 S )-4-(2-(( trans- To a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.550 mmol, 1 eq), 4 M hydrochloric acid in 1,4-dioxane (12 mL, 48 mmol) was added, and the reaction solution was stirred at 15°C. After 14 hours, the reaction solution was concentrated. The resulting solid was diluted to pH 8 to 9 using a saturated bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (30 mL), dried with anhydrous sodium sulfate, and concentrated to form a yellow solid, 4-(3-( trans- 4-(2-((2 R ,4 r ,6 S)-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.330 g, 0.56 mmol) was obtained and passed to the next step without further purification. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.0, 8.4 Hz, 1H), 3.73 - 3.59 (m, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.30 (m, 1H), 3.03 - 2.80 (m, 2H), 2.74 (m, 2H), 2.20 (br d, J = 12.4 Hz, 2H), 1.82 (br d, J = 11.6 Hz, 2H), 1.68 (br d, J = 13.2 Hz, 2H), 1.61 (s, 6H), 1.54 - 1.48 (m, 2H), 1.41 - 1.27 (m, 3H), 1.14 (br d, J = 6.4 Hz, 6H), 0.92 - 0.76 (m, 2H).

[0442] 2-((2 R ,4 r ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N,N -4-(3-( in dimethylformamide (1 mL, 0.11 M) trans- 4-(2-((2 S ,4 r ,6 R)-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.060 g, 0.110 mmol, 1 eq) and 2-chloro- N In a solution of -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.048 g, 0.160 mmol, 1.5 eq). N,N -Diisopropylethylamine (0.09 mL, 0.540 mmol, 5 eq) and sodium iodide (0.016 g, 0.110 mmol, 1 eq) were added. The reaction mixture was stirred at 80°C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to obtain 2-((2 R ,4 r ,6 S )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.041 g, 0.0498 mmol, 46% yield) was obtained. MS (ESI) m / z 810.3 [M+1] + ; 1 H NMR (400 MHz, 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 = 8.4 Hz, 1H), 8.18 (s, 1H), 7.96 (dd, J= 1.6, 8.4 Hz, 1H), 7.10 - 7.00 (m, 1H), 6.99 - 6.89 (m, 1H), 6.83 (br d, J = 8.0 Hz, 1H), 6.47 (m, 1H), 4.30 - 4.22 (m, 1H), 4.21 - 4.15 (m, 1H), 4.09 - 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 = 5.2 Hz, 3H), 1.30 - 1.22 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.15 - 1.06 (m, 1H).

[0443] Examples 17: 2-((2 R ,6 S )-4-(4-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0444]

[0445] tert -butyl ( trans- 4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate. N,N -2- in dimethylformamide (20 mL, 0.38 M) trans- 4-(( tert -butoxycarbonyl)amino)cyclohexyl)acetic acid (2.000 g, 7.770 mmol, 1 eq) and N,O- In a solution of dimethylhydroxylamine hydrochloride (0.830 g, 8.550 mmol, 1.1 eq) N , N Diisopropylethylamine (6.94 mL, 38.86 mmol) and HATU (4.430 g, 11.66 mmol, 5 eq) were added, and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) as a white solid tert -butyl ( trans- 4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.200 g, 7.323 mmol, 94% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 4.41 (s, 1H), 3.66 (s, 3H), 3.37 (s, 1H), 3.17 (s, 3H), 2.31 - 2.29 (d, J = 6.4 Hz, 2H), 2.04 - 1.97 (m, 2H), 1.85 - 1.79 (m, 3H), 1.43 (s, 9H), 1.18 - 1.02 (m, 4H).

[0446] tert -butyl ( trans- 4-(2-oxoethyl)cyclohexyl)carbamate. in dichloromethane (10 mL) tert -butyl ( trans-To a solution of 4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.2 g, 7.320 mmol, 1 eq), a 70% bis(2-methoxyethoxy)aluminum hydride solution in toluene (4.08 mL, 14.65 mmol, 2 eq) was added at 0°C. After stirring for 2 hours, the reaction solution was diluted with water (20 mL) and a saturated aqueous ammonium chloride solution (10 mL). The solution was extracted with dichloromethane (3 x 30 mL), the combined organic layer was dried with anhydrous sodium sulfate, and concentrated. The resulting crude oil was purified by silica gel column chromatography (0 to 25% ethyl acetate in petroleum ether) as a white solid tert -butyl ( trans- 4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.008 mmol, 82% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 9.65 - 9.64 (t, J = 2.0 Hz, 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).

[0447] ethyl ( E )-4-( trans- 4-(( tert -Butoxycarbonyl)amino)cyclohexyl)but-2-enoate. In toluene (10 mL, 0.6 M) tert -butyl ( trans-Ethyl 2-(triphenylphosphoranilidene)acetate (2.300 g, 6.610 mmol, 1.1 eq) was added to a solution of 4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.010 mmol, 1 eq), and the reaction mixture was stirred at 80°C. After 12 hours, the reaction solution was concentrated, and the resulting crude material was purified by silica gel column chromatography (0 to 20% ethyl acetate in hexane) to obtain ethyl ( E )-4-( trans- 4-(( tert -butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.858 mmol, 48% yield) was obtained. 1 H NMR (400 MHz, 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 = 7.2 Hz, 3H), 1.13 - 0.99 (m, 4H).

[0448] tert -butyl ( trans- 4-(4-hydroxybutyl)cyclohexyl)carbamate. Anhydrous lithium chloride (0.900 g, 21.43 mmol, 7.5 eq) was added to a solution of sodium borohydrogen (0.811 g, 21.43 mmol, 7.5 eq) in ethanol (16 mL) and THF (16 mL) at 0°C, and the solution was stirred for 10 minutes. Ethyl (in 8 mL of THF) in the reaction solution E )-4-( trans- 4-(( tertA solution of -butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.860 mmol, 1 eq) was added, and the reaction solution was stirred at 15°C. After 12 hours, the reaction solution was quenched by slowly adding 1 M aqueous hydrochloric acid solution (10 mL), and the solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layer was dried with anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0 to 25% ethyl acetate in hexane) as a white solid tert -butyl ( trans- 4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.763 mmol, 96% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 4.37 (s, 1H), 3.66 - 3.62 (t, J = 6.8 Hz, 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).

[0449] 4-( trans- 4-aminocyclohexyl)butan-1-ol. in dichloromethane (2 mL) tert -butyl ( trans- To a solution of 4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.760 mmol, 1 eq), 4 M hydrochloric acid in 1,4-dioxane (4 mL, 16 mmol, 5.8 eq) was added, and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to remove the organic solvent, then diluted with saturated sodium bicarbonate (30 mL), and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried with anhydrous sodium sulfate, and concentrated to form a white solid, 4-( trans- 4-aminocyclohexyl)butan-1-ol (0.410 g, 2.394 mmol, 87% yield) was obtained and passed to the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 3.62 - 3.59 (t, J = 6.4 Hz, 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).

[0450] methyl 2-(( trans- 4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate. Methyl 2-bromo-2-methylpropanoate (1.733 g, 9.570 mmol, 4 eq) and 4-( trans- Potassium carbonate (0.993 g, 7.180 mmol, 3 eq) and sodium iodide (0.072 g, 0.480 mmol, 0.2 eq) were added to a solution of 4-aminocyclohexyl)butan-1-ol (0.410 g, 2.390 mmol, 1 eq), and the reaction solution was stirred at 80°C. After 12 hours, the reaction solution was diluted with ethyl acetate, filtered, and concentrated to obtain crude methyl 2-(( trans- 4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, crude state) was obtained. MS (ESI) m / z 272.3 [M+1] + .

[0451] 4-(3-( trans- 4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. Methyl 2-((in ethyl acetate (12 mL) trans-In a solution of 4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, 2.320 mmol, 1 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.556 g, 2.440 mmol, 1.1 eq) N,N Diisopropylethylamine (1.15 mL, 6.960 mmol, 3 eq) was added, and the reaction mixture was stirred at 80°C. After 3 hours, the reaction solution was diluted with ethyl acetate (20 mL) and concentrated. The resulting crude oil was purified by silica gel column chromatography (0 to 35% ethyl acetate in petroleum ether) and obtained as a brown solid 4-(3-( trans- 4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.736 mmol, 32% yield) was obtained. MS (ESI) m / z 468.1 [M+1] + .

[0452] 4-(3-( trans- 4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile. 4-(3-( in dichloromethane (3 mL) trans- In a solution of 4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.770 mmol, 1 eq) N,N- Dimethylformamide (0.30 mL) and thionyl bromide (0.400 g, 1.920 mmol, 2.5 eq) were added, and the reaction solution was stirred at 15°C. After 12 hours, the reaction solution was concentrated and purified by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to obtain a brown solid, 4-(3-( trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.280 g, 0.517 mmol, 67% yield) was obtained. MS (ESI) m / z 530.0 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.96 - 7.94 (d, J = 8.4 Hz, 1H), 7.86 - 7.85 (d, J = 1.6 Hz, 1H), 7.75 - 7.72 (d, J = 8.4, 1.6 Hz, 1H), 3.85 (s, 1H), 3.45 - 3.41 (t, J = 6.8 Hz, 2H), 2.69 (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).

[0453] 2-((2 R ,6 S )-4-(4-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . N,N - 4-(3-( in dimethylformamide (2 mL) trans- 4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (0.075 g, 0.140 mmol, 1 eq) and 2-((2 S ,6 R )-2,6-dimethylpiperazine-1-yl)- N In a solution of -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrobromide (0.084 g, 0.180 mmol, 1.3 eq) N,NDiisopropylethylamine (0.12 mL, 0.710 mmol, 5 eq) was added, and the reaction solution was stirred at 50°C. After 12 hours, the reaction solution was diluted with water (20 mL) and extracted with 20:1 dichloromethane / methanol (3 x 15 mL). The combined organic layer was dried with anhydrous sodium sulfate, concentrated, and purified by standard methods to form a white solid 2-((2 R ,6 S )-4-(4-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.034 g, 0.041 mmol, 29% yield) was obtained. MS (ESI) m / z 823.3 [M+1] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.79 (s, 1H), 8.35 - 8.33 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 7.99 - 7.97 (d, J = 8.0 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.98 (s, 1H), 6.84 - 6.82 (d, J = 8.0 Hz, 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).

[0454] Examples 18: 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( S )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0455]

[0456] 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( S )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . 2-((2 R ,6 S )-4-(3-( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid (200 mg, 0.33 mmol) and ( S In a 2-dram vial containing )-3-((3-aminophenyl)amino)piperidine-2,6-dione (93.8 mg, 0.43 mmol, 1.3 eq). N,N - Dimethylformamide (1.65 mL, 0.2 M) was added and stirred until all solids were dissolved. After adding 1-methylimidazole (0.26 mL, 3.29 mmol, 10 eq), N -(chloro(dimethylamino)methylene)- N -Methylmethaneamul hexafluorophosphate(V)(138.5 mg, 0.49 mmol, 1.5 eq) was added, and the reaction solution was stirred at room temperature. After 20 minutes, the reaction solution was diluted with DMSO until the total volume was 4 ml, filtered, and purified by standard methods, 2-((2 R ,6 S )-4-(3-( trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)- N -(3-((( S )-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (62 mg, 0.076 mmol, 23% yield) was obtained. MS (ESI) m / z 809.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ = 10.77 (s, 1H), 9.34 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.98 (dd, J = 1.7, 8.3 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.81 - 6.77 (m, 1H), 6.40 (dd, J = 1.7, 8.1 Hz, 1H), 5.90 (d, J = 7.9 Hz, 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) = 6.1 Hz, 6H)

[0457] Examples 19: 2-(( R )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0458]

[0459] tert -butyl ( R )-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. In a 40 ml vial tert -butyl ( R)-3-(trifluoromethyl)piperazine-1-carboxylate (0.5 g, 1.97 mmol), N,N Diisopropylethylamine (0.69 mL, 3.93 mmol, 2 eq), methyl bromoacetate (1.09 mL, 11.8 mmol, 6 eq), and THF (20 mL, 0.1 M) were added. 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. Subsequently, the combined organic layer was dried with magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1 to 50% ethyl acetate in hexane) as a yellow oil tert -butyl ( R )-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.557 g, 1.71 mmol, 88% yield) was obtained. MS (ESI) m / z 227 [M-99] + .

[0460] methyl ( R )-2-(2-(trifluoromethyl)piperazine-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 eq) were mixed in dichloromethane (7.6 mL, 1 M) and stirred at room temperature in a screw-capped scintillation vial. After 1 hour, the solution was concentrated and methyl ( R )-2-(2-(trifluoromethyl)piperazine-1-yl)acetate (255 mg, 0.75 mmol, 98% yield) was obtained and transferred to the next step without further purification. MS (ESI) m / z 227 [M+1] + .

[0461] methyl2-(( R )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate . 4-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile(0.5 g, 0.96 mmol, 1 eq), methyl ( S After adding acetonitrile (5 mL) to a 1-dram vial containing )-2-(2-(trifluoromethyl)piperazine-1-yl)acetate (0.33 g, 0.96 mmol, 1 eq) and sodium iodide (2.7 mg, 0.02 mmol, 0.1 eq), N,N Diisopropylethylamine (0.8 mL, 4.82 mmol, 5 eq) was added. The reaction vial was heated to 60°C while stirring. After 16 hours, the reaction solution was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium chloride solution (100 mL), dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexane) to obtain methyl 2-(( R )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate (0.6 g, 0.89 mmol, 91% yield) was obtained. MS (ESI) m / z 664.2 [M+1] + .

[0462] 2-(( R )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetic acid . Methyl 2-(( in a mixture of tetrahydrofuran / methanol / water (3:1:1, 5 mL) R )-4-(2-(( trans-Lithium hydroxide monohydrate (0.58 g, 1.3 mmol, 1.5 eq) was added all at once at 0°C to a cooled solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate (0.6 g, 0.9 mmol, 1 eq). The resulting solution was stirred at room temperature. After 3 hours, the reaction solution was diluted with water (20 mL) and extracted with 10% methanol (4 x 50 mL) in dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated to 2-(( R )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetic acid (0.33 g, 0.46 mmol, 51% yield) was obtained and transferred to the next step without further purification. MS (ESI) m / z 650.2 [M+1] + .

[0463] 2-(( R )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride . 2-(( R )-4-(2-(( trans- Acetonitrile (1.5 mL) and acetonitrile in a 2-dram vial containing 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetic acid (0.12 g, 0.19 mmol, 1 eq) and 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.05 g, 0.22 mmol, 1.2 eq) N,N-Dimethylformamide (1.5 mL) was added, and the reaction solution was stirred until all solids were dissolved. After adding 1-methylimidazole (0.07 mL, 0.84 mmol, 5 eq) to the reaction solution, N -(chloro(dimethylamino)methylene)- N -Methylmethaneumin hexafluorophosphate (0.12 g, 0.41 mmol, 2.2 eq) was added, and the reaction solution was stirred at room temperature. After 1 hour, the reaction solution was diluted with dimethyl sulfoxide until the total volume was 3 ml, filtered, and purified by standard methods to obtain 2-(( R )-4-(2-(( trans- 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.09 g, 0.11 mmol, 58% yield) was obtained. MS (ESI) m / z 851.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.68 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 1.5 Hz, 1H), 7.90 (dd, J = 1.6, 8.2 Hz, 1H), 7.04 - 6.89 (m, 2H), 6.77 (br d, J = 6.5 Hz, 1H), 6.36 (br d, J = 8.2 Hz, 1H), 4.20 (br dd, J = 4.5, 10.9 Hz, 2H), 3.87 - 3.44 (m, 8H), 3.30 (br d, J = 11.2 Hz, 4H), 3.06 (br d, J= 9.7 Hz, 3H), 2.89 - 2.51 (m, 4H), 2.10 - 1.97 (m, 3H), 1.84 (dq, J = 4.7, 12.1 Hz, 1H), 1.72 - 1.61 (m, 2H), 1.48 (s, 6H), 1.38 - 1.19 (m, 2H).

[0464] Examples 20: 2-(( R )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride

[0465]

[0466] methyl 2-(( R )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate . 5-(3-( trans- 4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (375 mg, 0.72 mmol, 1 eq) and methyl ( R In a 1-dram vial containing )-2-(2-(trifluoromethyl)piperazine-1-yl)acetate trifluoroacetate (491.3 mg, 1.44 mmol, 2 eq). N,N -Dimethylformamide (3.6101 mL, 0.2 M) and N,N-Diisopropylethylamine (0.75 mL, 4.33 mmol, 6 eq) was added. The reaction solution was heated to 55°C while stirring. After 16 hours, the reaction solution was diluted with 75 mL of ethyl acetate and washed with 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of brine. The organic layer was separated and dried with magnesium sulfate to obtain a yellowish oil. The crude material was purified by reverse-phase HPLC to obtain the title compound as a formate salt. This material was absorbed into ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried with magnesium sulfate and concentrated to obtain methyl 2-(( R )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate (310 mg, 0.4664 mmol, 65% yield) was obtained. MS (ESI) m / z 655.2 [M+1] + ; 1 ¹H NMR (400 MHz, chloroform- d ) δ 1.62 (s, 6 H) 1.81 (br d, J = 11.86 Hz, 2 H) 2.20 (br d, J = 10.76 Hz, 2 H) 2.48 (ddd, J = 11.03, 7.92, 3.30 Hz, 1 H) 2.52 - 2.69 (m, 4 H) 2.81 - 2.94 (m, 4 H) 2.94 - 3.03 (m, 1 H) 3.27 - 3.38 (m, 1 H) 3.46 (dd, J = 17.85, 0.98 Hz, 1 H) 3.56 - 3.70 (m, 5 H) 3.71 (s, 3 H) 8.23 ​​(d, J = 2.20 Hz, 1 H) 8.97 (d, J = 2.20 Hz, 1 H)

[0467] 2-(( R )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate . Methyl 2-(( R )-4-(2-(( trans- 1,4-dioxane (1 mL, 0.3 M) was added to a 2-dram vial containing 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate (200 mg, 0.30 mmol), followed by the addition of a 1 M solution of lithium hydroxide in water (0.36 mL, 0.36 mmol, 1.2 eq). The reaction solution was stirred at room temperature for 2 hours, at which point no residual starting material remained according to LCMS. The reaction solution was concentrated, and the resulting material was dried by dezeotropic elimination with dioxane to form a glassy yellow oil, 2-(( R )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate (193 mg, 0.29 mmol, 98% yield) was obtained. This material was transferred to the next step without further purification. MS (ESI) m / z 651.2 [M+1] + .

[0468] 2-(( R )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride. N -(chloro(dimethylamino)methylene)- N - In a 1-dram vial containing methylmethaneamul hexafluorophosphate (V) (112.2 mg, 0.40 mmol, 2 eq) N,N -2-((in dimethylformamide (1.0 mL, 0.2 M) R)-4-(2-(( trans- After adding a solution of 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetate (131.31 mg, 0.20 mmol, 1 eq), 3-((3-aminophenyl)amino)piperidine-2,6-dione (66 mg, 0.30 mmol, 1.5 eq) and 1-methylimidazole (98.5 mg, 1.2 mmol, 6 eq) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with DMSO until the total volume was 2 ml, filtered, and purified by standard methods to obtain 2-(( R )-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)- N -(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (98 mg, 0.11 mmol, 53% yield) was obtained. MS (ESI) m / z 852.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 10.72 (br s, 1H), 9.72 (s, 1H), 9.15 (d, J = 1.8 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.06 - 6.94 (m, 2H), 6.89 - 6.77 (m, 1H), 6.42 (br d, J= 7.6 Hz, 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).

[0469] Examples 21: 2-((2S,4r,6R)-4-(2-(( trans- 4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)- N -(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

[0470]

[0471] 5-(3-(( Trans )4-(2-((2S,4r,6R)-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile45 M HCl (30.0 mL, 120 mmol) in dioxane was added to a solution of (2S,4r,6R)-tert-butyl 4-(2-(((1r,4R)-4-(3-(6-cyano-5-(1,1-difluoroethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.000 g, 3.070 mmol) in DCM (5 mL). The reaction mixture was stirred at 15°C for 3 hours, and the reaction mixture was concentrated to obtain the residue. The residue was diluted to pH 8 to 9 using a saturated aqueous sodium bicarbonate solution (50 mL), and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, and concentrated to obtain 5-(3-((1R,4r)-4-(2-((2S,4r,6R)-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (1.940 g, 3.517 mmol) as a yellow solid, which was transferred to the next step without further purification. MS (ESI) m / z: 552.4 [M+1] + ; 1 1H NMR (400 MHz, CDCl₃ 3 ) δ 8.97 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 3.79 - 3.58 (m, 1H), 3.56 - 3.46 (m, 2H), 3.30 (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 = 13.2 Hz, 2H), 1.62 (s, 6H), 1.52 (q, J = 6.8 Hz, 2H), 1.41 - 1.29 (m, 2H), 1.27 - 1.11 (m, 6H), 0.88 (q, J = 11.2 Hz, 2H).

[0472] 2-((2S,4r,6R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide N-ethyl-N-isopropylpropane-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-((1R,4r)-4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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). 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 x 30 mL), the combined organic layer was washed with brine (50 mL), dried with sodium sulfate, and concentrated. The resulting residue was purified by standard methods to obtain 2-((2S,4r,6R)-4-(2-(((1r,4R)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopipperidine-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 (400 MHz, 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 = 2.0 Hz, 1H), 9.07 (br s, 1H), 8.74 (d, J = 1.6 Hz, 1H), 7.05 (m, 1H), 6.99 (br d, J = 7.2 Hz, 1H), 6.87 (br d, J = 8.0 Hz, 1H), 6.57 - 6.36 (m, 1H), 4.26 (m, 1H), 4.21 (br s, 1H), 4.12 (br d, J = 3.6 Hz, 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 = 1.6 Hz, 6H), 1.50 (m, 1H), 1.47 - 1.38 (m, 2H), 1.38 - 1.22 (m, 5H), 1.20 (d, J = 6.4 Hz, 3H), 1.17 - 1.07 (m, 1H).

[0473] Examples 22: 2-((2S,4s,6R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0474]

[0475] 5-(3-(( Trans )-4-(2-((2S,4s,6R)-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile . DCM(3 mL) 중 (2S,4s,6R)-tert-부틸 4-(2-((( Trans4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.885 g, 1.360 mmol) was added to a solution of 0.885 g, 1.360 mmol of 4 M HCl in dioxane (20 mL, 80 mmol), and the reaction solution was stirred at 15°C. After 12 hours, the solution was concentrated, and the resulting residue was diluted with an aqueous sodium bicarbonate solution. This aqueous solution was extracted with ethyl acetate (3 x 100 mL), the combined organic layer was washed with brine (50 mL), dried with sodium sulfate, and concentrated to obtain a yellow solid 5-(3-(( Trans )-4-(2-((2S,4s,6R)-2,6-dimethylpiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-3-(trifluoromethyl)picolinonitrile (0.750 g, 1.360 mmol) was obtained and transferred to the next step without further purification. MS (ESI) m / z: 552.5 [M+1] + ; 1 1H NMR (400 MHz, CDCl₃ 3 ) δ 8.97 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 3.78 - 3.59 (m, 1H), 3.51 (t, J = 6.8 Hz, 2H), 3.31 (m, 1H), 3.02 - 2.72 (m, 4H), 2.21 (br d, J = 12.4 Hz, 2H), 2.01 - 1.95 (m, 1H), 1.82 (br d, J = 12.0 Hz, 2H), 1.70 (q, J = 6.8 Hz, 2H), 1.63 (s, 6H), 1.52 (br d, J = 13.6 Hz, 2H), 1.41 - 1.26 (m, 4H), 1.10 (d, J = 6.4 Hz, 6H).

[0476] 2-((2S,4s,6R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. 5-(3-(( in DMF (0.500 mL) Trans N-ethyl-N-isopropylpropane-2-amine (0.19 mL, 1.090 mmol) and sodium iodide (0.033 g, 0.220 mmol) were added to a solution of )-4-(2-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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). 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 x 30 mL). The combined organic layer was washed with brine (50 mL), dried with sodium sulfate, and concentrated. The resulting residue was purified by standard methods to form a yellow solid, 2-((2S,4s,6R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.064 g, 0.079 mmol, 36.1% yield) was obtained. MS (ESI) m / z: 811.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.80 (br d, J = 3.6 Hz, 1H), 10.62 (s, 1H), 10.27 - 9.86 (m, 1H), 9.14 (d, J = 1.2 Hz, 1H), 9.08 - 8.97 (m, 1H), 8.74 (d, J = 1.6 Hz, 1H), 7.17 - 6.94 (m, 2H), 6.93 - 6.73 (t, J = 6.8 Hz, 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 = 6.0 Hz, 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 = 1.2 Hz, 6H), 1.35 (br s, 3H), 1.33 - 1.25 (m, 2H), 1.19 (br d, J = 6.0 Hz, 3H).

[0477] Examples 23: 2-((R)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide

[0478]

[0479] 2-((R)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamidePotassium iodide (0.048 g, 0.290 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.15 mL, 0.870 mmol) were added to a solution of 4-(3-((1R,4R)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.150 g, 0.350 mmol) in DMF (3 mL). 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 x 30 mL). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, and concentrated. The resulting residue was purified by standard methods to form a yellow solid, 2-((R)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide (0.062 g, 0.070 mmol, 24.2% yield) was obtained. MS (ESI) m / z: 869.6 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.93 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.97 (dd, J = 1.6, 8.3 Hz, 1H), 6.80 - 6.59 (m, 2H), 6.22 (d, J = 12.1 Hz, 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).

[0480] Examples 24: 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide

[0481]

[0482] (3R)-tert-butyl 4-(2-((3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylateN-ethyl-N-isopropylpropane-2-amine (0.44 mL, 2.53 mmol) and 3-((3-amino-5-fluorophenyl)amino)piperazine-1-yl)acetic acid (0.263 g, 0.840 mmol) and HATU (0.641 g, 1.69 mmol) were added to a solution of (S)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazine-1-yl)acetic acid (0.263 g, 0.840 mmol) and HATU (0.641 g, 1.69 mmol) in DMF (5 mL). 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 x 30 mL). The combined organic layer was washed with brine (2 x 20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (0 to 4% methanol in dichloromethane) to obtain (3S)-tert-butyl 4-(2-((3-((2,6-dioxopiperidine-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] + .

[0483] N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide.33% hydrogen bromide (0.5 mL) in acetic acid was added 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), and the reaction mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to obtain N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((S)-2-(trifluoromethyl)piperazine-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] + .

[0484] 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide Potassium iodide (0.032 g, 0.190 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.1 mL, 0.580 mmol) were added to a solution of 5-(3-((1R,4R)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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)piperazine-1-yl)acetamide (0.100 g, 0.230 mmol) in DMF (3 mL). The reaction mixture was stirred at 50°C for 12 hours, diluted with DMSO, and purified by standard methods as a green solid, 2-((R)-4-(2-((( Trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide (0.062 g, 0.071 mmol, 36.8% yield) was obtained. MS (ESI) m / z 870.6 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.53 - 10.98 (m, 1H), 10.79 (s, 1H), 9.94 (br s, 1H), 9.14 (d, J = 1.9 Hz, 1H), 8.74 (d, J = 1.9 Hz, 1H), 6.85 - 6.57 (m, 2H), 6.22 (d, J = 11.9 Hz, 1H), 4.40 (s, 1H), 4.28 (dd, J = 4.7, 11.2 Hz, 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, 17.0 Hz, 1H), 2.63 - 2.54 (m, 1H), 2.14 - 2.03 (m, 3H), 1.94 - 1.84 (m, 1H), 1.72 (br d, J = 11.3 Hz, 2H), 1.56 (s, 6H), 1.41 - 1.29 (m, 2H).

[0485] Examples 25: 2-((R)-4-(3-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0486]

[0487] 2-((R)-4-(3-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide hydrobromide (0.180 g, 0.360 mmol) and 5-(3-(( Trans N-ethyl-N-isopropylpropane-2-amine (0.32 mL, 1.820 mmol) was added to a solution of )-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.188 g, 0.360 mmol). The reaction mixture was stirred at 50°C for 12 hours. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (3 x 30 mL), and the combined organic layer was dried with sodium sulfate and concentrated. The resulting crude material was purified by standard methods and found to be a yellow solid, 2-((R)-4-(3-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.078 g, 0.090 mmol, 25% yield) was obtained. MS (ESI) m / z 850.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.27 - 11.00 (m, 1H), 10.79 (s, 1H), 9.80 - 9.59 (m, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.09 - 6.95 (m, 2H), 6.90 - 6.75 (m, 1H), 6.43 (br d, J = 8.0 Hz, 1H), 4.38 (br s, 1H), 4.27 (br dd, J = 4.8, 11.2 Hz, 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).

[0488] Examples 26: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide

[0489]

[0490] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide . In a solution of N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.172 g, 0.390 mmol) in DMF (1 mL), 5-(3-(( Trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.100 g, 0.190 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.026 g, 0.960 mmol) were added. Subsequently, the reaction mixture was stirred at 50°C for 12 hours. The reaction solution was diluted with DMSO and purified by standard methods to obtain N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.072 g, 0.075 mmol, 39% yield) was obtained. MS (ESI) m / z 886.0 [M+1] + ; 1 H NMR (400 MHz, DMSO - d6) δ 10.83 - 10.77 (m, 1H), 9.97 - 9.66 (m, 1H), 9.15 (d, J = 1.6 Hz, 1H), 8.74 (d, J = 1.6 Hz, 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 - 2.02 (m, 3H), 1.98 - 1.84 (m, 1H), 1.78 - 1.68 (m, 2H), 1.57 (s, 6H), 1.44 - 1.31 (m, 2H).

[0491] Examples 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-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide

[0492]

[0493] (3R)-tert-butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidine-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate EDCI (0.246 g, 1.28 mmol) was added to a solution of 3-(3-amino-5-chloro-anilino)piperidin-2,6-dione (0.162 g, 0.640 mmol) and (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazine-1-yl)acetic acid (0.200 g, 0.640 mmol) in pyridine (1 mL), and the reaction solution was heated to 50°C. After 12 hours, the reaction solution was concentrated, diluted with water (40 mL), and extracted with ethyl acetate (3 x 40 mL). The combined organic layer was dried with anhydrous sodium sulfate and purified by standard methods to obtain (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] + .

[0494] (3R)-tert-butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidine-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 (0.5 mL, 0.460 mmol) in AcOH was stirred at 25°C. After 12 hours, the reaction solution was concentrated to obtain (3R)-tert-butyl 4-(2-((3-chloro-5-((2,6-dioxopiperidine-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 transferred to the next step without further purification. MS (ESI) m / z 448.1 [M+1] + .

[0495] 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-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.172 g, 0.390 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.124 g, 0.960 mmol) were added to a solution of 4-[3-[4-(2-bromoethoxy)cyclohexyl]-4,4-dimethyl-5-oxo-2-thiooxo-imidazolidin-1-yl]-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.172 g, 0.390 mmol) in DMF (1 mL), and the reaction solution was heated to 50°C. After 12 hours, the reaction solution was diluted with DMSO and purified by standard methods to obtain a yellow solid, 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-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.083 g, 0.089 mmol, 46.0% yield) was obtained. MS (ESI) m / z 885.0 [M+1] + ; 1H NMR (400 MHz, DMSO - d6) δ 10.80 (s, 2H), 10.01 - 9.67 (m, 1H), 8.34 (d, J = 8.4 Hz, 1 H), 8.20 (d, J = 1.6 Hz, 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), 2.14 - 2.02 (m, 3H), 1.98 - 1.83 (m, 1H), 1.74 (dd, J = 12 Hz, 2H), 1.55 (s, 6H), 1.45 - 1.30 (m, 2H).

[0496] Examples 28: 2-((R)-4-(3-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0497]

[0498] tert-butyl (3R)-4-(2-((3-((2,6-dioxopiperidine-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.737 g, 3.84 mmol) was added to a mixture of 3-(3-aminoanilino)piperidin-2,6-dione hydrochloride (0.737 g, 2.88 mmol) and 2-[(2R)-4-tert-butoxycarbonyl-2-(trifluoromethyl)piperazine-1-yl]acetic acid (0.600 g, 1.92 mmol) in pyridine (2 mL), 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), the organic layer was dried with sodium sulfate, and concentrated. The resulting crude residue was purified by standard methods to obtain 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] + .

[0499] N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide Hydrobromide. 30% hydrogen bromide (0.60 mL, 8.76 mmol) in acetic acid was added 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), and the reaction solution was stirred at room temperature. After 16 hours, the reaction solution was concentrated to obtain crude N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide hydrobromide (0.500 g, 1.01 mmol), which was transferred to the next step without further purification. MS (ESI) m / z 414.1 [M+1] + .

[0500] 2-((R)-4-(3-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Diisopropylethylamine (0.06 mL, 0.73 mmol) was added to a mixture of 5-(3-((1r,4r)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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)piperazine-1-yl)acetamide hydrobromide (0.120 g, 0.24 mmol) in N,N-dimethylformamide (2 mL), and the reaction solution was stirred at 50°C. After 16 hours, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (2 x 80 mL), the combined organic layer was dried with anhydrous sodium sulfate, and concentrated. The resulting crude residue was purified by standard methods to obtain 2-((R)-4-(3-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.045 g, 0.05 mmol, 20.7% yield) was obtained. MS (ESI) m / z 866.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.08 (br d, J = 5.6 Hz, 1H), 10.80 (s, 1H), 9.82 - 9.56 (m, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J = 1.6, 8.0 Hz, 1H), 7.01 (br t, J = 8.0 Hz, 2H), 6.92 - 6.72 (m, 1H), 6.43 (br d, J = 8.0 Hz, 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).

[0501] Examples 29: 2-((R)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0502]

[0503] 2-((R)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamideDiisopropylethylamine (0.06 mL, 0.73 mmol) was added to a mixture of 4-(3-((1r,4r)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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), and the reaction solution was stirred at 50°C. After 16 hours, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (2 x 80 mL), the combined organic layer was dried with sodium sulfate, and concentrated. The resulting crude material was purified by standard methods and found to be a yellow solid, 2-((R)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.057 g, 0.06 mmol, 26.7% yield) was obtained. MS (ESI) m / z 849.3 [M+1] + ; 1H NMR (400 MHz, 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 = 3.2 Hz, 6H), 1.42 - 1.24 (m, 2H).

[0504] Examples 30: 2-((R)-4-(3-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0505]

[0506] 2-((R)-4-(3-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide N-ethyl-N-isopropylpropane-2-amine (0.25 mL, 1.45 mmol) and potassium iodide (80.31 mg, 0.4800 mmol) were added to a solution of 4-(3-((1r,4r)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.200 g, 0.480 mmol) in DMF (3 mL), 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 with sodium sulfate, concentrated, and purified by standard methods to obtain a yellow solid, 2-((R)-4-(3-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.059 g, 0.068 mmol, 14.1% yield) was obtained. MS (ESI) m / z 865.5 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.71 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 1.6, 8.2 Hz, 1H), 7.05 - 6.94 (m, 2H), 6.87 - 6.74 (m, 1H), 6.41 (br d, J = 8.5 Hz, 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, 6.0 Hz, 3H), 1.99 - 1.82 (m, 3H), 1.71 (d, J = 11.1 Hz, 2H), 1.54 (s, 6H), 1.36 - 1.25 (m, 2H).

[0507] Examples 31: N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide

[0508]

[0509] (3R)-tert-butyl 4-(2-((3-cyano-5-((2,6-dioxopiperidine-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylateN-ethyl-N-isopropylpropane-2-amine (0.21 mL, 1.23 mmol) and 3-amino-5-((2,6-dioxopiperidine-3-yl)amino)benzonitrile (100 mg, 0.4100 mmol) were added to a solution of (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazine-1-yl)acetic acid (0.128 g, 0.410 mmol) and HATU (311.34 mg, 0.8200 mmol) in DMF (3 mL). 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 x 30 mL). The combined organic layer was washed with brine (2 x 20 mL), dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to obtain (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] + .

[0510] N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide Trifluoroacetic acid (1.0 mL, 12.89 mmol) was added 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), and the reaction mixture was stirred at 25°C. After 12 hours, the reaction solution was concentrated to obtain crude N-(3-cyano-5-((2,6-dioxopiperidine-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.380 g, 0.867 mmol, 99% yield) as a yellow solid, which was transferred to the next step without further purification. MS (ESI) m / z439.2 [M+1] + .

[0511] N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide Potassium iodide (0.068 g, 0.410 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.21 mL, 1.23 mmol) were added to a solution of 5-(3-((1r,4r)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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)piperazine-1-yl)acetamide (0.180 g, 0.410 mmol) in DMF (3 mL), 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 layer was dried with anhydrous sodium sulfate, concentrated, and purified by standard methods to obtain a green solid, N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetamide (0.059 g, 0.0675 mmol, 16% yield) was obtained. MS (ESI) m / z 877.5 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.76 (s, 1H), 9.14 (d, J = 1.8 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H), 7.22 (s, 2H), 6.77 (s, 1H), 6.50 (d, J = 8.0 Hz, 1H), 4.43 - 4.36 (m, 1H), 3.94 - 3.81 (m, 1H), 3.71 - 3.57 (m, 2H), 3.54 (t, J = 5.6 Hz, 2H), 3.40 (d, J = 16.1 Hz, 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 = 11.4 Hz, 2H), 1.56 (s, 6H), 1.36 - 1.24 (m, 2H).

[0512] Examples 32: 2-((2R,4r,6S)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0513]

[0514] 2-((2R,4r,6S)-4-(3-((1r,4R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . 피리딘(2 mL) 중 2-((2R,4r,6S)-4-(3-(( TransEDCI (0.086 g, 0.480 mmol) was added to a solution of )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.150 g, 0.240 mmol) and 3-((3-aminophenyl)amino)piperidin-2,6-dione (0.079 g, 0.360 mmol), and the reaction solution was stirred at 50°C. After 12 hours, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The generated crude material was purified by standard methods and as a gray solid 2-((2R,4r,6S)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.068 g, 0.080 mmol, 33.4% yield) was obtained. MS (ESI) m / z 824.4 [M+1] + ; 1H NMR (400 MHz, 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 = 8.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 1.6, 8.4 Hz, 1H), 7.05 (q, J = 8.0 Hz, 1H), 6.94 (br d, J = 6.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 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 = 6.0 Hz, 2H), 1.29 (m, 2H), 1.21 (br d, J = 6.4 Hz, 6H), 1.14 - 0.97 (m, 2H).

[0515] Examples 33: 2-((2R,4r,6S)-4-(3-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0516]

[0517] 2-((2R,4r,6S)-4-(3-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride . DMF(1 mL) 중 5-(3-(( TransN-ethyl-N-isopropylpropane-2-amine (0.14 mL, 0.800 mmol) and sodium iodide (0.024 g, 0.160 mmol) were added to a solution of )-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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), 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 layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods and found to be a gray solid, 2-((2R,4r,6S)-4-(3-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.059 g, 0.070 mmol, 44% yield) was obtained. MS (ESI) m / z 825.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.54 - 10.38 (m, 1H), 9.15 (m, 2H), 8.74 (d, J = 1.6 Hz, 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 = 6.4 Hz, 2H), 1.33 - 1.24 (m, 2H), 1.21 (br d, J = 6.4 Hz, 6H), 1.15 - 1.00 (m, 2H).

[0518] Examples 34: 2-((R)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0519]

[0520] 2-((R)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . DMF(1 mL) 중 4-(3-(( TransPotassium iodide (68.16 mg, 0.4100 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.21 mL, 1.23 mmol) were added to a solution of )-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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)piperazine-1-yl)acetamide (0.180 g, 0.410 mmol), and the reaction solution was stirred at 50°C. After 12 hours, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (2 x 30 mL), the combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods and found to be a green solid, 2-((R)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.048 g, 0.054 mmol, 13% yield) was obtained. MS (ESI) m / z 876.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6) δ 10.89 - 10.79 (m, 1H), 9.76 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 7.98 (dd, J = 1.7, 8.2 Hz, 1H), 7.25 - 7.21 (m, 2H), 6.78 (s, 1H), 6.51 (d, J = 8.2 Hz, 1H), 4.40 (ddd, J = 4.7, 7.6, 12.3 Hz, 1H), 3.91 - 3.79 (m, 1H), 3.71 - 3.58 (m, 2H), 3.55 (t, J = 5.7 Hz, 2H), 3.41 (d, J = 16.6 Hz, 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).

[0521] Examples 35: 2-((2R,4r,6S)-4-(2-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0522]

[0523] 2-((2R,4r,6S)-4-(2-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride . DMF(2 mL) 중 5-(3-(( TransN-ethyl-N-isopropylpropane-2-amine (0.19 mL, 1.090 mmol) and sodium iodide (0.033 g, 0.220 mmol) were added to a solution of )-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.120 g, 0.220 mmol) and 2-chloro-N-(3-((2,6-dioxopipeperidin-3-yl)amino)phenyl)acetamide (0.129 g, 0.440 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 layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods and found to be a yellow solid, 2-((2R,4r,6S)-4-(2-(( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (0.086 g, 0.104 mmol, 47% yield) was obtained. MS (ESI) m / z 811.3 [M+1] + ; 1H NMR (400 MHz, 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 = 2.0 Hz, 1H), 7.10 - 7.01 (m, 1H), 6.98 (br d, J = 10.4 Hz, 1H), 6.86 (d, J = 8.0 Hz, 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 = 12.0 Hz, 2H), 1.76 - 1.62 (m, 3H), 1.56 (s, 6H), 1.47 - 1.27 (m, 7H), 1.22 (d, J = 6.4 Hz, 3H), 1.17 - 1.01 (m, 2H).

[0524] Examples 36: 2-((2R,4r,6S)-4-(2-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0525]

[0526] 2-((2R,4r,6S)-4-(2-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . 피리딘(2 mL) 중 2-((2R,4r,6S)-4-(2-(( TransEDCI (0.070 g, 0.390 mmol) was added to a solution of )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.120 g, 0.200 mmol) and 3-((3-aminophenyl)amino)piperidin-2,6-dione (0.065 g, 0.300 mmol), and the reaction solution was stirred at 50°C. After 12 hours, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The generated crude material was purified by standard methods and found to be a yellow solid, 2-((2R,4r,6S)-4-(2-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.071 g, 0.087 mmol, 44% yield) was obtained. MS (ESI) m / z 810.3 [M+1] + ; 1H NMR (400 MHz, 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 = 8.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 1.6, 8.4 Hz, 1H), 7.11 - 7.01 (m, 1H), 6.98 (br d, J = 10.0 Hz, 1H), 6.86 (d, J = 7.6 Hz, 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 = 12.4 Hz, 2H), 1.76 - 1.62 (m, 3H), 1.55 (s, 6H), 1.47 - 1.28 (m, 7H), 1.22 (d, J = 6.4 Hz, 3H), 1.16 - 0.99 (m, 2H).

[0527] Examples 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-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetamide

[0528]

[0529] 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-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetamide Hydrochloride . 2 2-((2R,6S)-4-(3-(( TransMeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethaneumin hexafluorophosphate (92.34 mg, 0.3300 mmol) were added to a flask containing )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid (100 mg, 0.1600 mmol), and 3-((3-amino-5-chlorophenyl)amino)piperidin-2,6-dione hydrochloride (52.52 mg, 0.1800 mmol). The reaction mixture was stirred at 25°C for 30 minutes. The reaction product was diluted with DMSO (1.0 mL) and purified by standard methods to obtain 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-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetamide hydrochloride (76.9 mg, 0.0858 mmol, 52% yield) was obtained. MS (ESI) m / z 844.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.34 (d, J = 8.31 Hz, 1H), 8.19 (d, J = 1.59 Hz, 1H), 7.97 (dd, J = 1.65, 8.25 Hz, 1H), 6.96 (s, 1H), 6.90 (br s, 1H), 6.49 (s, 1H), 4.34 (br dd, J= 4.89, 11.62 Hz, 5H), 3.74-3.92 (m, 3H), 3.52-3.65 (m, 2H), 2.90-3.11 (m, 4H), 2.68-2.83 (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 = 9.29 Hz, 4H), 1.49-1.61 (m, 6H), 1.16-1.33 (m, 9H), 1.01-1.15 (m, 2H).

[0530] Examples 38: 2-((2R,6S)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide

[0531]

[0532] 2-((2R,6S)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide . 2 2-((2R,6S)-4-(3-(( Trans MeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethaneumin hexafluorophosphate (92.34 mg, 0.3300 mmol) were added to a flask containing )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid (100 mg, 0.1600 mmol), and 3-((3-amino-5-fluorophenyl)amino)piperidin-2,6-dione (42.9 mg, 0.1800 mmol). The reaction mixture was stirred at 25°C for 30 minutes. The reaction product was diluted with DMSO (1.0 mL) and purified by standard methods to a yellowish-white solid, 2-((2R,6S)-4-(3-(( Trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)-5-fluorophenyl)acetamide hydrochloride (70.4 mg, 0.08 mmol, 49% yield) was obtained. MS (ESI) m / z 827.4 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.34 (d, J = 8.19 Hz, 1H), 8.19 (d, J = 1.59 Hz, 1H), 7.97 (dd, J = 1.59, 8.19 Hz, 1H), 6.67-6.81 (m, 2H), 6.27 (br d, J = 11.98 Hz, 1H), 4.31 (br dd, J = 4.89, 11.62 Hz, 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).

[0533] Examples 39: 2-((2R,6S)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(5-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)acetamide

[0534]

[0535] 2-((2R,6S)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(5-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)acetamide Hydrochloride . 2 2-((2R,6S)-4-(3-(( TransMeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethaneumin hexafluorophosphate (92.34 mg, 0.3300 mmol) were added to a flask containing )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)acetic acid (100 mg, 0.1600 mmol), and 3-((3-amino-4-fluorophenyl)amino)piperidin-2,6-dione (42.9 mg, 0.1800 mmol). The reaction mixture was stirred at 25°C for 30 minutes. The reaction product was diluted with DMSO (1.0 mL) and purified by standard methods to a yellowish-brown solid, 2-((2R,6S)-4-(3-(( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(5-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride (66 mg, 0.076 mmol, 46% yield) was obtained. MS (ESI) m / z 827.4 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.34 (d, J = 8.19 Hz, 1H), 8.19 (d, J = 1.59 Hz, 1H), 7.97 (dd, J = 1.65, 8.25 Hz, 1H), 7.21 (br d, J = 3.67 Hz, 1H), 7.01 (t, J = 9.78 Hz, 1H), 6.38-6.54 (m, 1H), 4.24 (br dd, J= 4.77, 11.25 Hz, 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 = 11.37 Hz, 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).

[0536] Examples 40: 2-((S)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0537]

[0538] 2-((S)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . 2-((S)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)acetic acid (40 mg, 0.0600 mmol) was mixed with 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-methylmethaneumin hexafluorophosphate (38.01 mg, 0.1400 mmol), MeCN (0.7738 mL), and DMF (0.7738 mL), and the reaction mixture was heated at 25°C The mixture was stirred. After 18 hours, the reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layer was dried with sodium sulfate, concentrated, and the resulting crude material was purified by standard methods to obtain a yellow solid 2-((S)-4-(2-((( Trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (9 mg, 0.01 mmol, 16% yield) was obtained. MS (ESI) m / z 851.3 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz) 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, 1H), 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).

[0539] Examples 41: 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0540]

[0541] 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride . 2-((R)-4-(2-(((( TransHATU (2.920 g, 7.68 mmol) and N-ethyl-N-isopropylpropane-2-amine (4.01 mL, 23.05 mmol) were added to a solution of (S)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-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), 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 layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods and found as a yellow solid, 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (1539.8 mg, 1.78 mmol, 23% yield) was obtained. 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 = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 7.14 - 6.97 (m, 2H), 6.94 - 6.78 (m, 1H), 6.44 (d, J = 8.0 Hz, 1H), 4.42 (s, 1H), 4.35 - 4.21 (m, 1H), 3.89 (s, 3H), 3.71 (d, J = 11.2 Hz, 1H), 3.60 (s, 2H), 3.51 (d, J = 11.2 Hz, 2H), 3.36 (d, J = 10.8 Hz, 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 = 10.0 Hz, 2H), 1.57 (s, 6H), 1.44 - 1.35 (m, 2H).

[0542] Examples 42: 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0543]

[0544] 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride . DMF(50 mL) 중 2-((R)-4-(2-((( TransHATU (2.922 g, 7.680 mmol) and N,N-diisopropylethylamine (4 mL, 23.05 mmol) were added to a solution of (R)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-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), 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 layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods and obtained as a yellowish-white solid 2-((R)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride (4.594 g, 5.376 mmol, 70% yield) was obtained. MS (ESI) m / z 852.1 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (br s, 1H), 10.80 (s, 1H), 9.76 - 9.56 (m, 1H), 9.16 (d, J = 1.6 Hz, 1H), 8.76 (d, J = 1.6 Hz, 1H), 7.04 - 6.94 (m, 2H), 6.80 (br d, J = 8.0 Hz, 1H), 6.40 (br d, J = 8.0 Hz, 1H), 4.41 (br s, 1H), 4.24 (br dd, J = 4.4, 11.2 Hz, 1H), 3.87 (br s, 3H), 3.72 (br d, J = 11.2 Hz, 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 = 10.4 Hz, 3H), 2.88 (br d, J = 11.2 Hz, 2H), 2.79 - 2.68 (m, 1H), 2.64 - 2.54 (m, 1H), 2.08 (br dd, J = 4.0, 8.8 Hz, 3H), 1.96 - 1.85 (m, 1H), 1.72 (br d, J = 10.0 Hz, 2H), 1.57 (s, 6H), 1.42 - 1.31 (m, 2H).

[0545] Examples 43: 2-((2R,4r,6S)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0546]

[0547] 2-((2R,4r,6S)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . 피리딘(2 mL) 중 2-((2R,4r,6S)-4-(2-((( TransEDCI (0.098 g, 0.510 mmol) was added to a solution of )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.080 g, 0.130 mmol) and 3-((3-aminophenyl)amino)piperidin-2,6-dione (0.042 g, 0.190 mmol), and the reaction solution was stirred at 60°C. After 12 hours, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (20 mL), dried with anhydrous sodium sulfate, and concentrated. The generated crude material was purified by standard methods and found as a green solid 2-((2R,4r,6S)-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.048 g, 0.0555 mmol, 43% yield) was obtained. MS (ESI) m / z 826.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.48 - 9.39 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.2 Hz, 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= 8.0 Hz, 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 = 11.2 Hz, 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 = 6.2 Hz, 6H).

[0548] Examples 44: 2-(4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0549]

[0550] tert-butyl 4-(2-((( Trans )-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. In 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) ( Trans4-(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) were added. The reaction mixture was heated at 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 layer was washed with brine, dried with sodium sulfate, and filtered. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain a pale yellow solid. The solid was absorbed into ethyl acetate and purified over 2000 mL using a silica gel column containing 0 to 75% ethyl acetate in hexane. Fractions containing the desired product are combined, and volatile organic compounds are removed under reduced pressure to obtain tert-butyl 4-(2-((( Trans )-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.79 g, 3.30 mmol, 63% yield) was obtained. MS (ESI) m / z 543.2 [M+1] + .

[0551] tert-butyl 4-(2-((( Trans )-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. tert-butyl 4-(2-((( in methanol (50 ml) TransPalladium carbon (500 mg, 4.70 mmol) was added to a solution of )-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (2.65 g, 4.88 mmol). The air in the flask was scavenged and replaced with hydrogen (3x, 15 psi, balloon). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction product was filtered through Celite. The filter cake was washed with additional methanol. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain tert-butyl 4-(2-((( Trans )-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol, 97% yield) was obtained. MS (ESI) m / z 363.2 [M+1] + .

[0552] tert-butyl 3,3-difluoro-4-(2-((( Trans )-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate . In acetonitrile (20 ml), tert-butyl 4-(2-((( Trans 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) were added to a solution of )-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 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 two more times with ethyl acetate. The combined organic layer was washed with brine, dried with sodium sulfate, and filtered. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain tert-butyl 3,3-difluoro-4-(2-((( Trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (2.20 g, 4.76 mmol) was obtained and passed to the next step without further purification. MS (ESI) m / z 463.2 [M+1] + .

[0553] tert-butyl-4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate . In ethyl acetate (7 mL), tert-butyl 3,3-difluoro-4-(2-((( Trans 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.360 g, 1.578 mmol) and diisopropylethylamine (0.827 mL, 4.73 mmol) were added to a solution of )-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (0.730 g, 1.578 mmol). The reaction vial was sealed and stirred at 90°C for 18 hours. The reaction mixture was divided between water and ethyl acetate. 5 mL of saline solution was added to reduce emulsification. The organic layer was removed, and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layer was washed with saline solution, dried with sodium sulfate, and filtered. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain a dark orange foamy semi-solid. The solid was absorbed in ethyl acetate and purified over 1000 mL of 0 to 100% ethyl acetate in hexane on a silica gel column. Fractions containing the desired product were combined, and volatile organic compounds were removed under reduced pressure to obtain tert-butyl 4-(2-((( Trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (396 mg, 0.601 mmol, 38% yield) was obtained. MS (ESI) m / z 559.2 [M-99] + .

[0554] 4-(3-(( Trans )-4-(2-(3,3-difluoropiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile Hydrochloride . 4-(3-(( in 1,4-dioxane (3.0 ml) Trans HCl (2.0 ml, 8.00 mmol) (4.0 M in dioxane) was added to a solution of )-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile, HCl (395 mg, 0.664 mmol, 110% yield). The reaction mixture was stirred at ambient temperature for 90 minutes. Volatile organic matter was removed under reduced pressure to form an orange foamy semi-solid, 4-(3-(( Trans )-4-(2-(3,3-difluoropiperidine-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (395 mg, 0.664 mmol) was obtained and transferred to the next step without further purification. MS (ESI) m / z 559.2 [M+1] + .

[0555] 2-(4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . 4-(3-(( in N,N-dimethylformamide (2 mL, 0.09 M) TransDiisopropylethylamine (0.094 mL, 0.537 mmol) and sodium iodide (0.027 g, 0.180 mmol, 1 eq) were added to a solution of )-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thiooxomidazolidin-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). 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 layer was washed with brine (30 mL), dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to obtain 2-(4-(2-((( Trans )-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (55 mg, 0.066 mmol, 37% yield) was obtained. MS (ESI) m / z 818.2 [M+1] + ; 1H NMR (DMSO-d6, 400 MHz) 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).

[0556] Examples 45: 2-((2R,4r,6S)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide

[0557]

[0558] 2-((2R,4r,6S)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide . 피리딘(2 mL) 중 2-((2 R ,4 r ,6 S )-4-(2-((( Trans3-((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) were added to a mixture of )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-yl)acetic acid (0.100 g, 0.160 mmol), and the reaction solution was heated to 50°C. After 8 hours, the reaction solution was diluted with water (80 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods and found to be a yellow solid, 2-((2R,4r,6S)-4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide (0.070 g, 0.083 mmol, 52% yield) was obtained. MS (ESI) m / z 827.6 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.41 (s, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.89 (d, J = 8.0 Hz, 1H), 4.32 - 4.26 (m, 1H), 3.84 (d, J= 8.0 Hz, 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 = 12.0 Hz, 2H), 1.14 (q, J = 11.2 Hz, 2H), 1.05 (d, J = 6.4 Hz, 6H).

[0559] Examples 46: 2-(4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride

[0560]

[0561] tert-butyl 4-(2-((( Trans )-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate.(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) were added 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). The reaction mixture was heated to 30°C for 24 hours. The reaction mixture was divided between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layer was washed with brine, dried with sodium sulfate, and filtered. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain a pale yellow solid. The solid was absorbed in ethyl acetate and purified over 2000 mL on a silica gel column using 0 to 75% ethyl acetate in hexane. The fractions containing the desired product were combined, and volatile organic compounds were removed under reduced pressure to obtain tert-butyl 4-(2-((( Trans )-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.79 g, 3.30 mmol, 63% yield) was obtained. MS (ESI) m / z 543.2 [M+1] + .

[0562] tert-butyl 4-(2-((( Trans )-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. tert-butyl 4-(2-((( in methanol (50 ml) TransPalladium carbon (500 mg, 4.70 mmol) was added to a solution of )-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (2.65 g, 4.88 mmol). The air in the flask was scavenged and replaced with hydrogen (3x, 15 psi, balloon). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction product was filtered through Celite. The filter cake was washed with additional methanol. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain tert-butyl 4-(2-((( Trans )-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol, 97% yield) was obtained. MS (ESI) m / z 363.2 [M+1] + .

[0563] tert-butyl 3,3-difluoro-4-(2-((( Trans )-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate . In acetonitrile (20 ml), tert-butyl 4-(2-((( Trans 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) were added to a solution of )-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 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 two more times with ethyl acetate. The combined organic layer was washed with brine, dried with sodium sulfate, and filtered. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain tert-butyl 3,3-difluoro-4-(2-((( Trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (2.20 g, 4.76 mmol) was obtained and passed to the next step without further purification. MS (ESI) m / z 463.2 [M+1] + .

[0564] tert-butyl 4-(2-((( Trans )-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate . In ethyl acetate (14 mL), tert-butyl 3,3-difluoro-4-(2-((( Trans 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (0.728 g, 3.18 mmol) and diisopropylethylamine (1.665 mL, 9.53 mmol) were added to a solution of )-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (1.47 g, 3.18 mmol). The reaction vial was sealed and stirred at 90°C for 18 hours. The reaction mixture was divided between water and ethyl acetate. Several mL of saline solution was added to reduce emulsification. The organic layer was removed, and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layer was washed with saline solution, dried with sodium sulfate, and filtered. The filtrate was taken, and volatile organic compounds were removed under reduced pressure to obtain a dark orange foamy semi-solid. The solid was absorbed in ethyl acetate and purified over 1800 mL of hexane using 0 to 100% ethyl acetate on a silica gel column. Fractions containing the desired product were combined, and volatile organic compounds were removed under reduced pressure to obtain a bright orange foamy semi-solid, tert-butyl 4-(2-((( Trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.10 g, 1.667 mmol, 52% yield) was obtained. MS (ESI) m / z 560.2 [M-99] + .

[0565] 5-(3-(( Trans )-4-(2-(3,3-difluoropiperidine-4-yl)ethoxy)cycl...

Claims

Claim 1 Compound selected from the following: 2-(((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide, 2-((2S,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazole pyridin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide Hydrochloride, 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride, 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide Hydrochloride, 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride, and 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide., Claim 2 In claim 1, a compound that is 2-(((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. Claim 3 In claim 1, a compound that is 2-((2S,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. Claim 4 The compound of claim 1, which is 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride. Claim 5 The compound of claim 1, which is 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. Claim 6 The compound of claim 1, which is 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide hydrochloride. Claim 7 The compound of claim 1, which is 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. Claim 8 In claim 1, a compound that is 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. Claim 9 A pharmaceutical composition for use in a method for treating an androgen receptor-mediated disease, comprising an effective amount of a compound of any one of claims 1 to 8 and a pharmaceutically acceptable carrier, excipient, or vehicle, wherein the androgen-mediated disease is prostate cancer. Claim 10 A pharmaceutical composition according to claim 9, wherein the prostate cancer is castration-resistant prostate cancer (CRPC). Claim 11 Compound selected from the following or pharmaceutically acceptable salt thereof: 2-(((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide ;2-((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide; and 2-(((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. Claim 12 Compound selected from the following: 2-(((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamino D;2-((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide; and 2-(((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. Claim 13 In paragraph 12, a compound that is 2-((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((S)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. Claim 14 In paragraph 12, a compound that is 2-(((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-(((R)-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. Claim 15 In paragraph 12, a compound that is 2-((2R,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thiooxomidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazine-1-yl)-N-(3-((-2,6-dioxopiperidine-3-yl)amino)phenyl)acetamide. Claim 16 A pharmaceutical composition for use in a method for treating an androgen receptor-mediated disease, comprising an effective amount of a compound of any one of claims 11 to 15 and a pharmaceutically acceptable carrier, excipient, or vehicle, wherein the androgen-mediated disease is prostate cancer. Claim 17 A pharmaceutical composition according to claim 16, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

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